Fused 1,5-Naphthyridines: Synthetic Tools and Applications

Heterocyclic nitrogen compounds, including fused 1,5-naphthyridines, have versatile applications in the fields of synthetic organic chemistry and play an important role in the field of medicinal chemistry, as many of them have a wide range of biological activities. In this review, a wide range of synthetic protocols for the construction of this scaffold are presented. For example, Friedländer, Skraup, Semmlere-Wolff, and hetero-Diels-Alder, among others, are well known classical synthetic protocols used for the construction of the main 1,5-naphthyridine scaffold. These syntheses are classified according to the nature of the cycle fused to the 1,5-naphthyridine ring: carbocycles, nitrogen heterocycles, oxygen heterocycles, and sulphur heterocycles. In addition, taking into account the aforementioned versatility of these heterocycles, their reactivity is presented as well as their use as a ligand for metal complexes formation. Finally, those fused 1,5-naphthyridines that present biological activity and optical applications, among others, are indicated.


Introduction
Several reviews have appeared in the area of naphthyridines [1][2][3][4] including some references to fused 1,5-naphthyridines. Among them, in 2005, Ivanov et al. [5] published a generic review on benzo[b]naphthyridines. However, there are no previous reviews that specifically address the chemistry and application of fused 1,5-naphthyridines. For these reasons, to avoid overlapping with previous contributions, our wish in this review is coverage since 2003.
Heterocyclic compounds, such as fused 1,5-naphthyridines, are significantly important in the field of medicinal chemistry, because many of them present a wide variety of biological activities. For example, it was reported that pyronaridine I (Figure 1) has a high activity against Plasmodium falciparum and Plasmodium vivax [6,7]. Benzo [b][1,5]naphthyridine II (Figure 1) presented noticeable cytotoxicity against human HL-60 and HeLa cells grown in culture and topoisomerase II inhibition [8]. Moreover, through chemotherapy of solid-tumor-bearing mice, this compound II resulted as potent as amsacrine (m-AMSA) but less toxic towards the host. In 1994, Sliwa et al. showed that benzo[b]1,5-naphthyridine III (Figure 1) presented higher activity against Gram-positive than Gram-negative strains [9]. Years later, 5H-benzo[c][1,5]naphthyridin-6-ones IV (Figure 1) showed poly ADP ribose polymerase (PARP)-1 inhibition and protective effects in rat models of stroke and heart ischemia [10].

Synthesis of 1,5-Naphthyridines Fused with Carbocycles
In this section, general methods of synthesis for 1,5-naphthyridines fused with benzene, naphthalene, and indene rings ( Figure 2) are analyzed.  Regarding the organization of this review, first of all, the synthesis of 1,5-naphthyridines fused with carbocycles will be addressed, followed by the synthesis of 1,5-naphthyridines fused with nitrogen heterocycles, fused with oxygen heterocycles, and fused with thieno heterocycles. Afterwards, the reactivity of fused 1,5-naphthyridines is classified by N-alkylation, electrophilic substitution reactions (S E Ar), nucleophilic substitution reactions (S N Ar), oxidations, reductions, side chain modifications, and metal complex formation. Finally, some properties and applications of these heterocycles studied during this period are reviewed.
Molecules 2020, 25, x FOR PEER REVIEW 2 of 54 ribose polymerase (PARP)-1 inhibition and protective effects in rat models of stroke and heart ischemia [10].
Regarding the organization of this review, first of all, the synthesis of 1,5-naphthyridines fused with carbocycles will be addressed, followed by the synthesis of 1,5-naphthyridines fused with nitrogen heterocycles, fused with oxygen heterocycles, and fused with thieno heterocycles. Afterwards, the reactivity of fused 1,5-naphthyridines is classified by N-alkylation, electrophilic substitution reactions (SEAr), nucleophilic substitution reactions (SNAr), oxidations, reductions, side chain modifications, and metal complex formation. Finally, some properties and applications of these heterocycles studied during this period are reviewed.
The process has been applied to the industrial preparation of pyronaridine tetraphosphate 21 (Scheme 6), a well-known antimalarial drug, by introducing several modifications [17]. The cyclization of compound 19 to derivative 20 is the most important stage in the synthesis of pyronaridine tetraphosphate 21. However, purification of compound 20 was difficult because of its poor solubility in common solvents. In order to reduce undesired impurities produced during reaction, ethylene dichloride (EDC) was used as solvent and short reaction times were applied to the process (Scheme 6, route b). Following this improved manufacturing process, 9-chloroacridine 20 was synthesized in a high purity, increased yield and lower production cost.
The process has been applied to the industrial preparation of pyronaridine tetraphosphate 21 (Scheme 6), a well-known antimalarial drug, by introducing several modifications [17]. The cyclization of compound 19 to derivative 20 is the most important stage in the synthesis of pyronaridine tetraphosphate 21. However, purification of compound 20 was difficult because of its poor solubility in common solvents. In order to reduce undesired impurities produced during reaction, ethylene dichloride (EDC) was used as solvent and short reaction times were applied to the process (Scheme 6, route b). Following this improved manufacturing process, 9-chloroacridine 20 was synthesized in a high purity, increased yield and lower production cost.
Synthetic routes based on Skraup synthesis are also convenient approaches to obtain benzo[c][1,5]naphthyridines. A modified Skraup method, namely, Michael addition of 4aminoisoquinoline 23 (Scheme 7) with methyl vinyl ketone 22 in the presence of As2O5 and concentrated sulfuric acid, was used to prepare 4-methylbenzo[c][1,5]naphthyridine 24 [4]. On the other hand, the treatment of oximes 25a-c with acid (Scheme 8), allows the formation of 3,4-dihydrobenzo[c] [1,5]naphthyridin-2(1H)-ones 27a-c [18]. The formation of derivatives 27a-c takes place through a Semmlere-Wolff transposition (Scheme 8) with good yields. It is important to note that the mechanism leading to derivatives 27a-c involves the formation of a stabilized Nacyliminium salt 26 followed by the opening of the lactam ring. The process has been applied to the industrial preparation of pyronaridine tetraphosphate 21 (Scheme 6), a well-known antimalarial drug, by introducing several modifications [17]. The cyclization of compound 19 to derivative 20 is the most important stage in the synthesis of pyronaridine tetraphosphate 21. However, purification of compound 20 was difficult because of its poor solubility in common solvents. In order to reduce undesired impurities produced during reaction, ethylene dichloride (EDC) was used as solvent and short reaction times were applied to the process (Scheme 6, route b). Following this improved manufacturing process, 9-chloroacridine 20 was synthesized in a high purity, increased yield and lower production cost.
Synthetic routes based on Skraup synthesis are also convenient approaches to obtain benzo[c][1,5]naphthyridines. A modified Skraup method, namely, Michael addition of 4aminoisoquinoline 23 (Scheme 7) with methyl vinyl ketone 22 in the presence of As2O5 and concentrated sulfuric acid, was used to prepare 4-methylbenzo[c][1,5]naphthyridine 24 [4]. On the other hand, the treatment of oximes 25a-c with acid (Scheme 8), allows the formation of 3,4-dihydrobenzo[c][1,5]naphthyridin-2(1H)-ones 27a-c [18]. The formation of derivatives 27a-c takes place through a Semmlere-Wolff transposition (Scheme 8) with good yields. It is important to note that the mechanism leading to derivatives 27a-c involves the formation of a stabilized Nacyliminium salt 26 followed by the opening of the lactam ring. On the other hand, the treatment of oximes 25a-c with acid (Scheme 8), allows the formation of 3,4-dihydrobenzo[c][1,5]naphthyridin-2(1H)-ones 27a-c [18]. The formation of derivatives 27a-c takes place through a Semmlere-Wolff transposition (Scheme 8) with good yields. It is important to note that the mechanism leading to derivatives 27a-c involves the formation of a stabilized N-acyliminium salt 26 followed by the opening of the lactam ring.
The preparation of benzo[c] [1,5]naphthyridines can be also performed by [4+2] cycloaddition reaction. Thus, the microwave-mediated intramolecular Diels-Alder (DA) reaction [19] of o-furyl(allylamino)pyridines 28a-c, in the presence of a catalytic amount of acid, gave 5,6-dihydrobenzo[c] [1,5]naphthyridines 30a-c (Scheme 9, method A). The initially formed DA-adduct 29 spontaneously underwent ring opening and subsequent aromatization to afford the 5,6-dihydrobenzo[c] [1,5]naphthyridines 30a-c. Electron-withdrawing substituents, especially R 1 = Cl, seem to stabilize the 5,6-dihydrobenzo[c][1,5]naphthyridines 30. Some of these dihydro compounds 30 were oxidized, with high yields, to the aromatic compounds 31 during workup and purification. When the reaction mixture was bubbled through air in the presence of UV light (Scheme 9, method B) or stirred with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ, 1.2 equivalent) at room temperature (Scheme 9, method C) aromatic benzo[c] [1,5]naphthyridine compounds 31a-c were obtained. The preparation of benzo[c] [1,5]naphthyridines can be also performed by [4+2] cycloaddition reaction. Thus, the microwave-mediated intramolecular Diels-Alder (DA) reaction [19] of ofuryl(allylamino)pyridines 28a-c, in the presence of a catalytic amount of acid, gave 5,6dihydrobenzo[c][1,5]naphthyridines 30a-c (Scheme 9, method A). The initially formed DA-adduct 29 spontaneously underwent ring opening and subsequent aromatization to afford the 5,6dihydrobenzo[c][1,5]naphthyridines 30a-c. Electron-withdrawing substituents, especially R 1 = Cl, seem to stabilize the 5,6-dihydrobenzo[c][1,5]naphthyridines 30. Some of these dihydro compounds 30 were oxidized, with high yields, to the aromatic compounds 31 during workup and purification. When the reaction mixture was bubbled through air in the presence of UV light (Scheme 9, method B) or stirred with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ, 1.2 equivalent) at room temperature (Scheme 9, method C) aromatic benzo[c] [1,5]naphthyridine compounds 31a-c were obtained.  The preparation of benzo[c] [1,5]naphthyridines can be also performed by [4+2] cycloaddition reaction. Thus, the microwave-mediated intramolecular Diels-Alder (DA) reaction [19] of ofuryl(allylamino)pyridines 28a-c, in the presence of a catalytic amount of acid, gave 5,6dihydrobenzo[c] [1,5]naphthyridines 30a-c (Scheme 9, method A). The initially formed DA-adduct 29 spontaneously underwent ring opening and subsequent aromatization to afford the 5,6dihydrobenzo[c] [1,5]naphthyridines 30a-c. Electron-withdrawing substituents, especially R 1 = Cl, seem to stabilize the 5,6-dihydrobenzo[c][1,5]naphthyridines 30. Some of these dihydro compounds 30 were oxidized, with high yields, to the aromatic compounds 31 during workup and purification. When the reaction mixture was bubbled through air in the presence of UV light (Scheme 9, method B) or stirred with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ, 1.2 equivalent) at room temperature (Scheme 9, method C) aromatic benzo[c] [1,5]naphthyridine compounds 31a-c were obtained.  Through metabolomics, several benzo[c] [1,5]naphthyridine alkaloids, known as fumisoquins, have been prepared. For this purpose, groups of microbial biosynthetic gene clusters (BGC) in the human pathogen Aspergillus fumigatus called fsq have been used [20]. The authors demonstrated that fsqF, which lacks a canonical condensation domain, is necessary for the formation of carbon-carbon bonds between the amino acids l-serine and l-tyrosine in the fumisoquin biosynthetic pathway. The fsqD appears to activate tyrosine for subsequent condensation with serine-derived dehydroalanine (Scheme 10), which is the first example of a new strategy for the formation of carbon-carbon bonds in fungi. Optimization of the extraction conditions and reverse phase fractionation followed by Molecules 2020, 25, 3508 7 of 54 two-dimensional NMR spectroscopy and HRMS analysis allowed the identification of fumisoquin C (Scheme 10) as the deep purple metabolite. While standing or during chromatography, fumisoquin C decomposes into 32 and 33 (Scheme 10) which are more stable and were isolated. human pathogen Aspergillus fumigatus called fsq have been used [20]. The authors demonstrated that fsqF, which lacks a canonical condensation domain, is necessary for the formation of carbon-carbon bonds between the amino acids L-serine and L-tyrosine in the fumisoquin biosynthetic pathway. The fsqD appears to activate tyrosine for subsequent condensation with serine-derived dehydroalanine (Scheme 10), which is the first example of a new strategy for the formation of carbon-carbon bonds in fungi. Optimization of the extraction conditions and reverse phase fractionation followed by twodimensional NMR spectroscopy and HRMS analysis allowed the identification of fumisoquin C (Scheme 10) as the deep purple metabolite. While standing or during chromatography, fumisoquin C decomposes into 32 and 33 (Scheme 10) which are more stable and were isolated.

Scheme 10. Microbial biosynthesis of benzo[c][1,5]naphthyridine alkaloids.
A visible-light-catalyzed synthesis of 5-phenyldibenzo[b,h][1,5]naphthyridine 36 from 3isocyano-2-phenylquinoline 34 and bromobenzene 35 at room temperature has been discovered [21]. This metal-free cross-coupling reaction offers rapid and sustainable access to a series of structurally complex dibenzo[b,h][1,5]naphthyridines 36 (Scheme 11). The usage of inexpensive Rhodamine 6G (Rh-6G) as the catalyst with easy operation makes this protocol very practical. A plausible mechanism was proposed through a radical anion [Rh-6G•-] formed by the use of the visible-light irradiation, that triggers a single electron transfer to bromobenzene producing the transient [Ph-Br•-] radical anion and regenerating Rh-6G completing the catalytic cycle. A novel procedure for hydride-induced anionic cyclization has been developed. It includes the reduction of a biaryl bromonitrile 37 with a nucleophilic aromatic substitution (SNAr). Dibenzo [b,h][1,5]naphthyridine 38a and benzo [b]naphtho [2,3-h][1,5]naphthyridine 38b were so obtained in moderate-to-good yield with good substrate tolerance (Scheme 12). In addition, the analogue of trisphaeridine 38c could be also obtained in moderate yield [22]. This method involves a concise transition-metal-free process, and it was applied to synthesize natural alkaloids. A tentative A visible-light-catalyzed synthesis of 5-phenyldibenzo[b,h][1,5]naphthyridine 36 from 3-isocyano-2-phenylquinoline 34 and bromobenzene 35 at room temperature has been discovered [21]. This metal-free cross-coupling reaction offers rapid and sustainable access to a series of structurally complex dibenzo[b,h][1,5]naphthyridines 36 (Scheme 11). The usage of inexpensive Rhodamine 6G (Rh-6G) as the catalyst with easy operation makes this protocol very practical. A plausible mechanism was proposed through a radical anion [Rh-6G•-] formed by the use of the visible-light irradiation, that triggers a single electron transfer to bromobenzene producing the transient [Ph-Br•-] radical anion and regenerating Rh-6G completing the catalytic cycle.
bonds between the amino acids L-serine and L-tyrosine in the fumisoquin biosynthetic pathway. The fsqD appears to activate tyrosine for subsequent condensation with serine-derived dehydroalanine (Scheme 10), which is the first example of a new strategy for the formation of carbon-carbon bonds in fungi. Optimization of the extraction conditions and reverse phase fractionation followed by twodimensional NMR spectroscopy and HRMS analysis allowed the identification of fumisoquin C (Scheme 10) as the deep purple metabolite. While standing or during chromatography, fumisoquin C decomposes into 32 and 33 (Scheme 10) which are more stable and were isolated.  5]naphthyridine 38b were so obtained in moderate-to-good yield with good substrate tolerance (Scheme 12). In addition, the analogue of trisphaeridine 38c could be also obtained in moderate yield [22]. This method involves a concise transition-metal-free process, and it was applied to synthesize natural alkaloids. A tentative  5]naphthyridine 38b were so obtained in moderate-to-good yield with good substrate tolerance (Scheme 12). In addition, the analogue of trisphaeridine 38c could be also obtained in moderate yield [22]. This method involves a concise transition-metal-free process, and it was applied to synthesize natural alkaloids. A tentative reaction pathway can be proposed as below (Scheme 12). The reaction is likely to be initiated by the chelating of compound 37 to lithium (complex A). Subsequent addition of hydride to nitrile provides the iminyl lithium complex (complex B). A subsequent nucleophilic aromatic substitution then takes place to generate the anionic intermediate C. Elimination of halide affords desired products 38 and precipitate LiBr. reaction pathway can be proposed as below (Scheme 12). The reaction is likely to be initiated by the chelating of compound 37 to lithium (complex A). Subsequent addition of hydride to nitrile provides the iminyl lithium complex (complex B). A subsequent nucleophilic aromatic substitution then takes place to generate the anionic intermediate C.  [4,5]. This reaction was carried out with glycerol 40 in the presence of an oxidant (nitrobenzenesulfonic acid) formed in situ upon the reaction of nitrobenzene with oleum.  [23]. Transformation of the nitro group to iodo followed by oxidation and cyclization results in an iodonium salt 43 (Scheme 14). Using the successful protocol for the transformation of annulated iodolium salts to pyrroles, Buchwald-Hartwig (Palladiumcatalyzed arylamination) with benzylamine (Bn-NH2) was achieved with 43 to give compound 44.  [4,5]. This reaction was carried out with glycerol 40 in the presence of an oxidant (nitrobenzenesulfonic acid) formed in situ upon the reaction of nitrobenzene with oleum. place to generate the anionic intermediate C.  [4,5]. This reaction was carried out with glycerol 40 in the presence of an oxidant (nitrobenzenesulfonic acid) formed in situ upon the reaction of nitrobenzene with oleum.  [23]. Transformation of the nitro group to iodo followed by oxidation and cyclization results in an iodonium salt 43 (Scheme 14). Using the successful protocol for the transformation of annulated iodolium salts to pyrroles, Buchwald-Hartwig (Palladiumcatalyzed arylamination) with benzylamine (Bn-NH2) was achieved with 43 to give compound 44.  [23]. Transformation of the nitro group to iodo followed by oxidation and cyclization results in an iodonium salt 43 (Scheme 14). Using the successful protocol for the transformation of annulated iodolium salts to pyrroles, Buchwald-Hartwig (Palladium-catalyzed arylamination) with benzylamine (Bn-NH 2 ) was achieved with 43 to give compound 44. The unsubstituted 7H-naphtho[1, 8- [24][25][26].
The process consists of a Povarov-type [4+2]-cycloaddition reaction, by both step-by-step and by multicomponent strategies (MCRs). First, the hetero-Diels-Alder reaction between indene 49 (Scheme 15, route a) and N-(3-pyridyl) aldimines 48, prepared in situ by reaction of 3-pyridylamine 46 and aldehydes 47, in the presence of two equivalents of BF3·Et2O in refluxing chloroform were performed. Afterwards, the corresponding tetracyclic endo-1,2,3,4-tetrahydro [1,5]naphthyridines 50 were selectively obtained with good yields (route a, Scheme 15) in a regio-and stereospecific way. Alternatively, three-component synthetic protocol was carried out (Scheme 15, route b) by reacting commercially available 3-pyridylamine 46, aromatic aldehydes 47 and indene 49 in the presence of 2 equivalents of BF3·Et2O in refluxing chloroform to afford also the corresponding endo-1,2,3,4tetrahydronaphthyridines 50 with good yields. The presence of electron-donating groups (OMe and SMe) seems to favor the direct formation of indeno[1,5]naphthyridines 51. Formation of these derivatives could be reasoned by a [4+2]-cycloaddition reaction between aldimines 48 and indene 49 and, subsequent, dehydrogenation of tetrahydroindeno[1,5]naphthyridines 50. The scope of this strategy is very wide, given that compounds 50 and 51 substituted not only with a pyridine group (R = 4 pyr) but also with a wide range of ortho, meta, and para aromatic substrates containing electronreleasing and -withdrawing groups, including fluorine substituents can be prepared. The process consists of a Povarov-type [4+2]-cycloaddition reaction, by both step-by-step and by multicomponent strategies (MCRs). First, the hetero-Diels-Alder reaction between indene 49 (Scheme 15, route a) and N-(3-pyridyl) aldimines 48, prepared in situ by reaction of 3-pyridylamine 46 and aldehydes 47, in the presence of two equivalents of BF 3 ·Et 2 O in refluxing chloroform were performed. Afterwards, the corresponding tetracyclic endo-1,2,3,4-tetrahydro[1,5]naphthyridines 50 were selectively obtained with good yields (route a, Scheme 15) in a regio-and stereospecific way. Alternatively, three-component synthetic protocol was carried out (Scheme 15, route b) by reacting commercially available 3-pyridylamine 46, aromatic aldehydes 47 and indene 49 in the presence of 2 equivalents of BF 3 ·Et 2 O in refluxing chloroform to afford also the corresponding endo-1,2,3,4-tetrahydronaphthyridines 50 with good yields. The presence of electron-donating groups (OMe and SMe) seems to favor the direct formation of indeno[1,5]naphthyridines 51. Formation of these derivatives could be reasoned by a [4+2]-cycloaddition reaction between aldimines 48 and indene 49 and, subsequent, dehydrogenation of tetrahydroindeno[1,5]naphthyridines 50. The scope of this strategy is very wide, given that compounds 50 and 51 substituted not only with a pyridine group (R = 4 pyr) but also with a wide range of ortho, meta, and para aromatic substrates containing electron-releasing and -withdrawing groups, including fluorine substituents can be prepared.  [24][25][26].
The process consists of a Povarov-type [4+2]-cycloaddition reaction, by both step-by-step and by multicomponent strategies (MCRs). First, the hetero-Diels-Alder reaction between indene 49 (Scheme 15, route a) and N-(3-pyridyl) aldimines 48, prepared in situ by reaction of 3-pyridylamine 46 and aldehydes 47, in the presence of two equivalents of BF3·Et2O in refluxing chloroform were performed. Afterwards, the corresponding tetracyclic endo-1,2,3,4-tetrahydro [1,5]naphthyridines 50 were selectively obtained with good yields (route a, Scheme 15) in a regio-and stereospecific way. Alternatively, three-component synthetic protocol was carried out (Scheme 15, route b) by reacting commercially available 3-pyridylamine 46, aromatic aldehydes 47 and indene 49 in the presence of 2 equivalents of BF3·Et2O in refluxing chloroform to afford also the corresponding endo-1,2,3,4tetrahydronaphthyridines 50 with good yields. The presence of electron-donating groups (OMe and SMe) seems to favor the direct formation of indeno[1,5]naphthyridines 51. Formation of these derivatives could be reasoned by a [4+2]-cycloaddition reaction between aldimines 48 and indene 49 and, subsequent, dehydrogenation of tetrahydroindeno[1,5]naphthyridines 50. The scope of this strategy is very wide, given that compounds 50 and 51 substituted not only with a pyridine group (R = 4 pyr) but also with a wide range of ortho, meta, and para aromatic substrates containing electronreleasing and -withdrawing groups, including fluorine substituents can be prepared.

Synthesis of 1,5-Naphthyridines Fused with Nitrogen Heterocycles
Nitrogen atoms are ubiquitous in biologically significant secondary metabolites (alkaloids, cytokinins), in biomacromolecules (proteins, peptides, DNA, RNA) as well as in synthetic organic substances, and often belong to atomic centers of importance for intra-and intermolecular interactions. Therefore, the addition of nitrogen atoms to a structure can contribute to the discovery and development of new therapeutic agents for the treatment of different diseases, which represents one of the most important objectives in medicinal chemistry.
This section, firstly, will analyze the general methods of synthesis of 1,5-naphthyridine fused with five-membered nitrogen heterocycles ( Figure 3).

Synthesis of 1,5-Naphthyridines Fused with Nitrogen Heterocycles
Nitrogen atoms are ubiquitous in biologically significant secondary metabolites (alkaloids, cytokinins), in biomacromolecules (proteins, peptides, DNA, RNA) as well as in synthetic organic substances, and often belong to atomic centers of importance for intra-and intermolecular interactions. Therefore, the addition of nitrogen atoms to a structure can contribute to the discovery and development of new therapeutic agents for the treatment of different diseases, which represents one of the most important objectives in medicinal chemistry.
This section, firstly, will analyze the general methods of synthesis of 1,5-naphthyridine fused with five-membered nitrogen heterocycles ( Figure 3). An efficient enantioselective total synthesis of the potent antibiotic GSK966587 52 (Scheme 16) was accomplished [27]. After the synthesis of the corresponding fused 1,5-naphthyridine and several structural modifications, the desired allylic alcohol 53 was obtained. A Sharpless asymmetric epoxidation of allylic alcohol 53 gives epoxy alcohol 54. When the unpurified epoxy alcohol 54 was treated with concentrated HCl and after aqueous workup, the solution was heated in butyronitrile to 100 °C for 1.5 h, causing cyclization and demethylation in one pot. Cooling to room temperature allowed the crystallization of tricyclic diol 55 from allylic alcohol 53 (Scheme 16). The preparation of the fully elaborated side chain and various final transformations gave GSK966587 as a precipitate directly from the reaction mixture. An efficient enantioselective total synthesis of the potent antibiotic GSK966587 52 (Scheme 16) was accomplished [27]. After the synthesis of the corresponding fused 1,5-naphthyridine and several structural modifications, the desired allylic alcohol 53 was obtained. A Sharpless asymmetric epoxidation of allylic alcohol 53 gives epoxy alcohol 54. When the unpurified epoxy alcohol 54 was treated with concentrated HCl and after aqueous workup, the solution was heated in butyronitrile to 100 • C for 1.5 h, causing cyclization and demethylation in one pot. Cooling to room temperature allowed the crystallization of tricyclic diol 55 from allylic alcohol 53 (Scheme 16). The preparation of the fully elaborated side chain and various final transformations gave GSK966587 as a precipitate directly from the reaction mixture.
Molecules 2020, 25 Two high-yielding and flexible syntheses of canthin-6-ones 77 (R = H, Scheme 20) were developed and optimized [36]. In the first one, through a stepwise approach, the desired 8- Two high-yielding and flexible syntheses of canthin-6-ones 77 (R = H, Scheme 20) were developed and optimized [36]. In the first one, through a stepwise approach, the desired 8-  Two high-yielding and flexible syntheses of canthin-6-ones 77 (R = H, Scheme 20) were developed and optimized [36]. In the first one, through a stepwise approach, the desired 8- The second one was a simple and useful one-pot protocol involving a sequential application of a Pd-catalyzed Suzuki-Miyaura coupling of naphthyridine 78 prepared from 8-bromo-2-Scheme 20. Syntheses of canthin-6-ones through a Suzuki-Miyaura coupling.
The second one was a simple and useful one-pot protocol involving a sequential application of a Pd-catalyzed Suzuki-Miyaura coupling of naphthyridine 78 prepared from 8-bromo-2-methoxynaphthyridine 74 (Scheme 20), followed by a Cu-catalyzed amidation, of general use for synthetic chemists. Using this new one-pot protocol, nine 6H-indolo[3,2,1de][1,5]naphthyridin-6-ones 77 with various substituents in the aromatic ring were quickly obtained in excellent yields (Scheme 20).
When the reaction of compound 84a (R 1 = H, R 2 = CO2Me) with several substituted allyl bromides 87a-d in the presence of Cs2CO3 in dry DMF is performed (Scheme 23) and the acetal group of obtained substituted alkenes (E-isomer exclusively) is deprotected as described earlier, the aldehydes 88a-d were obtained in high yields and good purity. The reaction of aldehydes 88a-d with NH2OH·HCl gave rise to the corresponding oximes which, upon treatment with NaOCl in the presence of Et3N, afforded the substituted isoxazoline derivatives 89a-d, respectively, as a mixture  The synthesis of a library of β-carboline fused systems was carried out via intramolecular 1,3dipolar cycloaddition reactions [38] starting from β-carboline protected aldehydes 84 (Scheme 23). Thus, protected aldehydes 84a-c reacted with allyl bromide in the presence of Cs2CO3 as base in dry DMF, the acetal group was deprotected by heating in the presence of AcOH/water (2:3, v/v) at 120 °C and aldehydes 85a-c were obtained. In the next step, the aldehydes 85a-c reacted with NH2OH·HCl in the presence of NaOAc to furnish the substituted oximes, whose treatment with NaOCl in the presence of Et3N at room temperature for three days resulted in the formation of the desired 9a,10dihydro-9H-indolo[3,2,1-ij]isoxazolo [4,3-c][1,5]naphthyridines 86a-c (Scheme 23).
When the reaction of compound 84a (R 1 = H, R 2 = CO2Me) with several substituted allyl bromides 87a-d in the presence of Cs2CO3 in dry DMF is performed (Scheme 23) and the acetal group of obtained substituted alkenes (E-isomer exclusively) is deprotected as described earlier, the aldehydes 88a-d were obtained in high yields and good purity. The reaction of aldehydes 88a-d with NH2OH·HCl gave rise to the corresponding oximes which, upon treatment with NaOCl in the presence of Et3N, afforded the substituted isoxazoline derivatives 89a-d, respectively, as a mixture The synthesis of a library of β-carboline fused systems was carried out via intramolecular 1,3-dipolar cycloaddition reactions [38] starting from β-carboline protected aldehydes 84 (Scheme 23). Thus, protected aldehydes 84a-c reacted with allyl bromide in the presence of Cs 2 CO 3 as base in dry DMF, the acetal group was deprotected by heating in the presence of AcOH/water (2:3, v/v) at 120 • C and aldehydes 85a-c were obtained. In the next step, the aldehydes 85a-c reacted with NH 2 OH·HCl in the presence of NaOAc to furnish the substituted oximes, whose treatment with NaOCl in the presence of Et 3 N at room temperature for three days resulted in the formation of the desired 9a,10-dihydro-9H-indolo[3,2,1-ij]isoxazolo [4,3-c][1,5]naphthyridines 86a-c (Scheme 23). of diastereomers (Scheme 23). Similarly, the reaction of aldehydes 84a-c with propargyl bromide in dry DMF using Cs2CO3 and the deprotection of the acetal moiety in the presence of AcOH/H2O resulted in the formation of aldehydes 90a-c (Scheme 23). The transformation of 90a-c was achieved by their reaction with NH2OH·HCl and with NaOCl to produce the required isoxazole derivatives 91a-c. Scheme  In order to further diversify the range of the products which could be generated by applying intramolecular 1,3-dipolar cycloaddition reaction, the aldehydes 90a-c were treated with sarcosine in dry toluene under refluxing conditions. This reaction yielded the β-carboline-fused pyrroles 92a-c (Scheme 23).
A series of dihydroindazolo [4,3-bc][1,5]naphthyridines 94 was prepared by condensation of 9chloro-2-methoxy-6-nitro-5,10-dihydrobenzo[b][1,5]naphthyridin-10-one 17 (previously prepared Scheme 5, vide supra) [15]. Thus, condensation of 17 with appropriate (ω-aminoalkyl) hydrazines 93 When the reaction of compound 84a (R 1 = H, R 2 = CO 2 Me) with several substituted allyl bromides 87a-d in the presence of Cs 2 CO 3 in dry DMF is performed (Scheme 23) and the acetal group of obtained substituted alkenes (E-isomer exclusively) is deprotected as described earlier, the aldehydes 88a-d were obtained in high yields and good purity. The reaction of aldehydes 88a-d with NH 2 OH·HCl gave rise to the corresponding oximes which, upon treatment with NaOCl in the presence of Et 3 N, afforded the substituted isoxazoline derivatives 89a-d, respectively, as a mixture of diastereomers (Scheme 23). Similarly, the reaction of aldehydes 84a-c with propargyl bromide in dry DMF using Cs 2 CO 3 and the deprotection of the acetal moiety in the presence of AcOH/H 2 O resulted in the formation of aldehydes 90a-c (Scheme 23). The transformation of 90a-c was achieved by their reaction with NH 2 OH·HCl and with NaOCl to produce the required isoxazole derivatives 91a-c.
In order to further diversify the range of the products which could be generated by applying intramolecular 1,3-dipolar cycloaddition reaction, the aldehydes 90a-c were treated with sarcosine in dry toluene under refluxing conditions. This reaction yielded the β-carboline-fused pyrroles 92a-c (Scheme 23).
Nitration of 96 with AgNO3 and I2, hydrogenation by using Pd/C, NaBH4, and then Pt II -catalyzed intramolecular cyclization with a catalytic amount of PtCl2 and oxidation with PbO2 afforded the 1,5naphthyridine-fused porphyrin dimer 97. In the next step, the dimer 97 was reduced with an excess of NaBH4 to give dimer 98 (Scheme 25). This product is quite electron-rich owing to the presence of a 1,2-diaminoethene bridge and oxidizes back to 97 within several hours in solution under ambient conditions. Furthermore, treatment of 98 with PbO2 cleanly afforded 97. Scheme 25. Synthesis of fused 1,5-naphthyridine porphyrin dimers.
Nitration of 96 with AgNO3 and I2, hydrogenation by using Pd/C, NaBH4, and then Pt II -catalyzed intramolecular cyclization with a catalytic amount of PtCl2 and oxidation with PbO2 afforded the 1,5naphthyridine-fused porphyrin dimer 97. In the next step, the dimer 97 was reduced with an excess of NaBH4 to give dimer 98 (Scheme 25). This product is quite electron-rich owing to the presence of a 1,2-diaminoethene bridge and oxidizes back to 97 within several hours in solution under ambient conditions. Furthermore, treatment of 98 with PbO2 cleanly afforded 97. Scheme 25. Synthesis of fused 1,5-naphthyridine porphyrin dimers.
Pyridine and quinoline ring systems are heterocycles with a wide range of synthetic and medicinal applications [40][41][42][43][44]. For this reason, fused pyrido-and/or quinolino-naphthyridines ( Figure 5) may be considered as very interesting and useful nitrogenated heterocycles. Nitration of 96 with AgNO 3 and I 2 , hydrogenation by using Pd/C, NaBH 4 , and then Pt II -catalyzed intramolecular cyclization with a catalytic amount of PtCl 2 and oxidation with PbO 2 afforded the 1,5-naphthyridine-fused porphyrin dimer 97. In the next step, the dimer 97 was reduced with an excess of NaBH 4 to give dimer 98 (Scheme 25). This product is quite electron-rich owing to the presence of a 1,2-diaminoethene bridge and oxidizes back to 97 within several hours in solution under ambient conditions. Furthermore, treatment of 98 with PbO 2 cleanly afforded 97.

Synthesis of 1,5-Naphthyridines Fused with Oxygen-Containing Heterocycles
The low toxicity of the natural products containing chromene and their broad pharmacological properties are attractive feature for medicinal chemists and a source of inspiration for the design of novel therapeutic agents [47,48]. Therefore, naphthyridines fused with 1,3-oxazines, chromenes or chromenones are very interesting substrates in the search of new drug candidates ( Figure 6).

Synthesis of 1,5-Naphthyridines Fused with Oxygen-Containing Heterocycles
The low toxicity of the natural products containing chromene and their broad pharmacological properties are attractive feature for medicinal chemists and a source of inspiration for the design of novel therapeutic agents [47,48]. Therefore, naphthyridines fused with 1,3-oxazines, chromenes or chromenones are very interesting substrates in the search of new drug candidates ( Figure 6). Molecules 2020, 25, x FOR PEER REVIEW 20 of 54 Metal-and solvent-free reaction of 1,5-naphthyridine 116 with two molecules of phenyltrifluoroacetylacetylene 117 afforded 3,4a-dihydro-[1,3]oxazino[3,2-a][1,5]naphthyridine 118 (Scheme 28). So, when reactants 116 and 117 were allowed to contact at room temperature in the absence of water and solvent, compound 116 appeared to be capable of assembling with two molecules of trifluoroacetylacetylene 117 to form 3,4a-dihydro-[1,3]oxazino[3,2-a][1,5]naphthyridine 118 [49]. The authors propose a mechanism in which the first step is the reversible formation of the intermediate 1,3-dipole A. Subsequent addition of the second molecule of acetylene 117 proceeds selectively to its carbonyl group. Afterwards, the oxygen center of formed anion B attacks position 2 of the naphthyridine ring to cause the product 118 (Scheme 28). The suggested mechanism is in agreement with the experimental results. Indeed, the reversible formation of 1,3-dipole complex A is supported by the fact that at a higher temperature, yields of the target products are not improved.   [49]. The authors propose a mechanism in which the first step is the reversible formation of the intermediate 1,3-dipole A. Subsequent addition of the second molecule of acetylene 117 proceeds selectively to its carbonyl group. Afterwards, the oxygen center of formed anion B attacks position 2 of the naphthyridine ring to cause the product 118 (Scheme 28). The suggested mechanism is in agreement with the experimental results. Indeed, the reversible formation of 1,3-dipole complex A is supported by the fact that at a higher temperature, yields of the target products are not improved.  [49]. The authors propose a mechanism in which the first step is the reversible formation of the intermediate 1,3-dipole A. Subsequent addition of the second molecule of acetylene 117 proceeds selectively to its carbonyl group. Afterwards, the oxygen center of formed anion B attacks position 2 of the naphthyridine ring to cause the product 118 (Scheme 28). The suggested mechanism is in agreement with the experimental results. Indeed, the reversible formation of 1,3-dipole complex A is supported by the fact that at a higher temperature, yields of the target products are not improved. A mild and efficient method for the synthesis of chromenonaphthyridine derivatives via domino reaction of 3-aminopyridine 46 and different O-propargylated salicylaldehydes 123 (Scheme 30) using CuI/InCl3 as an efficient catalyst, refluxed in acetonitrile have been reported [51]. Mild reaction conditions, operational simplicity, good-to-excellent yield, and easy isolation of product is the silent feature of this reaction to afford the corresponding 6H-chromeno [4,3-b][1,5]naphthyridine derivatives 124 in high yields (Scheme 30). Different O-propargylated salicylaldehydes 123, containing electron-withdrawing and electron-donating substituents, exhibited equal activity towards the formation of product in good to excellent yields. Plausible mechanistic rationalization for the formation of chromenonaphthyridine derivatives 124 is depicted in Scheme 30. Initially, imine A is formed which contained the aza-heterodiene moiety. This aza-heterodiene undergoes intramolecular aza Diels-Alder reaction with the propargyl triple bond, which is activated by indium chloride followed by aromatization to give the desired products 124. Scheme  A mild and efficient method for the synthesis of chromenonaphthyridine derivatives via domino reaction of 3-aminopyridine 46 and different O-propargylated salicylaldehydes 123 (Scheme 30) using CuI/InCl 3 as an efficient catalyst, refluxed in acetonitrile have been reported [51]. Mild reaction conditions, operational simplicity, good-to-excellent yield, and easy isolation of product is the silent feature of this reaction to afford the corresponding 6H-chromeno [4,3-b][1,5]naphthyridine derivatives 124 in high yields (Scheme 30). Different O-propargylated salicylaldehydes 123, containing electron-withdrawing and electron-donating substituents, exhibited equal activity towards the formation of product in good to excellent yields. Plausible mechanistic rationalization for the formation of chromenonaphthyridine derivatives 124 is depicted in Scheme 30. Initially, imine A is formed which contained the aza-heterodiene moiety. This aza-heterodiene undergoes intramolecular aza Diels-Alder reaction with the propargyl triple bond, which is activated by indium chloride followed by aromatization to give the desired products 124. A mild and efficient method for the synthesis of chromenonaphthyridine derivatives via domino reaction of 3-aminopyridine 46 and different O-propargylated salicylaldehydes 123 (Scheme 30) using CuI/InCl3 as an efficient catalyst, refluxed in acetonitrile have been reported [51]. Mild reaction conditions, operational simplicity, good-to-excellent yield, and easy isolation of product is the silent feature of this reaction to afford the corresponding 6H-chromeno [4,3-b][1,5]naphthyridine derivatives 124 in high yields (Scheme 30). Different O-propargylated salicylaldehydes 123, containing electron-withdrawing and electron-donating substituents, exhibited equal activity towards the formation of product in good to excellent yields. Plausible mechanistic rationalization for the formation of chromenonaphthyridine derivatives 124 is depicted in Scheme 30. Initially, imine A is formed which contained the aza-heterodiene moiety. This aza-heterodiene undergoes intramolecular aza Diels-Alder reaction with the propargyl triple bond, which is activated by indium chloride followed by aromatization to give the desired products 124. Scheme  Hybrid tetrahydro[1,5]naphthyridine and [1,5]naphthyridine derivatives fused with heterocycles such as chromenes and chromen-2-ones or coumarins were synthesized in good to high general yields [52]. The synthetic route involves an intramolecular [4+2] cycloaddition reaction of functionalized aldimines and aldehydes containing a double or triple carbon-carbon bond in ortho position and allows the selective generation of three stereogenic centers in a short, efficient and reliable synthesis (Scheme 31). Aldimines 128 (X = CH 2 ), prepared in situ by condensation reaction of 3-aminopyridines 125 and previously prepared functionalized aldehydes 126 (X = CH 2 ), cyclized intramolecularly in refluxing chloroform and in the presence of BF 3 ·Et 2 O (Scheme 31) to give 129 by a regio-and stereospecific intramolecular [4+2]-cycloaddition reaction which after prototropic tautomerization afforded compounds 127. When 2-(allyloxy)benzaldehyde 126 (R 2 = R 3 = H) and 6-bromo-3-aminopyridine 125 (R 1 = Br) were used, after formation of the corresponding tetrahydro[1,5]naphthyridine 127, subsequent dehydrogenation under the reaction conditions gave dehydrogenated derivative 130 (Scheme 31). In order to increase the molecular diversity, the methodology was extended to the preparation of angularly fused tetracyclic derivatives 132 (X = CO), in which the chromene scaffold was substituted by a coumarin (chromen-2-one). As before, functionalized aldehydes 131 (Scheme 31, X = CO) were condensed with 3-aminopyridines 125 to give aldimines 133 (X = CO). These imines 133 Scheme 31. Intramolecular aza-Diels-Alder reaction to obtain hybrid, fused naphthyridines.
In order to increase the molecular diversity, the methodology was extended to the preparation of angularly fused tetracyclic derivatives 132 (X = CO), in which the chromene scaffold was substituted by a coumarin (chromen-2-one). As before, functionalized aldehydes 131 (Scheme 31, X = CO) were condensed with 3-aminopyridines 125 to give aldimines 133 (X = CO). These imines 133 cyclized intramolecularly in refluxing chloroform in the presence of two equivalents of Lewis acid (BF 3 ·Et 2 O) to afford endo-6a,7,12,12a-tetrahydro-6Hchromeno [4,3-b][1,5]naphthyridin-6-ones 132 (X= CO) with good yields in a regio-and stereospecific way (Scheme 31). The formation of these polycyclic compounds 132 may be explained, as before, by a regio-and stereospecific intramolecular [4+2]-cycloaddition reaction of aldimines 133 (X = CO) to give intermediates 134 (X =CO) followed by prototropic tautomerization. The methodology tolerates electron-releasing and electron-withdrawing substituents in the aromatic aldehydes, even fluorinated ones that allow the preparation of fluoro containing compounds, interesting substrates from a biological point of view.

N-Alkylation
The N-alkylation of the fused dihydro-or tetrahydro[1,5]naphthyridines is one of the reactions frequently carried out in the fused system. They are generally SN reactions on alkyl halides or reductive alkylation reactions.

N-Alkylation
The N-alkylation of the fused dihydro-or tetrahydro[1,5]naphthyridines is one of the reactions frequently carried out in the fused system. They are generally S N reactions on alkyl halides or reductive alkylation reactions.

N-Alkylation
The N-alkylation of the fused dihydro-or tetrahydro[1,5]naphthyridines is one of the reactions frequently carried out in the fused system. They are generally SN reactions on alkyl halides or reductive alkylation reactions.

Electrophilic Substitution Reactions (SEAr)
It is known that the nitration of benzonaphthyridines with a HNO3/H2SO4 mixture occurs exclusively in the benzene ring. Thus, nitration of 6-methylbenzo[b][1,5]naphthyridine 4 gives the corresponding nitro derivative 155 (Scheme 36). In these reactions, the nitro group is also attached to the benzene ring in the para position with respect to the methyl substituent [5]. At the same time, 6-methylbenzo[b]naphthyridines are brominated at the peripheral pyridine ring in the β-position with respect to the nitrogen atom (rather than at the benzene ring). This reaction pathway cannot be explained in terms of the electrophilic substitution mechanism (aromatic SE (AE)). In this case, the behavior of benzonaphthyridine 4 (Scheme 36) is similar to that of quinoline and isoquinoline, when its bromination in weakly acidic media also occurs at the pyridine ring in the βposition with respect to the nitrogen atom giving 156, rather than at the benzene ring [5]. The mechanism for the bromination of these compounds entails nucleophilic addition-elimination [SN(AE)].

Electrophilic Substitution Reactions (S E Ar)
It is known that the nitration of benzonaphthyridines with a HNO 3 /H 2 SO 4 mixture occurs exclusively in the benzene ring. Thus, nitration of 6-methylbenzo[b][1,5]naphthyridine 4 gives the corresponding nitro derivative 155 (Scheme 36). In these reactions, the nitro group is also attached to the benzene ring in the para position with respect to the methyl substituent [5].

Electrophilic Substitution Reactions (SEAr)
It is known that the nitration of benzonaphthyridines with a HNO3/H2SO4 mixture occurs exclusively in the benzene ring. Thus, nitration of 6-methylbenzo[b][1,5]naphthyridine 4 gives the corresponding nitro derivative 155 (Scheme 36). In these reactions, the nitro group is also attached to the benzene ring in the para position with respect to the methyl substituent [5]. At the same time, 6-methylbenzo[b]naphthyridines are brominated at the peripheral pyridine ring in the β-position with respect to the nitrogen atom (rather than at the benzene ring). This reaction pathway cannot be explained in terms of the electrophilic substitution mechanism (aromatic SE (AE)). In this case, the behavior of benzonaphthyridine 4 (Scheme 36) is similar to that of quinoline and isoquinoline, when its bromination in weakly acidic media also occurs at the pyridine ring in the βposition with respect to the nitrogen atom giving 156, rather than at the benzene ring [5]. The mechanism for the bromination of these compounds entails nucleophilic addition-elimination [SN(AE)].
More recently, the synthesis of benzo[c][1,5]naphthyridine-6-carbonitrile 158, starting from benzonaphthyridine N-oxide 157 [55], has been achieved following the methodology of cyanation of two unsubstituted 1H-imidazole 3-oxides [56]. Benzo At the same time, 6-methylbenzo[b]naphthyridines are brominated at the peripheral pyridine ring in the β-position with respect to the nitrogen atom (rather than at the benzene ring). This reaction pathway cannot be explained in terms of the electrophilic substitution mechanism (aromatic SE (AE)). In this case, the behavior of benzonaphthyridine 4 (Scheme 36) is similar to that of quinoline and isoquinoline, when its bromination in weakly acidic media also occurs at the pyridine ring in the β-position with respect to the nitrogen atom giving 156, rather than at the benzene ring [5]. The mechanism for the bromination of these compounds entails nucleophilic addition-elimination [S N (AE)].

Nucleophilic Substitution Reactions (SNAr)
One  [15] or 162f [57]. The same reaction was used in the industrial preparation of pyronaridine tetraphosphate 21 (Scheme 6, vide supra) a well-known antimalarial drug. Thus, the halogen atom at position 10 of the benzo[b][1,5]naphthyridine ring in 20 was replaced (SNAr) by an aminophenol group to give compound 162g (Scheme 39) used later in the preparation of pyronaridine tetraphosphate [17].  [15] or 162f [57]. The same reaction was used in the industrial preparation of pyronaridine tetraphosphate 21 (Scheme 6, vide supra) a well-known antimalarial drug. Thus, the halogen atom at position 10 of the benzo[b][1,5]naphthyridine ring in 20 was replaced (S N Ar) by an aminophenol group to give compound 162g (Scheme 39) used later in the preparation of pyronaridine tetraphosphate [17].

Oxidation and Reduction
The most common reduction reaction of 1,5-naphthyridine system fused with carbocycles or heterocycles is the transformation of naphthyridinones into naphthyridines or what is the same, the transformation of the carbonyl group into methylene group in different conditions. For instance in Reference

Oxidation and Reduction
The most common reduction reaction of 1,5-naphthyridine system fused with carbocycles or heterocycles is the transformation of naphthyridinones into naphthyridines or what is the same, the transformation of the carbonyl group into methylene group in different conditions. For instance in Reference [4], tetrahydro-1H-benzo

Oxidation and Reduction
The most common reduction reaction of 1,5-naphthyridine system fused with carbocycles or heterocycles is the transformation of naphthyridinones into naphthyridines or what is the same, the transformation of the carbonyl group into methylene group in different conditions. For instance in Reference  [18]. So, bromine in AcONa/AcOH led only, in an irreproducible manner, to very few amounts of pyridones 174a-c from lactams 27a-c. However, when lactam 27a (R 1 = R 2 = R 3 = H) was refluxed with 1.2 equivalents of bromine in bromobenzene for 12 h, pyridine 174a, accompanied by monobrominated compound 175 (position of the bromine atom was not determined), was obtained. Alternatively, by heating 27a with thionyl chloride for 9 h, it furnished a mixture of 176 containing a chlorine and a sulphur atom (position of substituents was not determined) and chloronaphthyridine 177 (Scheme 44).

Side Chain Modifications
There are many modifications of functional groups and side chains that can be made in fused 1,5-naphthyridine derivatives, without altering the 1,5-naphthyridine system. For example, with a basic solution of silver oxide at 20 °C for 30 min, a methyl group in 6methylbenzo[b][1,5]naphthyridine 4 can be oxidized to the formyl group or the carboxyl group (Scheme 48) to get compounds 181 and 182 [4].

Side Chain Modifications
There are many modifications of functional groups and side chains that can be made in fused 1,5-naphthyridine derivatives, without altering the 1,5-naphthyridine system. For example, with a basic solution of silver oxide at 20 °C for 30 min, a methyl group in 6methylbenzo[b][1,5]naphthyridine 4 can be oxidized to the formyl group or the carboxyl group (Scheme 48) to get compounds 181 and 182 [4].

Side Chain Modifications
There are many modifications of functional groups and side chains that can be made in fused 1,5-naphthyridine derivatives, without altering the 1,5-naphthyridine system. For example, with a basic solution of silver oxide at 20 • C for 30 min, a methyl group in 6-methylbenzo[b][1,5]naphthyridine 4 can be oxidized to the formyl group or the carboxyl group (Scheme 48) to get compounds 181 and 182 [4]. Similarly, the nitrile group of benzo[c][1,5]naphthyridine-6-carbonitrile 158 can also undergo transformations without any modification occurring in the polycyclic system [56]. Thus, compound 158 is hydrolyzed to the corresponding acid 183 by boiling in aqueous alkali (Scheme 49). In the industrial preparation of antimalarial drug pyronaridine tetraphosphate 21, the compound 162g previously described (Scheme 39, vide supra) underwent a Mannich reaction with pyrrolidine in the presence of formaldehyde to give pyronaridine 184 (Scheme 50) and the yield increased about 20% [17]. Finally, 184 was treated with phosphoric acid to yield pyronaridine tetraphosphate 21. Scheme 50. Preparation of pyronaridine tetraphosphate 21.
The reduction of NO2 group in 162f (Scheme 39, vide supra) using SnCl2 as reducing agent (Scheme 51) led to the key intermediate 185 [57]. Then 185 and different aromatic aldehydes 186 were mixed in boiling ethanol affording the target compounds 187 bearing the C=N linkage moiety.  In the industrial preparation of antimalarial drug pyronaridine tetraphosphate 21, the compound 162g previously described (Scheme 39, vide supra) underwent a Mannich reaction with pyrrolidine in the presence of formaldehyde to give pyronaridine 184 (Scheme 50) and the yield increased about 20% [17]. Finally, 184 was treated with phosphoric acid to yield pyronaridine tetraphosphate 21. Scheme 50. Preparation of pyronaridine tetraphosphate 21.
The reduction of NO2 group in 162f (Scheme 39, vide supra) using SnCl2 as reducing agent (Scheme 51) led to the key intermediate 185 [57]. Then 185 and different aromatic aldehydes 186 were mixed in boiling ethanol affording the target compounds 187 bearing the C=N linkage moiety. In the industrial preparation of antimalarial drug pyronaridine tetraphosphate 21, the compound 162g previously described (Scheme 39, vide supra) underwent a Mannich reaction with pyrrolidine in the presence of formaldehyde to give pyronaridine 184 (Scheme 50) and the yield increased about 20% [17]. Finally, 184 was treated with phosphoric acid to yield pyronaridine tetraphosphate 21. In the industrial preparation of antimalarial drug pyronaridine tetraphosphate 21, the compound 162g previously described (Scheme 39, vide supra) underwent a Mannich reaction with pyrrolidine in the presence of formaldehyde to give pyronaridine 184 (Scheme 50) and the yield increased about 20% [17]. Finally, 184 was treated with phosphoric acid to yield pyronaridine tetraphosphate 21. Scheme 50. Preparation of pyronaridine tetraphosphate 21.
The reduction of NO2 group in 162f (Scheme 39, vide supra) using SnCl2 as reducing agent (Scheme 51) led to the key intermediate 185 [57]. Then 185 and different aromatic aldehydes 186 were mixed in boiling ethanol affording the target compounds 187 bearing the C=N linkage moiety. The reduction of NO 2 group in 162f (Scheme 39, vide supra) using SnCl 2 as reducing agent (Scheme 51) led to the key intermediate 185 [57]. Then 185 and different aromatic aldehydes 186 were mixed in boiling ethanol affording the target compounds 187 bearing the C=N linkage moiety. In the industrial preparation of antimalarial drug pyronaridine tetraphosphate 21, the compound 162g previously described (Scheme 39, vide supra) underwent a Mannich reaction with pyrrolidine in the presence of formaldehyde to give pyronaridine 184 (Scheme 50) and the yield increased about 20% [17]. Finally, 184 was treated with phosphoric acid to yield pyronaridine tetraphosphate 21. Scheme 50. Preparation of pyronaridine tetraphosphate 21.
The reduction of NO2 group in 162f (Scheme 39, vide supra) using SnCl2 as reducing agent (Scheme 51) led to the key intermediate 185 [57]. Then 185 and different aromatic aldehydes 186 were mixed in boiling ethanol affording the target compounds 187 bearing the C=N linkage moiety. To complete the efficient enantioselective total synthesis of the potent antibiotic GSK966587 52 (Scheme 16, vide supra), diol 55 was first converted to spiro-epoxide 195 (Scheme 55) using Et 3 N and perfluorobutanesulfonyl fluoride [27]. After 1 h at room temperature and filtration through silica gel, epoxide 195 was treated with functionalized piperidine 196 (1.5 equivalents) at room temperature for 14 h. Afterwards, GSK966587 52 precipitated directly from the reaction mixture.
Molecules 2020, 25, x FOR PEER REVIEW 33 of 54 To complete the efficient enantioselective total synthesis of the potent antibiotic GSK966587 52 (Scheme 16, vide supra), diol 55 was first converted to spiro-epoxide 195 (Scheme 55) using Et3N and perfluorobutanesulfonyl fluoride [27]. After 1 h at room temperature and filtration through silica gel, epoxide 195 was treated with functionalized piperidine 196 (1.5 equivalents) at room temperature for 14 h. Afterwards, GSK966587 52 precipitated directly from the reaction mixture.

Scheme 55. Enantioselective synthesis of the antibiotic GSK966587.
A modification of the above procedure for the total synthesis of 52, the antibiotic GSK966587 [28] was the transformation of racemic diol 55 by activation of the primary hydroxyl group as the tosylate using dibutyltin oxide (Scheme 56), reaction with tert-butyl piperidin A modification of the above procedure for the total synthesis of 52, the antibiotic GSK966587 [28] was the transformation of racemic diol 55 by activation of the primary hydroxyl group as the tosylate using dibutyltin oxide (Scheme 56), reaction with tert-butyl piperidin To complete the efficient enantioselective total synthesis of the potent antibiotic GSK966587 52 (Scheme 16, vide supra), diol 55 was first converted to spiro-epoxide 195 (Scheme 55) using Et3N and perfluorobutanesulfonyl fluoride [27]. After 1 h at room temperature and filtration through silica gel, epoxide 195 was treated with functionalized piperidine 196 (1.5 equivalents) at room temperature for 14 h. Afterwards, GSK966587 52 precipitated directly from the reaction mixture.

Metal Complex Formation
The relative nucleophilicity of the nitrogen atoms of the 1,5-naphthyridine bicyclic system present in the benzo [ [58]. Consistent with these data are isomeric structures 204a and 204b where the CO ligands are mutually cis; however, the structures differ from one another through restricted rotation along the Rh-N bond, due to restricted rotation of the coordinated square-planar Rh(CO)2Cl unit. The peri-H substituents to 5-nitrogen in the benzonaphthyridene unit are presumably responsible for this behavior (Scheme 60).

Metal Complex Formation
The relative nucleophilicity of the nitrogen atoms of the 1,5-naphthyridine bicyclic system present in the benzo [ 2 Cl] 2 leads to the product 204 (Scheme 60), which shows only coordination to the N5 atom [58]. Consistent with these data are isomeric structures 204a and 204b where the CO ligands are mutually cis; however, the structures differ from one another through restricted rotation along the Rh-N bond, due to restricted rotation of the coordinated square-planar Rh(CO) 2 Cl unit. The peri-H substituents to 5-nitrogen in the benzonaphthyridene unit are presumably responsible for this behavior (Scheme 60).

Biological Activity of Fused 1,5-Naphthyridines
In the last decade, complex heterocyclic systems containing 1,5-naphthyridines fragments have been synthesized, their reactions have been investigated, and the possibility of their use for the preparation of biologically active compounds have been studied extensively. For example, derivatives of annulated benzoindolo[1,5]naphthyridines attempting to improve memory were described, and these are benzo[b][1,5]naphthyridines which are analogs of inhibitors of neurokinin NK1-receptors [4].
The bromodomain and extra C-terminal (BET) domain family of bromodomains (BRDs) consists of four proteins, each containing two discrete bromodomain "reader" modules which recognize the ε-N-acetylation state of specific lysine residues found within histone tails and other proteins [64]. New naphthyridine analogues were synthesized and tested on BET family bromodomains [31]. Compounds 1H-imidazo [4,5-c][1,5]naphthyridin-2(3H)-ones 71b (Scheme 18, vide supra) that possess an isoxazole substituent have as potent inhibitors of the BET bromodomain family with good cell activity and oral pharmacokinetic parameters. Profiling was carried out against the three BET subtypes, as well as in peripheral blood mononuclear cells (PBMCs), where inhibition of cytokine IL-6 was measured after a lipopolysaccharide (LPS) challenge. The fused indenone naphthyridines were more or less equipotent with BRD2, BRD3, BRD4 and PBMC values of pIC 50 between 6.1 and 6.8. The best results of pIC 50 were for compounds 71bd and 71be (Figure 7). possess an isoxazole substituent have as potent inhibitors of the BET bromodomain family with good cell activity and oral pharmacokinetic parameters. Profiling was carried out against the three BET subtypes, as well as in peripheral blood mononuclear cells (PBMCs), where inhibition of cytokine IL-6 was measured after a lipopolysaccharide (LPS) challenge. The fused indenone naphthyridines were more or less equipotent with BRD2, BRD3, BRD4 and PBMC values of pIC50 between 6.1 and 6.8. The best results of pIC50 were for compounds 71bd and 71be (Figure 7).  Figure 8) was found to display good cytotoxicity and can bind with calf thymus DNA (ct DNA). A relaxation assay indicated that 162b inhibits TopI activity at 100 μM [16]. Compound 162b with methyl substitute at the para-position on the aniline ring displayed good antiproliferative activity with IC50 values of 15.9 and 18.9 μM against K562 and HepG-2 cells respectively in vitro. The ability of compound 162b to interact with ct DNA indicated that nuclear enzymes involved in DNA processing such as TopI might be inhibited. These data suggest that 162b might exert antiproliferative activity through TopI inhibition, and it may be a potential lead compound for the development of benzo[b][1,5]naphthyridines as TopI inhibitors.   Figure 8) was found to display good cytotoxicity and can bind with calf thymus DNA (ct DNA). A relaxation assay indicated that 162b inhibits TopI activity at 100 µM [16]. Compound 162b with methyl substitute at the para-position on the aniline ring displayed good antiproliferative activity with IC 50 values of 15.9 and 18.9 µM against K562 and HepG-2 cells respectively in vitro. The ability of compound 162b to interact with ct DNA indicated that nuclear enzymes involved in DNA processing such as TopI might be inhibited. These data suggest that 162b might exert antiproliferative activity through TopI inhibition, and it may be a potential lead compound for the development of benzo[b][1,5]naphthyridines as TopI inhibitors.
possess an isoxazole substituent have as potent inhibitors of the BET bromodomain family with good cell activity and oral pharmacokinetic parameters. Profiling was carried out against the three BET subtypes, as well as in peripheral blood mononuclear cells (PBMCs), where inhibition of cytokine IL-6 was measured after a lipopolysaccharide (LPS) challenge. The fused indenone naphthyridines were more or less equipotent with BRD2, BRD3, BRD4 and PBMC values of pIC50 between 6.1 and 6.8. The best results of pIC50 were for compounds 71bd and 71be (Figure 7).  Figure 8) was found to display good cytotoxicity and can bind with calf thymus DNA (ct DNA). A relaxation assay indicated that 162b inhibits TopI activity at 100 μM [16]. Compound 162b with methyl substitute at the para-position on the aniline ring displayed good antiproliferative activity with IC50 values of 15.9 and 18.9 μM against K562 and HepG-2 cells respectively in vitro. The ability of compound 162b to interact with ct DNA indicated that nuclear enzymes involved in DNA processing such as TopI might be inhibited. These data suggest that 162b might exert antiproliferative activity through TopI inhibition, and it may be a potential lead compound for the development of benzo[b][1,5]naphthyridines as TopI inhibitors.  (Scheme 45, vide supra) exhibited inhibitory effects against TopI mediated relaxation comparable to those observed for the natural inhibitor, camptothecin (CPT). All the prepared derivatives were further subjected to evaluation of their therapeutic efficacy against three different human cancer cell lines: breast (BT20), lung adenocarcinoma (A549), and ovarian carcinoma (SKOV3). These preliminary studies revealed that some of newly synthesized compounds exhibited a significant antiproliferative activity. Indeno[1,5]naphthyridine derivative 51g (Figure 9) showed a high cytotoxic effect in vitro against A549 cell line proliferation with an IC 50 of 2.9 ± 0.9 µM. Some of the fluorinated derivatives were the most cytotoxic, showing good enzyme inhibition and relatively low IC 50 values. It is worth noting that indeno[1,5]naphthyridine 51d ( Figure 9) showed a very high inhibition of TopI activity and the highest cytotoxic effect, with an IC 50 of 1.7 ± 0.1 µM, against the A549 cell line in vitro. The interesting biochemical and biological features found for these derivatives provide a promising basis for further development of biologically active fused naphthyridines [25]. effect in vitro against A549 cell line proliferation with an IC50 of 2.9 ± 0.9 μM. Some of the fluorinated derivatives were the most cytotoxic, showing good enzyme inhibition and relatively low IC50 values. It is worth noting that indeno[1,5]naphthyridine 51d (Figure 9) showed a very high inhibition of TopI activity and the highest cytotoxic effect, with an IC50 of 1.7 ± 0.1 μM, against the A549 cell line in vitro. The interesting biochemical and biological features found for these derivatives provide a promising basis for further development of biologically active fused naphthyridines [25]. The interesting biochemical and biological features found for the above derivatives provide a promising basis for further development of biologically active fused naphthyridines. Thus, tetrahydro[1,5]naphthyridine derivatives fused with heterocycles, such as chromenes 127 and chromen-2-ones 132 and the corresponding tetracyclic chromeno [4,3-b][1,5]naphthyridine 130 derivatives and/or chromeno [4,3-b][1,5]naphthyridin-6-ones 180 (Scheme 47, vide supra), showed activity as inhibitors of TopI [52]. Additionally, the cytotoxic behavior of these compounds has been studied in A549 and SKOV3 cell lines and on noncancerous lung fibroblasts cell line  where, on the last ones, the absence of cytotoxicity was observed.
7-Phenyl-6H-6a,7,12,12a-tetrahydrochromeno [4,3-b][1,5]naphthyridine 127a ( Figure 10) showed excellent cytotoxic activity with an IC 50 value of 1.03 ± 0.30 µM against the A549 cell line and an IC 50 value of 1.75 ± 0.20 µM against the SKOV3 cell line. The obtained results point to these compounds as good antiproliferative candidates. effect in vitro against A549 cell line proliferation with an IC50 of 2.9 ± 0.9 μM. Some of the fluorinated derivatives were the most cytotoxic, showing good enzyme inhibition and relatively low IC50 values. It is worth noting that indeno[1,5]naphthyridine 51d (Figure 9) showed a very high inhibition of TopI activity and the highest cytotoxic effect, with an IC50 of 1.7 ± 0.1 μM, against the A549 cell line in vitro. The interesting biochemical and biological features found for these derivatives provide a promising basis for further development of biologically active fused naphthyridines [25]. The interesting biochemical and biological features found for the above derivatives provide a promising basis for further development of biologically active fused naphthyridines. Thus, tetrahydro[1,5]naphthyridine derivatives fused with heterocycles, such as chromenes 127 and chromen-2-ones 132 and the corresponding tetracyclic chromeno [4,3-b][1,5]naphthyridine 130 derivatives and/or chromeno [4,3-b][1,5]naphthyridin-6-ones 180 (Scheme 47, vide supra), showed activity as inhibitors of TopI [52]. Additionally, the cytotoxic behavior of these compounds has been studied in A549 and SKOV3 cell lines and on noncancerous lung fibroblasts cell line  where, on the last ones, the absence of cytotoxicity was observed.
7-Phenyl-6H-6a,7,12,12a-tetrahydrochromeno [4,3-b][1,5]naphthyridine 127a ( Figure 10) showed excellent cytotoxic activity with an IC50 value of 1.03 ± 0.30 μM against the A549 cell line and an IC50 value of 1.75 ± 0.20 μM against the SKOV3 cell line. The obtained results point to these compounds as good antiproliferative candidates. compound with IC50 values of 3.25 ± 0.91 μM and 2.08 ± 1.89 μM against the A549 cell line and the SKOV3 cell line, respectively. Moreover, 5-tosylhexahydroquinolino [4,3-b][1,5]naphthyridine 110a and 5-tosyldihydroquinolino [4,3-b][1,5]naphthyridine 115a (R 1 = H) demonstrated to be cytotoxic with IC50 values of 7.25 ± 0.81 μM and 7.34 ± 0.17 μM against the A549 cell line, respectively, and with IC50 values of 8.08 ± 1.39 μM and 8.65 ± 0.57 μM against the SKOV3 cell line, respectively. None of the compounds had cytotoxic effects against non-malignant pulmonary fibroblasts (MRC-5).  Figure 12) have been discovered as inhibitors of bacterial type IIA topoisomerases. The compounds showed good potency against Gram-positive and Gram-negative pathogens [28]. The hERG inhibition of the compounds described was generally related to their lipophilicity and basicity and several compounds within this series were identified with hERG inhibition (Figure 12). The antitumor activity of fused 1,5-naphthyridines derivatives is closely connected with the intercalation characteristic of many planar ionisable systems. 2-[(Alkylamino)alkyl]-9-methoxy -5nitro-2,6-dihydroindazolo [4,3-bc][1,5]naphthyridines 94 (Scheme 24, vide supra) represent a new class of aza-acridine derivatives which have noticeable antitumor properties [15]. With enhanced DNA affinity and similar in vitro cytotoxic activity in respect to reference compound (pyrazinamide) PZA, but specially, with a capacity to induce oligonucleosomal DNA fragmentation and apoptotic  Figure 12) have been discovered as inhibitors of bacterial type IIA topoisomerases. The compounds showed good potency against Gram-positive and Gram-negative pathogens [28]. The hERG inhibition of the compounds described was generally related to their lipophilicity and basicity and several compounds within this series were identified with hERG inhibition (Figure 12). compound with IC50 values of 3.25 ± 0.91 μM and 2.08 ± 1.89 μM against the A549 cell line and the SKOV3 cell line, respectively. Moreover, 5-tosylhexahydroquinolino [4,3-b][1,5]naphthyridine 110a and 5-tosyldihydroquinolino [4,3-b][1,5]naphthyridine 115a (R 1 = H) demonstrated to be cytotoxic with IC50 values of 7.25 ± 0.81 μM and 7.34 ± 0.17 μM against the A549 cell line, respectively, and with IC50 values of 8.08 ± 1.39 μM and 8.65 ± 0.57 μM against the SKOV3 cell line, respectively. None of the compounds had cytotoxic effects against non-malignant pulmonary fibroblasts (MRC-5).  Figure 12) have been discovered as inhibitors of bacterial type IIA topoisomerases. The compounds showed good potency against Gram-positive and Gram-negative pathogens [28]. The hERG inhibition of the compounds described was generally related to their lipophilicity and basicity and several compounds within this series were identified with hERG inhibition (Figure 12). The antitumor activity of fused 1,5-naphthyridines derivatives is closely connected with the intercalation characteristic of many planar ionisable systems. 2-[(Alkylamino)alkyl]-9-methoxy -5nitro-2,6-dihydroindazolo [4,3-bc][1,5]naphthyridines 94 (Scheme 24, vide supra) represent a new class of aza-acridine derivatives which have noticeable antitumor properties [15]. With enhanced DNA affinity and similar in vitro cytotoxic activity in respect to reference compound (pyrazinamide) PZA, but specially, with a capacity to induce oligonucleosomal DNA fragmentation and apoptotic The antitumor activity of fused 1,5-naphthyridines derivatives is closely connected with the intercalation characteristic of many planar ionisable systems. 2-[(Alkylamino)alkyl]-9-methoxy -5-nitro-2,6-dihydroindazolo [4,3-bc][1,5]naphthyridines 94 (Scheme 24, vide supra) represent a new class of aza-acridine derivatives which have noticeable antitumor properties [15]. With enhanced DNA affinity and similar in vitro cytotoxic activity in respect to reference compound (pyrazinamide) PZA, but specially, with a capacity to induce oligonucleosomal DNA fragmentation and apoptotic cell death, not present in PZA. In particular the 9-methoxy-5-nitro-2-[2-(tetrahydro-1H-1-pyrrolyl) ethyl]-2,6-dihydroindazolo [4,3-bc][1,5]naphthyridine 94d, which possesses the most relevant biological characteristics in the series, can be regarded as a new lead in the field of potential anticancer derivatives ( Figure 13). Thus, the ability of this compound to early induce oligonucleosomal DNA fragmentation and apoptotic cell death of the hormone-refractory PC-3 prostate cancer cells may be particularly relevant to overcoming drug resistance or sensitize tumor cells to the effects of other antineoplastic agents. biological characteristics in the series, can be regarded as a new lead in the field of potential anticancer derivatives ( Figure 13). Thus, the ability of this compound to early induce oligonucleosomal DNA fragmentation and apoptotic cell death of the hormone-refractory PC-3 prostate cancer cells may be particularly relevant to overcoming drug resistance or sensitize tumor cells to the effects of other antineoplastic agents. To search for a structurally differentiated backup candidate to PF-04691502 (Figure 14), which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of a structure-based drug design and physical properties-based optimization (Scheme 18, vide supra) yielded PF-04979064, a potent and selective PI3K/mTOR dual kinase inhibitor [30]. The manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addresses a number of absortion, distribution, metabolism, excretion and toxicity (ADMET) properties including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.  [29]. Their mechanism of cytotoxicity action was unrelated to poisoning or inhibiting abilities against TopI. On the contrary, must be highlighted a direct intercalation of the drug into DNA by electrophoresis on agarose gel. The tumor cell growth inhibition was assessed on HT-1080 (fibrosarcoma), HT-29 (colon carcinoma), M-21 (skin melanoma), and MCF-7 (breast carcinoma) cells. Compounds 65 and 66 exhibited good values of GI50 ranging from 2.2 to 52 μM (Figure 15). Compound 66 seems to exhibit some specificity towards breast-derived cells such as MCF-7 where it showed a GI50 at least fourfold higher than in any other tumor cell lines ( Figure 15). To search for a structurally differentiated backup candidate to PF-04691502 (Figure 14), which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of a structure-based drug design and physical properties-based optimization (Scheme 18, vide supra) yielded PF-04979064, a potent and selective PI3K/mTOR dual kinase inhibitor [30]. derivatives ( Figure 13). Thus, the ability of this compound to early induce oligonucleosomal DNA fragmentation and apoptotic cell death of the hormone-refractory PC-3 prostate cancer cells may be particularly relevant to overcoming drug resistance or sensitize tumor cells to the effects of other antineoplastic agents. To search for a structurally differentiated backup candidate to PF-04691502 (Figure 14), which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of a structure-based drug design and physical properties-based optimization (Scheme 18, vide supra) yielded PF-04979064, a potent and selective PI3K/mTOR dual kinase inhibitor [30]. The manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addresses a number of absortion, distribution, metabolism, excretion and toxicity (ADMET) properties including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.  [29]. Their mechanism of cytotoxicity action was unrelated to poisoning or inhibiting abilities against TopI. On the contrary, must be highlighted a direct intercalation of the drug into DNA by electrophoresis on agarose gel. The tumor cell growth inhibition was assessed on HT-1080 (fibrosarcoma), HT-29 (colon carcinoma), M-21 (skin melanoma), and MCF-7 (breast carcinoma) cells. Compounds 65 and 66 exhibited good values of GI50 ranging from 2.2 to 52 μM (Figure 15). Compound 66 seems to exhibit some specificity towards breast-derived cells such as MCF-7 where it showed a GI50 at least fourfold higher than in any other tumor cell lines ( Figure 15). The manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addresses a number of absortion, distribution, metabolism, excretion and toxicity (ADMET) properties including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.  [29]. Their mechanism of cytotoxicity action was unrelated to poisoning or inhibiting abilities against TopI. On the contrary, must be highlighted a direct intercalation of the drug into DNA by electrophoresis on agarose gel. The tumor cell growth inhibition was assessed on HT-1080 (fibrosarcoma), HT-29 (colon carcinoma), M-21 (skin melanoma), and MCF-7 (breast carcinoma) cells. Compounds 65 and 66 exhibited good values of GI 50 ranging from 2.2 to 52 µM (Figure 15). Compound 66 seems to exhibit some specificity towards breast-derived cells such as MCF-7 where it showed a GI 50 at least fourfold higher than in any other tumor cell lines ( Figure 15).   (Figure 16) was synthesized to explore the effect of structurally diverse linkers on PrP Se replication in scrapie-infected neuroblastoma cells [4]. The data suggest that bis-acridine analogs may provide a potent alternative to the acridine-based compound quinacrine which is currently under clinical evaluation for the treatment of prion disease.  (Figure 17), a new Mannich base, schizontocide, originally developed in China and structurally related to the aminoacridine drug quinacrine, is currently undergoing clinical testing. Pyronaridine targets hematin, as demonstrated by its ability to inhibit in vitro β-hematin formation (at a concentration equal to that of chloroquine), to form a complex with hematin with a stoichiometry of 1:2, to enhance hematin-induced red blood cell lysis (but at 1/100 of the chloroquine concentration), and to inhibit glutathione dependent degradation of hematin. Pyronaridine exerted this mechanism of action in situ, based on growth studies of Plasmodium falciparum K1 in culture [65].  (Figure 16) was synthesized to explore the effect of structurally diverse linkers on PrP Se replication in scrapie-infected neuroblastoma cells [4]. The data suggest that bis-acridine analogs may provide a potent alternative to the acridine-based compound quinacrine which is currently under clinical evaluation for the treatment of prion disease.  (Figure 16) was synthesized to explore the effect of structurally diverse linkers on PrP Se replication in scrapie-infected neuroblastoma cells [4]. The data suggest that bis-acridine analogs may provide a potent alternative to the acridine-based compound quinacrine which is currently under clinical evaluation for the treatment of prion disease.  (Figure 17), a new Mannich base, schizontocide, originally developed in China and structurally related to the aminoacridine drug quinacrine, is currently undergoing clinical testing. Pyronaridine targets hematin, as demonstrated by its ability to inhibit in vitro β-hematin formation (at a concentration equal to that of chloroquine), to form a complex with hematin with a stoichiometry of 1:2, to enhance hematin-induced red blood cell lysis (but at 1/100 of the chloroquine concentration), and to inhibit glutathione dependent degradation of hematin. Pyronaridine exerted this mechanism of action in situ, based on growth studies of Plasmodium falciparum K1 in culture [65]. Pyronaridine targets hematin, as demonstrated by its ability to inhibit in vitro β-hematin formation (at a concentration equal to that of chloroquine), to form a complex with hematin with a stoichiometry of 1:2, to enhance hematin-induced red blood cell lysis (but at 1/100 of the chloroquine concentration), and to inhibit glutathione dependent degradation of hematin. Pyronaridine exerted this mechanism of action in situ, based on growth studies of Plasmodium falciparum K1 in culture [65].  were studied and their antileishmanial activity on promastigotes and amastigote-infected splenocytes of Leishmania infantum were evaluated [25]. Some of the prepared heterocycles showed selective inhibition of LtopIB, while no inhibition of hTopIB was observed at evaluated conditions. In addition, the cytotoxic effects of newly synthesized compounds were assessed on host murine splenocytes in order to calculate the corresponding selective indexes (SI). Tetrahydro indeno[1,5]naphthyridines 50e and 50h ( Figure 18) showed good antileishmanial activity (IC50 values of 0.67 ± 0.06 and 0.54 ± 0.17 μM) with similar activity than the standard drug amphotericin B (0.32 ± 0.05 μM) and even tetrahydro indeno[1,5]naphthyridine 50h showed higher (SI) towards L. Infantum amastigotes. Likewise, in the family of indeno[1,5]naphthyridines 51, compound 51b ( Figure 18) showed good antileishmanial activity (IC50 value 0.74 ± 0.08 μM) and higher selective index towards L. Infantum amastigotes than amphotericin. The anti-intestinal nematode activities against Nippostrongylus brazilliensis of a series of benzonaphthyridine derivatives bearing the C=N linkage moiety 187 (Scheme 51, vide supra) were evaluated in vivo by an oral route in male rats [57]. Some of compounds showed significant antiintestinal nematode activity in a two-day in vivo test in rats. Among these compounds, at concentrations of 10 mg/kg of rat, the compound 7-chloro-2-methoxy-10-(4-(4′-(1H-indol-5′-yl) methylene)aminophenyl)-amino-benzo[b][1,5]naphthyridine 187n (Figure 19) produced the highest activity against Nippostrongylus brazilliensis, with 80.3% deparasitization. These compounds may find usefulness in the discovery and development of new anti-intestinal drugs. The inhibition of leishmania (LTopIB) and human TopIB (HTopIB) of tetrahydroindeno[1, 5]naphthyridines 50 and indeno[1,5]naphthyridines 51 (Scheme 15, vide supra) were studied and their antileishmanial activity on promastigotes and amastigote-infected splenocytes of Leishmania infantum were evaluated [25]. Some of the prepared heterocycles showed selective inhibition of LtopIB, while no inhibition of hTopIB was observed at evaluated conditions. In addition, the cytotoxic effects of newly synthesized compounds were assessed on host murine splenocytes in order to calculate the corresponding selective indexes (SI). Tetrahydro indeno[1,5]naphthyridines 50e and 50h ( Figure 18) showed good antileishmanial activity (IC 50 values of 0.67 ± 0.06 and 0.54 ± 0.17 µM) with similar activity than the standard drug amphotericin B (0.32 ± 0.05 µM) and even tetrahydro indeno[1,5]naphthyridine 50h showed higher (SI) towards L. Infantum amastigotes. Likewise, in the family of indeno[1,5]naphthyridines 51, compound 51b ( Figure 18) showed good antileishmanial activity (IC 50 value 0.74 ± 0.08 µM) and higher selective index towards L. Infantum amastigotes than amphotericin.  were studied and their antileishmanial activity on promastigotes and amastigote-infected splenocytes of Leishmania infantum were evaluated [25]. Some of the prepared heterocycles showed selective inhibition of LtopIB, while no inhibition of hTopIB was observed at evaluated conditions. In addition, the cytotoxic effects of newly synthesized compounds were assessed on host murine splenocytes in order to calculate the corresponding selective indexes (SI). Tetrahydro indeno[1,5]naphthyridines 50e and 50h ( Figure 18) showed good antileishmanial activity (IC50 values of 0.67 ± 0.06 and 0.54 ± 0.17 μM) with similar activity than the standard drug amphotericin B (0.32 ± 0.05 μM) and even tetrahydro indeno[1,5]naphthyridine 50h showed higher (SI) towards L. Infantum amastigotes. Likewise, in the family of indeno[1,5]naphthyridines 51, compound 51b ( Figure 18) showed good antileishmanial activity (IC50 value 0.74 ± 0.08 μM) and higher selective index towards L. Infantum amastigotes than amphotericin. The anti-intestinal nematode activities against Nippostrongylus brazilliensis of a series of benzonaphthyridine derivatives bearing the C=N linkage moiety 187 (Scheme 51, vide supra) were evaluated in vivo by an oral route in male rats [57]. Some of compounds showed significant antiintestinal nematode activity in a two-day in vivo test in rats. Among these compounds, at concentrations of 10 mg/kg of rat, the compound 7-chloro-2-methoxy-10-(4-(4′-(1H-indol-5′-yl) methylene)aminophenyl)-amino-benzo[b][1,5]naphthyridine 187n (Figure 19) produced the highest activity against Nippostrongylus brazilliensis, with 80.3% deparasitization. These compounds may find usefulness in the discovery and development of new anti-intestinal drugs. The anti-intestinal nematode activities against Nippostrongylus brazilliensis of a series of benzonaphthyridine derivatives bearing the C=N linkage moiety 187 (Scheme 51, vide supra) were evaluated in vivo by an oral route in male rats [57]. Some of compounds showed significant anti-intestinal nematode activity in a two-day in vivo test in rats. Among these compounds, at concentrations of 10 mg/kg of rat, the compound 7-chloro-2-methoxy-10-(4-(4 -(1H-indol-5 -yl) methylene)aminophenyl)-amino-benzo[b][1,5]naphthyridine 187n (Figure 19) produced the highest activity against Nippostrongylus brazilliensis, with 80.3% deparasitization. These compounds may find usefulness in the discovery and development of new anti-intestinal drugs.

Other Applications of Fused 1,5-Naphthyridines
In biological reactions, on the other hand, the NAD+/NADH redox couple, in which the oxidized form (NAD+) with a pyridinium structure is reversibly converted into the reduced form (NADH) with two electrons and one proton, plays a key role in reversible hydride transfer reactions. Transition-metal complexes operating in the same way as the NAD+/NADH system have been reported. Many of these systems present in their structure model ligands that include benzo[b][1,5]naphthyridin-2-yl groups. The electrochemical reduction of 206 (Scheme 68) under aqueous acidic conditions induces formation of the hydrogenated product [Ru(pbnH2)(bpy)2](PF6)2] 221 [11]. The electrochemical reduction of acetone to generate 2-propanol by using complex 206 as a precatalyst with two electrons and H2O as a proton source was described. The key points of this catalytic system are "hydride" generation and transfer, similar to the function of the NAD+/NADH redox couple. Clear evidence of the photochemical and radiolytic formation of 221 with H + have been reported in Reference [66]. The mechanistic pathways of formation of the NADH-like [Ru(bpy)2(pbnHH)] 2+ species from [Ru(bpy)2(pbn)] 2+ were studied in an aqueous medium [67] and D2O [68] showing is controlled by the pH of the solution.

Other Applications of Fused 1,5-Naphthyridines
In biological reactions, on the other hand, the NAD+/NADH redox couple, in which the oxidized form (NAD+) with a pyridinium structure is reversibly converted into the reduced form (NADH) with two electrons and one proton, plays a key role in reversible hydride transfer reactions. Transition-metal complexes operating in the same way as the NAD+/NADH system have been reported. Many of these systems present in their structure model ligands that include benzo[b][1,5]naphthyridin-2-yl groups. The electrochemical reduction of 206 (Scheme 68) under aqueous acidic conditions induces formation of the hydrogenated product [Ru(pbnH2)(bpy)2](PF6)2] 221 [11]. The electrochemical reduction of acetone to generate 2-propanol by using complex 206 as a precatalyst with two electrons and H2O as a proton source was described. The key points of this catalytic system are "hydride" generation and transfer, similar to the function of the NAD+/NADH redox couple. Clear evidence of the photochemical and radiolytic formation of 221 with H + have been reported in Reference [66]. The mechanistic pathways of formation of the NADH-like [Ru(bpy)2(pbnHH)] 2+ species from [Ru(bpy)2(pbn)] 2+ were studied in an aqueous medium [67] and D2O [68] showing is controlled by the pH of the solution.

Other Applications of Fused 1,5-Naphthyridines
In biological reactions, on the other hand, the NAD+/NADH redox couple, in which the oxidized form (NAD+) with a pyridinium structure is reversibly converted into the reduced form (NADH) with two electrons and one proton, plays a key role in reversible hydride transfer reactions. Transition-metal complexes operating in the same way as the NAD+/NADH system have been reported. Many of these systems present in their structure model ligands that include benzo[b][1,5]naphthyridin-2-yl groups. The electrochemical reduction of 206 (Scheme 68) under aqueous acidic conditions induces formation of the hydrogenated product [Ru(pbnH 2 )(bpy) 2 ](PF 6 ) 2 ] 221 [11]. The electrochemical reduction of acetone to generate 2-propanol by using complex 206 as a precatalyst with two electrons and H 2 O as a proton source was described. The key points of this catalytic system are "hydride" generation and transfer, similar to the function of the NAD+/NADH redox couple. Clear evidence of the photochemical and radiolytic formation of 221 with H + have been reported in Reference [66]. The mechanistic pathways of formation of the NADH-like [Ru(bpy) 2 (pbnHH)] 2+ species from [Ru(bpy) 2 (pbn)] 2+ were studied in an aqueous medium [67] and D 2 O [68] showing is controlled by the pH of the solution. On the other hand, on study demonstrated that the introduction of a methyl group of the pyridine moiety in the pbn ligands played a key role in controlling photo-induced NAD+/NADH type hydrogenation reactions by twisting the ligand at a certain level compared with the case of the non-substituted pbn ligand [69].
The  The design and synthesis of new catalysts having a capability for photo-and electro-chemical reduction of carbon dioxide (CO2) to produce CO, HCOOH, alcohols, etc., have been pursued to alleviate the global crisis caused by depletion of fossil fuels and the rising atmospheric concentration of CO2. Among the various catalysts, ruthenium complexes may be viable candidates to realize such an innovative function, since they are widely used as catalysts in photo-and electrochemical reduction of CO2 as well as a variety of organic syntheses. The development of a renewable hydride donor is a key process to construct a catalytic system that has the ability to catalyze multi-electron reduction of CO2. Reduction of CO2 using the renewable hydride donor embarks on a new stage of the construction of a sustainable society [70].
An addition of a base to Ru-pbnHH greatly enhanced the hydride donor ability, since [Ru(bpy)2(pbnHH)] 2+ 212 reacted with CO2 in the presence of PhCOO _ to give HCOO _ with Scheme 68. Formation of the NADH-like species from bpn-ruthenium(II) complex.
On the other hand, on study demonstrated that the introduction of a methyl group of the pyridine moiety in the pbn ligands played a key role in controlling photo-induced NAD+/NADH type hydrogenation reactions by twisting the ligand at a certain level compared with the case of the non-substituted pbn ligand [69].
The use of the multielectron redox reactions of mononuclear metal complexes under visible light irradiation is a fascinating approach to harvesting solar energy. The photoinduced four-and six-electron reduction of [Ru(bpy)(pbn) 2 ](PF 6 ) 2 209 and [Ru(pbn) 3 ](PF 6 ) 2 210 ( Figure 21), with two and three pbn ligands, respectively, under irradiation with visible light (l > 420 nm) conducted in dry CH 3 CN/TEA (4:1, v/v) resulted in only one-electron reduction of these complexes to give (209) + and (210) + . The high-efficiency storage of photoinduced two-, four-, and six-electron reducing equivalents in 207 (Scheme 68, vide supra), 209 and 210, respectively, using the NAD+ analogous pbn ligands may provide a new pathway for multiple electron and proton transfer to reaction sites under illumination with visible light [60]. On the other hand, on study demonstrated that the introduction of a methyl group of the pyridine moiety in the pbn ligands played a key role in controlling photo-induced NAD+/NADH type hydrogenation reactions by twisting the ligand at a certain level compared with the case of the non-substituted pbn ligand [69].
The use of the multielectron redox reactions of mononuclear metal complexes under visible light irradiation is a fascinating approach to harvesting solar energy. The photoinduced four-and sixelectron reduction of [Ru(bpy)(pbn)2](PF6)2 209 and [Ru(pbn)3](PF6)2 210 (Figure 21), with two and three pbn ligands, respectively, under irradiation with visible light (l > 420 nm) conducted in dry CH3CN/TEA (4:1, v/v) resulted in only one-electron reduction of these complexes to give (209) + and (210) + . The high-efficiency storage of photoinduced two-, four-, and six-electron reducing equivalents in 207 (Scheme 68, vide supra), 209 and 210, respectively, using the NAD+ analogous pbn ligands may provide a new pathway for multiple electron and proton transfer to reaction sites under illumination with visible light [60]. The design and synthesis of new catalysts having a capability for photo-and electro-chemical reduction of carbon dioxide (CO2) to produce CO, HCOOH, alcohols, etc., have been pursued to alleviate the global crisis caused by depletion of fossil fuels and the rising atmospheric concentration of CO2. Among the various catalysts, ruthenium complexes may be viable candidates to realize such an innovative function, since they are widely used as catalysts in photo-and electrochemical reduction of CO2 as well as a variety of organic syntheses. The development of a renewable hydride donor is a key process to construct a catalytic system that has the ability to catalyze multi-electron reduction of CO2. Reduction of CO2 using the renewable hydride donor embarks on a new stage of the construction of a sustainable society [70].
An addition of a base to Ru-pbnHH greatly enhanced the hydride donor ability, since [Ru(bpy)2(pbnHH)] 2+ 212 reacted with CO2 in the presence of PhCOO _ to give HCOO _ with The design and synthesis of new catalysts having a capability for photo-and electro-chemical reduction of carbon dioxide (CO 2 ) to produce CO, HCOOH, alcohols, etc., have been pursued to alleviate the global crisis caused by depletion of fossil fuels and the rising atmospheric concentration of CO 2 . Among the various catalysts, ruthenium complexes may be viable candidates to realize such an innovative function, since they are widely used as catalysts in photo-and electrochemical reduction of CO 2 as well as a variety of organic syntheses. The development of a renewable hydride donor is a key process to construct a catalytic system that has the ability to catalyze multi-electron reduction of CO 2 . Reduction of CO 2 using the renewable hydride donor embarks on a new stage of the construction of a sustainable society [70].
Molecules 2020, 25 Figure 22) that offers many favorable properties, such as improved solid-state packing, high charge carrier mobility, and moderate photoluminescence quantum yields (PLQYs), required for fast optoelectronics. Photophysical properties of PTNT were explored in solution and thin film. Thus, a new strategy to improve the speed of organic light-emitting diodes (OLEDs) using a new class of luminescent polymer with high charge carrier mobilities has been demonstrated [74]. Aqueous nanoparticle dispersions were prepared from PTNT and fullerene blend utilizing chloroform as well as a nonchlorinated and environmentally benign solvent, o-xylene, as the miniemulsion dispersed phase solvent. The nanoparticles (NPs) in the solid-state film were found to coalesce and offered a smooth surface topography upon thermal annealing [75]. Recently, PTNT-conjugated polymer was used as the donor polymer. The preparation of environmentally friendlier polymer solar cell devices [76,77].  (Figure 23), which has a 2-naphthyl group, has been used as an optical DNA biosensor to unravel the inhibitory mechanism of human topoisomerase I activity by blocking enzyme-DNA dissociation [78]. This represents the first characterized example of a small molecule drug that inhibits a post-ligation step of catalysis.  Figure 22) that offers many favorable properties, such as improved solid-state packing, high charge carrier mobility, and moderate photoluminescence quantum yields (PLQYs), required for fast optoelectronics. Photophysical properties of PTNT were explored in solution and thin film. Thus, a new strategy to improve the speed of organic light-emitting diodes (OLEDs) using a new class of luminescent polymer with high charge carrier mobilities has been demonstrated [74]. Aqueous nanoparticle dispersions were prepared from PTNT and fullerene blend utilizing chloroform as well as a non-chlorinated and environmentally benign solvent, o-xylene, as the miniemulsion dispersed phase solvent. The nanoparticles (NPs) in the solid-state film were found to coalesce and offered a smooth surface topography upon thermal annealing [75]. Recently, PTNT-conjugated polymer was used as the donor polymer. The preparation of environmentally friendlier polymer solar cell devices [76,77].  Figure 22) that offers many favorable properties, such as improved solid-state packing, high charge carrier mobility, and moderate photoluminescence quantum yields (PLQYs), required for fast optoelectronics. Photophysical properties of PTNT were explored in solution and thin film. Thus, a new strategy to improve the speed of organic light-emitting diodes (OLEDs) using a new class of luminescent polymer with high charge carrier mobilities has been demonstrated [74]. Aqueous nanoparticle dispersions were prepared from PTNT and fullerene blend utilizing chloroform as well as a nonchlorinated and environmentally benign solvent, o-xylene, as the miniemulsion dispersed phase solvent. The nanoparticles (NPs) in the solid-state film were found to coalesce and offered a smooth surface topography upon thermal annealing [75]. Recently, PTNT-conjugated polymer was used as the donor polymer. The preparation of environmentally friendlier polymer solar cell devices [76,77].  (Figure 23), which has a 2-naphthyl group, has been used as an optical DNA biosensor to unravel the inhibitory mechanism of human topoisomerase I activity by blocking enzyme-DNA dissociation [78]. This represents the first characterized example of a small molecule drug that inhibits a post-ligation step of catalysis.   (Figure 23), which has a 2-naphthyl group, has been used as an optical DNA biosensor to unravel the inhibitory mechanism of human topoisomerase I activity by blocking enzyme-DNA dissociation [78]. This represents the first characterized example of a small molecule drug that inhibits a post-ligation step of catalysis.  Figure 22) that offers many favorable properties, such as improved solid-state packing, high charge carrier mobility, and moderate photoluminescence quantum yields (PLQYs), required for fast optoelectronics. Photophysical properties of PTNT were explored in solution and thin film. Thus, a new strategy to improve the speed of organic light-emitting diodes (OLEDs) using a new class of luminescent polymer with high charge carrier mobilities has been demonstrated [74]. Aqueous nanoparticle dispersions were prepared from PTNT and fullerene blend utilizing chloroform as well as a nonchlorinated and environmentally benign solvent, o-xylene, as the miniemulsion dispersed phase solvent. The nanoparticles (NPs) in the solid-state film were found to coalesce and offered a smooth surface topography upon thermal annealing [75]. Recently, PTNT-conjugated polymer was used as the donor polymer. The preparation of environmentally friendlier polymer solar cell devices [76,77].  (Figure 23), which has a 2-naphthyl group, has been used as an optical DNA biosensor to unravel the inhibitory mechanism of human topoisomerase I activity by blocking enzyme-DNA dissociation [78]. This represents the first characterized example of a small molecule drug that inhibits a post-ligation step of catalysis.  The dimmer 98 is quite electron-rich owing to the presence of a 1,2-diaminoethene bridge and is oxidized back to 97 (Scheme 71) within several hours in solution under ambient conditions. Furthermore, 97 possesses a redox-active 1,4-diazabutadiene linkage that is interconvertible with its reduced 1,2-diaminoethene linkage upon treatment of 97 with NaBH 4 or PbO 2 . The dimmer 97 exhibits an intense NIR absorption and narrow HOMO-LUMO gap with a remarkably low reduction potential mainly due to the effective bonding interactions in the LUMO through the 1,4-diazabutadiene linkage. In contrast, the reduced dimmer 98 has high HOMO energy and shows a relative large HOMO-LUMO gap compared to that of 97 [39].
Molecules 2020, 25, x FOR PEER REVIEW 50 of 54 The dimmer 98 is quite electron-rich owing to the presence of a 1,2-diaminoethene bridge and is oxidized back to 97 (Scheme 71) within several hours in solution under ambient conditions. Furthermore, 97 possesses a redox-active 1,4-diazabutadiene linkage that is interconvertible with its reduced 1,2-diaminoethene linkage upon treatment of 97 with NaBH4 or PbO2. The dimmer 97 exhibits an intense NIR absorption and narrow HOMO-LUMO gap with a remarkably low reduction potential mainly due to the effective bonding interactions in the LUMO through the 1,4diazabutadiene linkage. In contrast, the reduced dimmer 98 has high HOMO energy and shows a relative large HOMO-LUMO gap compared to that of 97 [39]. Scheme 71. Redox system of 1,5-naphthyridine-fused porphyrin dimers.
A highly selective and sensitive acridine-base colorimetric sensor 2-((7-chloro-2methoxybenzo[b]1,5]naphthyridine-10-yl)amino)phenol 224 (NAP, Figure 24) was developed for detection of Cu 2+ ions both in aqueous solution and on test papers. Sensor NAP responses to Cu 2+ ions by changing its color from yellow to pink, which could be easily observed by the naked eyes [79].

Conclusions
The contributions published in the last 18 years related to the synthesis and reactivity of the fused 1,5-naphthyridine derivatives were analyzed. According to the data presented, these types of fused heterocycles have attracted great interest, not only for synthetic but also for medicinal chemists.
Some fused 1,5-naphthyridines presented in this review show important biological activity as enzymatic inhibitors with antiproliferative, antiparasitic and antibacterial capacities. Likewise, some polycyclic 1,5-naphthyridines has also been reported as a biological sensor for many techniques. Moreover, some fused heterocycles show applications as light-emitting compounds, CO2 reductors, and hydride donors.
In this sense, this revision could be useful to synthetic and medicinal chemists because of the information related to the synthesis and biological activity of fused 1,5-naphthyridines and, on the other hand, by taking advantage of the electronic and optical properties of the described heterocycles, progress could be made in the development of new technologies.
The dimmer 98 is quite electron-rich owing to the presence of a 1,2-diaminoethene bridge and is oxidized back to 97 (Scheme 71) within several hours in solution under ambient conditions. Furthermore, 97 possesses a redox-active 1,4-diazabutadiene linkage that is interconvertible with its reduced 1,2-diaminoethene linkage upon treatment of 97 with NaBH4 or PbO2. The dimmer 97 exhibits an intense NIR absorption and narrow HOMO-LUMO gap with a remarkably low reduction potential mainly due to the effective bonding interactions in the LUMO through the 1,4diazabutadiene linkage. In contrast, the reduced dimmer 98 has high HOMO energy and shows a relative large HOMO-LUMO gap compared to that of 97 [39]. Scheme 71. Redox system of 1,5-naphthyridine-fused porphyrin dimers.
A highly selective and sensitive acridine-base colorimetric sensor 2-((7-chloro-2methoxybenzo[b]1,5]naphthyridine-10-yl)amino)phenol 224 (NAP, Figure 24) was developed for detection of Cu 2+ ions both in aqueous solution and on test papers. Sensor NAP responses to Cu 2+ ions by changing its color from yellow to pink, which could be easily observed by the naked eyes [79].

Conclusions
The contributions published in the last 18 years related to the synthesis and reactivity of the fused 1,5-naphthyridine derivatives were analyzed. According to the data presented, these types of fused heterocycles have attracted great interest, not only for synthetic but also for medicinal chemists.
Some fused 1,5-naphthyridines presented in this review show important biological activity as enzymatic inhibitors with antiproliferative, antiparasitic and antibacterial capacities. Likewise, some polycyclic 1,5-naphthyridines has also been reported as a biological sensor for many techniques. Moreover, some fused heterocycles show applications as light-emitting compounds, CO2 reductors, and hydride donors.
In this sense, this revision could be useful to synthetic and medicinal chemists because of the information related to the synthesis and biological activity of fused 1,5-naphthyridines and, on the other hand, by taking advantage of the electronic and optical properties of the described heterocycles, progress could be made in the development of new technologies.

Conflicts of Interest:
The authors declare no conflict of interest.

Conclusions
The contributions published in the last 18 years related to the synthesis and reactivity of the fused 1,5-naphthyridine derivatives were analyzed. According to the data presented, these types of fused heterocycles have attracted great interest, not only for synthetic but also for medicinal chemists.
Some fused 1,5-naphthyridines presented in this review show important biological activity as enzymatic inhibitors with antiproliferative, antiparasitic and antibacterial capacities. Likewise, some polycyclic 1,5-naphthyridines has also been reported as a biological sensor for many techniques. Moreover, some fused heterocycles show applications as light-emitting compounds, CO 2 reductors, and hydride donors.
In this sense, this revision could be useful to synthetic and medicinal chemists because of the information related to the synthesis and biological activity of fused 1,5-naphthyridines and, on the other hand, by taking advantage of the electronic and optical properties of the described heterocycles, progress could be made in the development of new technologies.