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Int J Mol Sci. 2018 Aug 7;19(8). pii: E2318. doi: 10.3390/ijms19082318.

Synthesis and Spectrum of Biological Activities of Novel N-arylcinnamamides.

Author information

1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojarov 10, 83232 Bratislava, Slovakia. sharka.pospisilova@gmail.com.
2
Department of Infectious Diseases and Microbiology, Faculty of Veterinary Medicine, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 61242 Brno, Czech Republic. sharka.pospisilova@gmail.com.
3
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojarov 10, 83232 Bratislava, Slovakia. jirikos85@gmail.com.
4
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojarov 10, 83232 Bratislava, Slovakia. michnova.hana@gmail.com.
5
Department of Infectious Diseases and Microbiology, Faculty of Veterinary Medicine, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 61242 Brno, Czech Republic. michnova.hana@gmail.com.
6
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojarov 10, 83232 Bratislava, Slovakia. kapustikova@fpharm.uniba.sk.
7
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojarov 10, 83232 Bratislava, Slovakia. strharsky2@uniba.sk.
8
Global Change Research Institute CAS, Belidla 986/4a, 60300 Brno, Czech Republic. oravec.m@czechglobe.cz.
9
Plant Protection Institute, Centre for Agricultural Research, Hungarian Academy of Sciences, Herman Otto Str. 15, 1022 Budapest, Hungary. moricz.agnes@agrar.mta.hu.
10
Plant Protection Institute, Centre for Agricultural Research, Hungarian Academy of Sciences, Herman Otto Str. 15, 1022 Budapest, Hungary. bakonyi.jozsef@agrar.mta.hu.
11
Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 61242 Brno, Czech Republic. tereza.kauerova@gmail.com.
12
Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 61242 Brno, Czech Republic. kollarp@vfu.cz.
13
Department of Infectious Diseases and Microbiology, Faculty of Veterinary Medicine, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 61242 Brno, Czech Republic. cizeka@vfu.cz.
14
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojarov 10, 83232 Bratislava, Slovakia. josef.jampilek@gmail.com.

Abstract

: A series of sixteen ring-substituted N-arylcinnamamides was prepared and characterized. Primary in vitro screening of all the synthesized compounds was performed against Staphylococcus aureus, three methicillin-resistant S. aureus strains, Mycobacterium tuberculosis H37Ra, Fusarium avenaceum, and Bipolaris sorokiniana. Several of the tested compounds showed antistaphylococcal, antitubercular, and antifungal activities comparable with or higher than those of ampicillin, isoniazid, and benomyl. (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-phenylprop-2-enamide and (2E)-3-phenyl-N-[3-(trifluoromethyl)phenyl]prop-2-enamide showed the highest activities (MICs = 22.27 and 27.47 µM, respectively) against all four staphylococcal strains and against M.tuberculosis. These compounds showed an activity against biofilm formation of S.aureus ATCC 29213 in concentrations close to MICs and an ability to increase the activity of clinically used antibiotics with different mechanisms of action (vancomycin, ciprofloxacin, and tetracycline). In time-kill studies, a decrease of CFU/mL of >99% after 8 h from the beginning of incubation was observed. (2E)-N-(3,5-Dichlorophenyl)- and (2E)-N-(3,4-dichlorophenyl)-3-phenylprop-2-enamide had a MIC = 27.38 µM against M. tuberculosis, while a significant decrease (22.65%) of mycobacterial cell metabolism determined by the MTT assay was observed for the 3,5-dichlorophenyl derivative. (2E)-N-(3-Fluorophenyl)- and (2E)-N-(3-methylphenyl)-3-phenylprop-2-enamide exhibited MICs = 16.58 and 33.71 µM, respectively, against B. sorokiniana. The screening of the cytotoxicity of the most effective antimicrobial compounds was performed using THP-1 cells, and these chosen compounds did not shown any significant lethal effect. The compounds were also evaluated for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. (2E)-N-(3,5-dichlorophenyl)-3-phenylprop-2-enamide (IC50 = 5.1 µM) was the most active PET inhibitor. Compounds with fungicide potency did not show any in vivo toxicity against Nicotiana tabacum var. Samsun. The structure⁻activity relationships are discussed.

KEYWORDS:

MTT assay; PET inhibition; antifungal activity; antistaphylococcal activity; antitubercular activity; biofilm; cinnamamides; structure–activity relationship; time-kill assay; toxicity

PMID:
30087309
PMCID:
PMC6121455
DOI:
10.3390/ijms19082318
[Indexed for MEDLINE]
Free PMC Article

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