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Eur J Med Chem. 2015 Sep 18;102:223-32. doi: 10.1016/j.ejmech.2015.07.049. Epub 2015 Jul 31.

Carbonic anhydrase inhibitors: Design, synthesis and structural characterization of new heteroaryl-N-carbonylbenzenesulfonamides targeting druggable human carbonic anhydrase isoforms.

Author information

1
Dipartimento Scienze del Farmaco e dei Prodotti per la salute, Università degli Studi di Messina, Viale Annunziata, I-98168 Messina, Italy.
2
Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, Università degli Studi di Firenze, Sesto Fiorentino (Florence), Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
3
Institute of Molecular Genetics, ASCR, v.v.i., Vídeňská 1083, Prague 4, 14220, Czech Republic.
4
Institute of Molecular Genetics, ASCR, v.v.i., Vídeňská 1083, Prague 4, 14220, Czech Republic; Institute of Organic Chemistry and Biochemistry, ASCR, v.v.i., Flemingovo nám. 2, Prague 6, 16610, Czech Republic.
5
Dipartimento Scienze del Farmaco e dei Prodotti per la salute, Università degli Studi di Messina, Viale Annunziata, I-98168 Messina, Italy. Electronic address: rgitto@unime.it.

Abstract

A set of heteroaryl-N-carbonylbenzenesulfonamides has been designed, synthesized, and screened as inhibitors of human carbonic anhydrases (hCAs). The new sulfonamide derivatives were tested against hCA I, hCA II, hCA VII, hCA IX, and hCA XII isoforms using acetazolamide (AAZ, 1) and topiramate (TPM, 2) as reference compounds. Six compounds were low nanomolar inhibitors of tumor-associated hCA IX isoform (Ki values < 10 nM); among them we identified three arylsulfonamides showing unexpected inefficacy over brain distributed hCA VII isoform (hCA IX/hCA VII selectivity ratio > 1500 for compound 5c). Thus, these compounds can offer the opportunity to highlight the interactions preventing the inhibition of hCA VII mainly expressed in central nervous system. Thereby, we used structural and computational techniques to study in depth the interaction with hCAs. In an effort to confirm the inhibitory action we determined crystal structures of five selected heteroaryl-N-carbonylbenzenesulfonamides (4a, 4b, 4e, 5c, and 5e) in complex with hCA II. Moreover, to explore the lack of inhibitory effects of selected compounds (e.g.4b and 5c) we also performed docking studies into hCA VII catalytic site.

KEYWORDS:

Human carbonic anhydrase; Isoquinoline; Molecular docking; Quinoline; X-ray

PMID:
26276436
DOI:
10.1016/j.ejmech.2015.07.049
[Indexed for MEDLINE]

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