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Eur J Med Chem. 2015 Aug 28;101:334-47. doi: 10.1016/j.ejmech.2015.06.022. Epub 2015 Jun 25.

Probing the 'bipolar' nature of the carbonic anhydrase active site: aromatic sulfonamides containing 1,3-oxazol-5-yl moiety as picomolar inhibitors of cytosolic CA I and CA II isoforms.

Author information

1
Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii Prospect, Peterhof, 198504, Russian Federation. Electronic address: m.krasavin@spbu.ru.
2
The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl, 150000, Russian Federation.
3
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy.
4
Neurofarba Dept., Section of Pharmaceutical Sciences, Universita degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
5
Neurofarba Dept., Section of Pharmaceutical Sciences, Universita degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.

Abstract

A series of potent inhibitors of human carbonic anhydrase (CA) isoforms I and II has been prepared via a direct, chemoselective sulfochlorination of a range of 1,3-oxazolyl benzenes and thiophenes, followed by primary sulfonamide synthesis. The latter functionality is a known zinc-binding group (ZBG) responsible for anchoring the inhibitors to the CA's zinc metal ion. The compound's periphery as well as the overall scaffold geometry was designed to enable optimal interactions with the two distinct sides of the enzyme's active site, one of which is lined with hydrophobic residues and while the other is predominantly hydrophilic. As a result, several compounds inhibiting the therapeutically important cytosolic CA I and CA II in picomolar range have been identified. These compounds are one of the most potent CA inhibitors identified to-date. Not only the remarkable (>10 000-fold), cytosolic CA I and CA II selectivity vs. the membrane-bound CA IX and CA XII isoforms, but also the pronounced CA II/I selectivity observed in some cases, allow considering this series as a set of isoform-selective chemical biology tools and promising starting points for drug candidate development.

KEYWORDS:

1,3-oxadiazol-5-yl aromatics; Anti-glaucoma drugs; Carbonic anhydrase inhibitors; Chemoselective sulfochlorination; Drug discovery; Isoform selectivity

PMID:
26160114
DOI:
10.1016/j.ejmech.2015.06.022
[Indexed for MEDLINE]

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