Benzenesulfonamide bearing 1,2,4-triazole scaffolds as potent inhibitors of tumor associated carbonic anhydrase isoforms hCA IX and hCA XII

SitaRam; Gulsah Celik; Poonam Khloya; Daniela Vullo; Claudiu T Supuran; Pawan K Sharma

doi:10.1016/j.bmc.2014.01.055

Benzenesulfonamide bearing 1,2,4-triazole scaffolds as potent inhibitors of tumor associated carbonic anhydrase isoforms hCA IX and hCA XII

Bioorg Med Chem. 2014 Mar 15;22(6):1873-82. doi: 10.1016/j.bmc.2014.01.055. Epub 2014 Feb 7.

Authors

SitaRam¹, Gulsah Celik², Poonam Khloya¹, Daniela Vullo³, Claudiu T Supuran⁴, Pawan K Sharma⁵

Affiliations

¹ Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India.
² Chemistry Department, Balıkesir University, 10145 Balıkesir, Turkey.
³ Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
⁴ Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy; Università degli Studi di Firenze, Neurofarba Dept., Section of Pharmaceutical and Nutraceutical Sciences, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.
⁵ Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India. Electronic address: pksharma@kuk.ac.in.

PMID: 24560737
DOI: 10.1016/j.bmc.2014.01.055

Abstract

Three series of novel heterocyclic compounds (3a-3g, 4a-4g and 5a-5g) containing benzenesulfonamide moiety and incorporating a 1,2,4-triazole ring, have been synthesized and investigated as inhibitors against four isomers of the α-class carbonic anhydrases (CAs, EC 4.2.1.1), comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor associated isozymes). Against the human isozymes hCA I and II, compounds of two series (3a-3g and 4a-4g) showed Ki values in the range of 84-868 nM and 5.6-390 nM, respectively whereas compounds of series 5a-5g were found to be poor inhibitors (Ki values exceeding 10,000 nM in some cases). Against hCA IX and XII, all the tested compounds exhibited excellent to moderate inhibitory potential with Ki values in the range of 2.8-431 nM and 1.3-63 nM, respectively. Compounds 3d, 3f and 4f exhibited excellent inhibitory potential against all of the four isozymes hCA I, II, IX and XII, even better than the standard drug acetazolamide (AZA) whereas compound of the series 5a-5g were comparatively less potent but more selective towards hCA IX and XII.

Keywords: Acetazolamide; Benzenesulfonamide; Carbonic anhydrase isoforms I, II, IX, XII; Triazoles.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzenesulfonamides
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Dose-Response Relationship, Drug
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Molecular Structure
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Triazoles / chemistry*

Substances

Carbonic Anhydrase Inhibitors
Isoenzymes
Sulfonamides
Triazoles
1,2,4-triazole
Carbonic Anhydrases