Pyrazolylbenzo[d]imidazoles as new potent and selective inhibitors of carbonic anhydrase isoforms hCA IX and XII

Satish Kumar; Mariangela Ceruso; Tiziano Tuccinardi; Claudiu T Supuran; Pawan K Sharma

doi:10.1016/j.bmc.2016.04.061

Pyrazolylbenzo[d]imidazoles as new potent and selective inhibitors of carbonic anhydrase isoforms hCA IX and XII

Bioorg Med Chem. 2016 Jul 1;24(13):2907-2913. doi: 10.1016/j.bmc.2016.04.061. Epub 2016 Apr 28.

Authors

Satish Kumar¹, Mariangela Ceruso², Tiziano Tuccinardi³, Claudiu T Supuran⁴, Pawan K Sharma⁵

Affiliations

¹ Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India.
² Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm 188, and Neurofarba Department, Sezione di Scienze Farmaceutiche, Via U. Schiff 6, I-50019 Sesto Fiorentino (Firenze), Italy.
³ Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
⁴ Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm 188, and Neurofarba Department, Sezione di Scienze Farmaceutiche, Via U. Schiff 6, I-50019 Sesto Fiorentino (Firenze), Italy. Electronic address: claudiu.supuran@unifi.it.
⁵ Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India. Electronic address: pksharma@kuk.ac.in.

PMID: 27166574
DOI: 10.1016/j.bmc.2016.04.061

Abstract

Novel pyrazolylbenzo[d]imidazole derivatives (2a-2f) were designed, synthesized and evaluated against four human carbonic anhydrase isoforms belonging to α family comprising of two cytosolic isoforms hCA I and II as well as two transmembrane tumor associated isoforms hCA IX and XII. Starting from these derivatives that showed high potency but low selectivity in favor of tumor associated isoforms hCA IX and XII, we investigated the impact of removing the sulfonamide group. Thus, analogs 3a-3f without sulfonamide moiety were synthesized and biological assay revealed a good activity as well as an excellent selectivity as inhibitors for tumor associated hCA IX and hCA XII and the same was analyzed by molecular docking studies.

Keywords: Acetazolamide; Carbonic anhydrase isoforms; Inhibition constant (K(i)); Pyrazolylbenzo[d]imidazoles.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Biological Assay
Carbonic Anhydrase IX / chemistry
Carbonic Anhydrase IX / metabolism*
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / chemistry
Carbonic Anhydrases / metabolism*
Enzyme Activation / drug effects
Humans
Imidazoles / chemical synthesis
Imidazoles / pharmacology*
Molecular Docking Simulation*
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / metabolism
Sulfonamides / chemistry

Substances

Antineoplastic Agents
Carbonic Anhydrase Inhibitors
Imidazoles
Protein Isoforms
Sulfonamides
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII