Benzenesulfonamide bearing imidazothiadiazole and thiazolotriazole scaffolds as potent tumor associated human carbonic anhydrase IX and XII inhibitors

Rajiv Kumar; Silvia Bua; Sita Ram; Sonia Del Prete; Clemente Capasso; Claudiu T Supuran; Pawan K Sharma

doi:10.1016/j.bmc.2016.12.047

Benzenesulfonamide bearing imidazothiadiazole and thiazolotriazole scaffolds as potent tumor associated human carbonic anhydrase IX and XII inhibitors

Bioorg Med Chem. 2017 Feb 1;25(3):1286-1293. doi: 10.1016/j.bmc.2016.12.047. Epub 2016 Dec 29.

Authors

Rajiv Kumar¹, Silvia Bua², Sita Ram¹, Sonia Del Prete³, Clemente Capasso⁴, Claudiu T Supuran⁵, Pawan K Sharma⁶

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 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; Istituto di Bioscienze e Biorisorse, CNR, Via PietroCastellino 111, 80131 Napoli, Italy.
⁴ Istituto di Bioscienze e Biorisorse, CNR, Via PietroCastellino 111, 80131 Napoli, Italy.
⁵ 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: [email protected].
⁶ Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India. Electronic address: [email protected].

PMID: 28065499
DOI: 10.1016/j.bmc.2016.12.047

Abstract

Two series of 20 novel heterocyclic compounds, imidazothiadiazoles (3a-3j) and thiazolotriazoles (4a-4j) bearing benzenesulfonamide moiety were synthesized in order to investigate the inhibition potential of both scaffolds against four selected human carbonic anhydrase isoforms (hCA I, II, IX & XII). Against human isoform hCA I, compounds 3j, 4a-4c, and 4j showed better inhibition potential (K_i<100nM) than the standard drug acetazolamide (AZA). Against hCA II, all the compounds showed moderate inhibition with the exception of 3a which showed nearly two fold better profile compared to AZA. Against hCA IX, all the compounds showed moderate inhibitory potential than AZA, whereas against hCA XII, compounds 3a-3c showed better inhibitory potential compared to AZA.

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

Publication types

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

MeSH terms

Antigens, Neoplasm / metabolism
Carbonic Anhydrase IX / antagonists & inhibitors*
Carbonic Anhydrase IX / metabolism
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Humans
Models, Molecular
Molecular Structure
Neoplasms / enzymology*
Structure-Activity Relationship

Substances

Antigens, Neoplasm
Carbonic Anhydrase Inhibitors
CA9 protein, human
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII