Synthesis, biological evaluation and computational studies of novel iminothiazolidinone benzenesulfonamides as potent carbonic anhydrase II and IX inhibitors

Shams-Ul Mahmood; Aamer Saeed; Sivia Bua; Alessio Nocentini; Paola Gratteri; Claudiu T Supuran

doi:10.1016/j.bioorg.2018.01.031

Synthesis, biological evaluation and computational studies of novel iminothiazolidinone benzenesulfonamides as potent carbonic anhydrase II and IX inhibitors

Bioorg Chem. 2018 Apr:77:381-386. doi: 10.1016/j.bioorg.2018.01.031. Epub 2018 Jan 31.

Authors

Shams-Ul Mahmood¹, Aamer Saeed², Sivia Bua³, Alessio Nocentini⁴, Paola Gratteri⁵, Claudiu T Supuran³

Affiliations

¹ Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
² Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan. Electronic address: aamersaeed@yahoo.com.
³ Università degli Studi di Firenze, Department NEUROFARBA - Pharmaceutical and Nutraceutical Section, University of Firenze, via Ugo Schiff 6, I-50019 Sesto Fiorentino, Firenze, Italy.
⁴ Università degli Studi di Firenze, Department NEUROFARBA - Pharmaceutical and Nutraceutical Section, University of Firenze, via Ugo Schiff 6, I-50019 Sesto Fiorentino, Firenze, Italy; Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy. Electronic address: alessio.nocentini@unifi.it.
⁵ Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.

PMID: 29421714
DOI: 10.1016/j.bioorg.2018.01.031

Abstract

A series of iminothiazolidinone-sulfonamide hybrids (2a-k) was synthesized by heterocyclization of sulfanilamide thioureas with methyl bromoacetate and characterized by spectroscopic techniques, mass and elemental analysis. The synthesized derivatives were screened against four relevant human (h) isoforms of carbonic anydrases (CAs, EC 4.2.1.1) I, II, IV and IX. These enzymes are involved in a variety of diseases, including glaucoma, retinitis pigmentosa, epilepsy, arthritis, and tumors. Derivatives 2a-2k exhibited the best inhibitory activity against the cytosolyc hCA II (K_Is are reaching the sub-nanomolar range, 0.41-37.8 nM) and against the tumor-associated isoform hCA IX (K_Is are spanning between 24.3 and 368.3 nM). The binding mode of the reported iminothiazolidinone benzenesulfonamides within hCA II and IX catalytic clefts was investigated by docking studies.

Keywords: Anti-glaucoma; Anti-tumour; Carbonic anhydrase; Nanomolar inhibition; Zinc-binding group.

MeSH terms

Antigens, Neoplasm / genetics
Antigens, Neoplasm / metabolism
Benzenesulfonamides
Benzenesulfonates / chemical synthesis
Benzenesulfonates / chemistry
Benzenesulfonates / pharmacology*
Biocatalysis
Carbonic Anhydrase II / antagonists & inhibitors*
Carbonic Anhydrase II / genetics
Carbonic Anhydrase II / metabolism
Carbonic Anhydrase IX / antagonists & inhibitors*
Carbonic Anhydrase IX / genetics
Carbonic Anhydrase IX / metabolism
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Humans
Molecular Docking Simulation*
Molecular Structure
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Thiazolidines / chemical synthesis
Thiazolidines / chemistry
Thiazolidines / pharmacology*

Substances

Antigens, Neoplasm
Benzenesulfonates
Carbonic Anhydrase Inhibitors
Sulfonamides
Thiazolidines
Carbonic Anhydrase II
CA9 protein, human
Carbonic Anhydrase IX