5-Substituted-benzylsulfanyl-thiophene-2-sulfonamides with effective carbonic anhydrase inhibitory activity: Solution and crystallographic investigations

Jekaterīna Ivanova; Agnese Balode; Raivis Žalubovskis; Janis Leitans; Andris Kazaks; Daniela Vullo; Kaspars Tars; Claudiu T Supuran

doi:10.1016/j.bmc.2016.11.045

5-Substituted-benzylsulfanyl-thiophene-2-sulfonamides with effective carbonic anhydrase inhibitory activity: Solution and crystallographic investigations

Bioorg Med Chem. 2017 Feb 1;25(3):857-863. doi: 10.1016/j.bmc.2016.11.045. Epub 2016 Nov 25.

Authors

Jekaterīna Ivanova¹, Agnese Balode¹, Raivis Žalubovskis², Janis Leitans³, Andris Kazaks³, Daniela Vullo⁴, Kaspars Tars⁵, Claudiu T Supuran⁶

Affiliations

¹ Latvian Institute of Organic Synthesis, 21 Aizkraukles Str., Riga LV-1006, Latvia; Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, 3/7 Paula Valdena Str., Riga LV-1048, Latvia.
² Latvian Institute of Organic Synthesis, 21 Aizkraukles Str., Riga LV-1006, Latvia. Electronic address: raivis@osi.lv.
³ Latvian Biomedical Research and Study Center, Rātsupītes 1, LV-1067 Riga, Latvia.
⁴ Università degli Studi di Firenze, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
⁵ Latvian Biomedical Research and Study Center, Rātsupītes 1, LV-1067 Riga, Latvia; Faculty of Biology, Department of Molecular Biology, University of Latvia, Jelgavas 1, LV1004 Riga, Latvia.
⁶ Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di ScienzeFarmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 28024887
DOI: 10.1016/j.bmc.2016.11.045

Abstract

A series of 5-substituted-benzylsulfanyl-thiophene-2-sulfonamides was prepared by reacting 5-bromo-thiophene-2-sulfonamide with 5-substituted-benzyl mercaptans. The new compounds were investigated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The cytosolic human (h) isoforms hCA I was poorly inhibited by the new sulfonamides (K_Is in the range of 683-4250nM), whereas hCA II, and the transmembrane, tumor associated isoforms hCA IX and XII were effectively inhibited in the subnanomolar-nanomolar range. A high resolution X-ray crystal structure of the adduct of hCA II with one of the new sulfonamides allowed us to rationalize the excellent inhibitory activity of these heterocyclic sulfonamides.

Keywords: Carbonic anhydrase; Inhibitor; Mercaptan; Thiophene-2-sulfonamide.

Publication types

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

MeSH terms

Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Crystallography, X-Ray
Dose-Response Relationship, Drug
Humans
Models, Molecular
Molecular Structure
Solutions
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Thiophenes / chemical synthesis
Thiophenes / chemistry
Thiophenes / pharmacology*

Substances

Carbonic Anhydrase Inhibitors
Solutions
Sulfonamides
Thiophenes
Carbonic Anhydrases