New Dihydrothiazole Benzensulfonamides: Looking for Selectivity toward Carbonic Anhydrase Isoforms I, II, IX, and XII.

Rita Meleddu,Andrea Angeli,Stefano Alcaro,Simona Distinto,Pierluigi Caboni,Filippo Cottiglia,Rossella Angius,Elias Maccioni,Claudia Melis,Serenella Deplano,Claudiu T Supuran,Francesco Ortuso

doi:10.1021/acsmedchemlett.9b00644

Abstract

In the present study we investigated the structure-activity relationships of a new series of 4-[(3-ethyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides (EMAC10101a-m). All synthesized compounds, with the exception of compound EMAC10101k, preferentially inhibit off-target hCA II isoform. Within the series, compound EMAC10101d, bearing a 2,4-dichorophenyl substituent in position 4 of the dihydrothiazole ring, was the most potent and selective toward hCA II with an inhibitory activity in the low nanomolar range.

Highlights

In the present study we investigated the structure− activity relationships of a new series of 4-[(3-ethyl-4-aryl-2,3dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides (EMAC10101a−m)
Most of CAs inhibitors (CAIs) are generally characterized by a zinc-binding group (ZBG), which could be a sulfonamide or a bioisoster
The ZBG is often linked to a scaffold capable of interacting with one or both hydrophobic and hydrophilic halves of the active site and by a tail that may interact with the most variable sites of the enzyme such as the entrance of the cavity, enhancing the isoform selectivity profile of CA inhibitors.[25]

Summary

Introduction

In the present study we investigated the structure− activity relationships of a new series of 4-[(3-ethyl-4-aryl-2,3dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides (EMAC10101a−m). All the obtained compounds were characterized by means of analytical and spectroscopic methods (Figures S1−S39 and Tables S1−S3) and submitted to biological evaluation to assess their activity against hCA I, II, IX, and XII (Table 1).

Results

Conclusion