Novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiazolidin-2-ylidene) amino) benzenesulfonamides: Synthesis, carbonic anhydrase inhibitory activity, anticancer activity and molecular modelling studies

Herein we report the synthesis of two series of novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiazolidin-2-ylidene)amino)benzenesulfonamides (4a-m and 7a-g). All the newly prepared sulfonamides were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. In particular, hCA isoforms II and IX (tumor associated) were more susceptible to inhibition by the synthesized derivatives, with K(1)s in the range of 2.6-598.2 nM for hCA II, and of 16.1-321 nM for hCA IX. All compounds (4a-m and 7a-g) were evaluated for their anti-proliferative activity against breast cancer MCF-7 and colorectal cancer Caco-2 cell lines. Compound 4c was found to be the most potent derivative against MCF-7 (IC50 = 3.96 +/- 0.21 mu M), while 4j was the most active member against Caco-2 cells (IC50 = 5.87 +/- 0.37 mu M). Compound 4c induced the intrinsic apoptotic mitochondrial pathway in MCF-7 cells; evidenced by the enhanced expression of the pro-apoptotic protein Bax and the reduced expression of the anti-apoptotic protein Bc1-2, and the up regulated active caspase-9 and caspase-3 levels. (C) 2017 Elsevier Masson SAS. All rights reserved.