Novel hydrazido benzenesulfonamides-isatin conjugates: Synthesis, carbonic anhydrase inhibitory activity and molecular modeling studies

As a part of our ongoing efforts towards developing novel carbonic anhydrase inhibitors based on the isatin moiety, herein we report the synthesis and biological evaluation of novel sulfonamides (5a-h, 10a-g and 11a-c) incorporating substituted 2-indolinone moiety (as tail) linked to benzenesulfonamide (as zinc anchoring moiety) through a hydrazide linker. The synthesized sulfonamides were evaluated in vitro for their inhibitory activity against the following human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII. All these isoforms were inhibited by the sulfonamides reported here in variable degrees. hCA I was inhibited with KIs in the range of 671.8: 3549.5 nM, hCA II in the range of 36.8: 892.4 nM; hCA IX in the range of 8.9: 264.5 nM, whereas hCA XII in the range of 9.0: 78.1 nM. In particular, compound 10b emerged as a single-digit nanomolar hCA IX and XII inhibitor (8.9 and 9.2 nM, respectively). Molecular docking studies carried out for compound 10b within the hCA II, IX and XII active sites allowed us to rationalize the obtained inhibition results. (C) 2018 Elsevier Masson SAS. All rights reserved.