Discovery of indolylchalcone benzenesulfonamides as selective inhibitors of tumor-associated carbonic anhydrase IX and XII.

Indole, characterized by its favorable bioavailability, unique structural attributes, and a broad pharmacological profile, represents a privileged scaffold in anticancer drug discovery. Chalcones constitute another important scaffold in medicinal chemistry and numerous chalcone derivatives have been reported to exhibit diverse biological activities, including anticancer and enzyme inhibitory effects. Several chalcone-based compounds have also been investigated as carbonic anhydrase inhibitors. Sulfonamides are a classical class of carbonic anhydrase (CA, EC 4.2.1.1) inhibitors with diverse therapeutic relevance, being employed as diuretics, anticonvulsants, topical antiglaucoma agents and in the management of obesity and cancer. Herein, we designed and synthesized a novel series of indolylchalcone-benzenesulfonamide hybrids (15a-m and 16a-d) and evaluated their inhibitory activities against a panel of four human carbonic anhydrases (hCA isoforms I, II, IX and XII). Interestingly, most of the tested compounds inhibited the tumor-associated hCA IX and XII isoforms with single- to double-digit nanomolar inhibition constants (K