Development of Novel Indole-3-sulfonamide-heteroaryl Hybrids as Carbonic Anhydrase Inhibitors: Design, Synthesis and in-vitro Screening

Background: Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. Inhibition of isoforms IX and XII has induced potent anticancer effects. Objective: A series of indole-3-sulfonamide-heteroaryl hybrid (6a-y) was synthesized and screened for the inhibition of human (h) hCA isoforms I, II, IX, and XII. Methods: The synthesis of target compounds (6a-y) was carried out in multistep starting from 5-nitro indole as starting material by using classical reported reaction conditions. The steps involved are N-Alkylation Chlorosulfonation, amination, reduction, and finally amidation reaction. Results: Amongst all the compounds (6a-y) synthesized and screened, 6l was found to be active against all the screened hCA isoforms, with Ki ranging 8.03 μM, 4.15 μM, 7.09 μM, and 4.06 μM respectively. On the other hand, 6i, 6j, 6q, 6s, and 6t were highly selective against tumor-associated hCA IX, and 6u was selective against both hCA II and hCA IX with moderate inhibitory activities under the range of 100 μM. These compounds showed good activity against the tumor-associated hCA IX and might be developed as future drug leads for anticancer drug discovery. Conclusion: These compounds may be useful as starting points for the design and development of more selective and potent hCA IX and XII inhibitors.