Coumarin and Piperazine Conjugates as Selective Inhibitors of the Tumor-associated Carbonic Anhydrase IX and XII Isoforms

Background: Carbonic Anhydrases (CAs) are a family of metalloenzymes that catalyze the reversible interconversion of CO2 and water to bicarbonate and proton. CA isoforms I, II, IX, and XII are considered physiologically and pharmacologically relevant. Objective: The objective of this study is to synthesize potent and selective tumor-associated CA IX and XII inhibitors. Methods: A library of 17 coumarin derivatives clubbed with piperazine and benzyl moiety was designed, synthesized and evaluated for its inhibitory effects and selectivity profile towards physiologically and pharmacologically relevant CA isoforms I, II, IX, and XII. Results: All the derivatives were found to be active against the tumor-associated isoforms IX and XII. The most active compound against hCA (human Carbonic Anhydrase) IX was found to possess a Ki of 229 nM, while the one against hCA XII had a Ki of 294.2 nM. Additionally, two of the compounds were found to have exquisite selectivity towards the off-target hCA I and II isoforms. Moreover, they were found to be approximately 20-fold more selective towards hCA IX than XII. The selectivity of the compounds was further investigated via molecular modeling techniques. Conclusion: Coumarin-piperazine hybrids were identified as potent and selective CA IX and XII inhibitors. Molecular modeling techniques provided interesting cues pertaining to observed selectivity.