Pyrazolylbenzo[d]imidazoles as new potent and selective inhibitors of carbonic anhydrase isoforms hCA IX and XII

• 12 novel pyrazolylbenzo[d]imidazoles were designed and synthesized.
• Their inhibition potential was evaluated against hCA I, II, IX and XII.
• Compounds having sulfonamide moiety were better inhibitors with poor selectivity.
• Selectivity against tumor isoforms hCA IX abd XII enhanced on removing sulfonamide.
• Inhibition results were promising as compared to antitumor drug acetazolamide.

Novel pyrazolylbenzo[d]imidazole derivatives (2a–2f) were designed, synthesized and evaluated against four human carbonic anhydrase isoforms belonging to α family comprising of two cytosolic isoforms hCA I and II as well as two transmembrane tumor associated isoforms hCA IX and XII. Starting from these derivatives that showed high potency but low selectivity in favor of tumor associated isoforms hCA IX and XII, we investigated the impact of removing the sulfonamide group. Thus, analogs 3a–3f without sulfonamide moiety were synthesized and biological assay revealed a good activity as well as an excellent selectivity as inhibitors for tumor associated hCA IX and hCA XII and the same was analyzed by molecular docking studies.

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