Design, synthesis, molecular modelling investigation and biological studies of novel human carbonic anhydrase inhibitors based on coumalic acid

The present study provides the design, synthesis, molecular modelling investigation and biological evaluation of a series of coumalic acid-based selective inhibitors of hCA IX and XII. Based on the previously obtained results with carboxamide analogues of coumalic acid, here we explored some modifications of the original scaffold with the aim to expand our knowledge about these compounds and to promote structure–activity relationship (SAR) studies. Structural modifications as lactone-to-lactam conversion, repositioning of the carboxylic acid moiety, and the introduction of ester or amidic linkers, as well as triazole-based elongation via click chemistry have been performed. The synthesised compounds were tested for their inhibitory activities against hCA I, II, IX, and XII showing the lactone moiety to be crucial for inhibitory potency. Particularly, ester derivatives demonstrated selectivity for hCA IX and XII, with certain compounds exhibiting micromolar affinities. Notably, compound 8, featuring a bromine substitution, displayed the highest selectivity and potency against hCA IX and XII. Molecular docking studies further elucidated the binding mechanisms, revealing that the lactone ring hydrolysis plays a significant role in the inhibition process. These results offer valuable insights into the structure–activity relationships (SAR) of coumalic acid analogues and support their further biological investigation for cancer therapy by targeting hCA IX and XII.