Enaminone-based carboxylic acids as novel non-classical carbonic anhydrases inhibitors: design, synthesis and <i>in vitro</i> biological assessment

Abstract

In searching for new molecular drug targets, Carbonic Anhydrases (CAs) have emerged as valuable targets in diverse diseases. CAs play critical functions in maintaining pH and CO₂ homeostasis, metabolic pathways, and much more. So, it is becoming attractive for medicinal chemists to design novel inhibitors for this class of enzymes with improved potency and selectivity towards the different isoforms. In the present study, three sets of carboxylic acid derivatives <b>5a-q</b>, <b>7a-b</b> and <b>12a-c</b> were designed, developed and evaluated for the hCA inhibitory effects against hCA I, II, IX and XII. Compounds <b>5l, 5m,</b> and <b>5q</b> elicited the highest inhibitory activities against hCA II, IX and XII. In summary, structural rigidification, regioisomerism and structural extension, all played obvious roles in the degree of hCA inhibition. This present work could be a good starting point for the design of more non-classical selective hCA inhibitors as potential targets for several diseases.