New 7-hydroxycoumarin acetamide derivatives as human carbonic anhydrase IX and XII inhibitors: Design, synthesis, biological evaluation and molecular docking studies

Abstract

Carbonic anhydrases (CAs) are crucial in regulating various physiological processes in the body. The overexpression of isoforms human carbonic anhydrases (hCA) IX and hCA XII is linked to tumour progression. The selective inhibition of CA IX and CA XII isoforms can result in the development of better cancer treatment strategies. The tail approach based on coumarin derivatives was known for selective inhibition of isoforms IX and XII. This study explores the potential of coumarin derivatives (7a–k, 8a–s and 9a–g) as selective hCA IX and hCA XII inhibitors. The synthesised derivatives exhibited potent and selective inhibition towards hCA IX and XII, with K_i values in the range of 0.58‒3.33 µM and 0.48‒2.59 µM, respectively. The oxime ether derivative 7d was found to be the most potent one against hCA IX, with a K_i value of 0.58 µM, and phenyl hydrazine derivative 8a, with a K_i value of 0.48 µM against hCA XII, was the most potent one among the synthesised molecules. The potent isoform-specific carbonic anhydrase IX and XII inhibition suggests that 7d and 8a can be taken further towards the development of potent anticancer agents.