Discovery of new 6-ureido/amidocoumarins as highly potent and selective inhibitors for the tumour-relevant carbonic anhydrases IX and XII

Abstract

A series of 6-ureido/amidocoumarins (<b>5a-p</b> and <b>7a-c</b>) has been designed and synthesised to develop potent and isoform- selective carbonic anhydrase <i>h</i>CA XI and XII inhibitors. All coumarin derivatives were investigated for their CA inhibitory effect against <i>h</i>CA I, II, IX, and XII. Interestingly, target coumarins potently inhibited both tumour-related isoforms <i>h</i>CA IX (<i>K</i>_Is: 14.7-82.4 nM) and <i>h</i>CA XII (<i>K</i>_Is: 5.9-95.1 nM), whereas the cytosolic off-target <i>h</i>CA I and II isoforms have not inhibited by all tested coumarins up to 100 μM. These findings granted the target coumarins an excellent selectivity profile towards both <i>h</i>CA IX and <i>h</i>CA XII isoforms, supporting their development as promising anticancer candidates. Moreover, all target molecules were evaluated for their anticancer activities against HCT-116 and MCF-7 cancer cells. The 3,5-bis-trifluoromethylphenyl ureidocoumarin <b>5i</b>, exerted the best anticancer activity. Overall, ureidocoumarins, particularly compound <b>5i,</b> could serve as a promising prototype for the development of potent anticancer CAIs.