Discovery of 2,4-thiazolidinedione-tethered coumarins as novel selective inhibitors for carbonic anhydrase IX and XII isoforms

Abstract

Different 2,4-thiazolidinedione-tethered coumarins <b>5a–b</b>, <b>10a–n</b> and <b>11a–d</b> were synthesised and evaluated for their inhibitory action against the cancer-associated <i>h</i>CAs IX and XII, as well as the physiologically dominant <i>h</i>CAs I and II to explore their selectivity. Un-substituted phenyl-bearing coumarins <b>10a</b>, <b>10 h</b>, and 2-thienyl/furyl-bearing coumarins <b>11a–c</b> exhibited the best <i>h</i>CA IX (K_Is between 0.48 and 0.93 µM) and <i>h</i>CA XII (K_Is between 0.44 and 1.1 µM) inhibitory actions. Interestingly, none of the coumarins had any inhibitory effect on the off-target <i>h</i>CA I and II isoforms. The sub-micromolar compounds from the biochemical assay, coumarins <b>10a</b>, <b>10 h</b> and <b>11a–c</b>, were assessed in an <i>in vitro</i> antiproliferative assay, and then the most potent antiproliferative agent <b>11a</b> was tested to explore its impact on the cell cycle phases and apoptosis in MCF-7 breast cancer cells to provide more insights into the anticancer activity of these compounds.