Discovery of 2,4-thiazolidinedione-tethered coumarins as novel selective inhibitors for carbonic anhydrase IX and XII isoforms
Wagdy M. Eldehna, Mohammed S. Taghour, Tarfah Al‐Warhi, Alessio Nocentini, Mostafa M. Elbadawi, Hazem A. Mahdy, Mohamed A. Abdelrahman, Ohoud J. Alotaibi, Nada Aljaeed, Diaaeldin M. Elimam, Kamyar Afarinkia, Hatem A. Abdel‐Aziz, Claudiu T. Supuran
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<sub>I</sub>s between 0.48 and 0.93 µM) and <i>h</i>CA XII (K<sub>I</sub>s 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.