Harnessing coumarin-thio(seleno)cyanate conjugates: potent <i>In vivo</i> antiproliferative agents targeting carbonic anhydrases

We synthesised coumarin-based derivatives bearing thio- and selenocyanates to selectively inhibit tumour-associated carbonic anhydrases (CAs) IX and XII and to exert antiproliferative effects on tumour cells. Structural variations included chalcogen atom type (S, Se), substitutions at C-3/C-4, and tether length at C-7 of the coumarin core. Thiocyanates <b>4</b> and <b>7b</b> showed potent CA IX/XII inhibition (<i>K</i>_i = 17.9–27.4 nM) with &gt;5000-fold selectivity over off-target isoforms (CAs I and II). Selenocyanate <b>8a</b> exhibited strong antiproliferative activity (GI₅₀ = 0.78–2.6 µM) across six human solid tumour cell lines. Mechanistic studies revealed a cytostatic effect <i>via</i> cell cycle arrest and reduced mitotic progression. <i>In vivo</i> assays in <i>Caenorhabditis elegans</i> confirmed selective cytostatic action of selenocyanate <b>8c</b>, reducing tumorous germline size without affecting healthy tissues at therapeutic doses.