Amongst our findings, we identified a cluster of 17 novel coumarins with predicted activity against tumor-associated carbonic anhydrases. Subsequent to the synthesis of those 17 new chemical entities, their inhibitory activities were evaluated against HeLa cells and the oncogenic carbonic anhydrases IX and XII. Our results demonstrate that these 3-substituted coumarins exhibit promising inhibitory activity against those cancer therapeutic targets, suggesting their potential as anticancer agents. Furthermore, we investigated the enzyme binding mechanism of three representative compounds from the identified cluster, providing insight into the molecular interaction responsible for their inhibitory activity. The study contributes to the development of novel coumarin-based compounds with potential anticancer activity and highlights the value of ligand-based approaches in computational pharmacology. Overall, our findings underscore the potential of 3-substituted coumarins as a promising class of compounds for the development of targeted anticancer therapies, emphasizing the importance of exploring diverse chemical spaces in the discovery of new therapeutic agents against cancer. (