Exploring the Structural Diversity of Novel 3-Substituted Coumarins as Potent Inhibitors of Tumor-Associated Carbonic Anhydrases: Expanding the Pharmacological Space for Anticancer Drug Discovery

Innovations in cancer chemotherapy continue to occupy the priority list of demands to ensure our health security. The vast chemical space provides a plethora of anticancer discovery opportunities, however, limited by the boundaries of synthetic feasibility. This study aims at expanding the established pharmacological space of tumor-associated carbonic anhydrases by exploring the synthetically feasible chemical space of 3-substituted coumarins. A series of 52 novel 3-substituted coumarins were randomly sketched by our team of synthetic chemists with priority given to synthetic feasibility. The pharmacological potentials of the novel coumarin series were computationally estimated using a machine-learning approach exploiting both chemical and statistical inference. 17 members of the novel series were predicted to possess cytotoxic activity against HeLa cells by interfering with the tumor-associated carbonic anhydrases IX and XII. Those 17 compounds were synthesized and biologically tested against HeLa cells, subsequently; the 3 most potent compounds were assayed against carbonic anhydrases I, II, IX, and XII employing Acetazolamide as a reference. The molecular binding mechanism of those 3 chosen compounds with the four enzyme isoforms was studied using molecular docking simulation. Most of the compounds exhibited competent inhibitory activity against HeLa cells. The carbonic anhydrase inhibition results unveiled the powerful but non-selective nature of those suicide inhibitors. In conclusion, Novel 3-substituted coumarins have been dispatched to join the pharmacological space of tumor-associated carbonic anhydrases’ suicide inhibitors.