OBJECTIVE: This study presents the design and synthesis of a new series of human carbonic anhydrase (hCA) inhibitors based on a 5-methyl/phenyl-7-(7'-oxycoumarin)-[1,2,4]triazolo[1,5-a]pyrimidine scaffold. METHODS: The chemical structures of novel coumarin-based triazolopyrimidines 3a-u were confirmed after using NMR and MS analyses. Their inhibitory profiles were evaluated against a panel of five hCA isoforms. Molecular docking simulations were conducted to elucidate the binding modes of compounds 3d and 3s with hCA IX and XII isoforms. Selected derivatives 3d and 3g were tested for their antiproliferative effects on the medulloblastoma HD-MB03 and the glioblastoma U87MG cell lines. Additionally, compounds 3d and 3g were evaluated alone or in combination with cisplatin (cis-Pt) for their ability to induce apoptosis in HD-MB03 cells. RESULTS: In vitro kinetic studies demonstrated that all 5-methyl triazolopyrimidine derivatives (3a-r) selectively inhibited the tumor-associated hCA isoforms (hCA IX and XII), with KI values ranging from 0.75 to 10.5 μM, while hCA I, II, IV isoforms were not significantly inhibited (KIs > 100 μM). Compound 3d emerged as the most potent and selective inhibitor, with KIs of 0.92 and 0.75 μM for hCA IX and XII, respectively. This derivative significantly suppressed cell proliferation in human brain tumor cell lines, particularly HD-MB03, when it was studied for its adjuvant effects in combination with cisplatin. CONCLUSION: In this study, we have identified compound 3d as a selective inhibitor of the isoforms hCA IX and XII, showing minimal inhibition over hCA I, II, and IV isoenzymes (selectivity indices > 100). Its moderate inhibitory effects on hCA IX and XII at submicromolar levels were paralleled by significant antiproliferative activity against HD-MB03 cells. These findings underscore the potential of compound 3d as a promising candidate for further therapeutic development, especially in combination with clinically used chemotherapeutic agents.

Department of Chemical Pharmaceutical and Agricultural Sciences University of Ferrara Ferrara 44121 Italy

Department of Life and Environmental Sciences Polytechnic University of Marche Ancona 60131 Italy

Department of NEUROFARBA Section of Pharmaceutical and Nutraceutical Sciences University of Florence Sesto Fiorentino 50019 Italy

Department of Organic Chemistry University of Chemistry and Technology Prague 16628 Prague Czech Republic

Department of Pharmaceutical and Pharmacological Sciences Section of Pharmacology University of Padova Padova 35131 Italy

Department of Woman's and Child's Health Hemato Oncology Lab University of Padova Padova 35128 Italy

Laboratory of Experimental Pharmacology Istituto di Ricerca Pediatrica Fondazione Città della Speranza Padova 35128 Italy

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