2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases

Abstract

We have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of the linker connecting both units were modified to obtain useful structure-activity relationships. CA inhibition studies revealed a good selectivity towards tumour-associated CAs IX and XII (K_i within the mid-nanomolar range in most of the cases) in comparison with CAs I, II, IV, and VII (K_i > 10 µM); CA IX was found to be slightly more sensitive towards structural changes. Docking calculations suggested that the coumarin scaffold might act as a prodrug, binding to the CAs in its hydrolysed form, which is in turn obtained due to the esterase activity of CAs. An increase of the tether length and of the substituents steric hindrance was found to be detrimental to in vitro antiproliferative activities. Incorporation of a chlorine atom on C-3 of the coumarin moiety achieved the strongest antiproliferative agent, with activities within the low micromolar range for the panel of tumour cell lines tested.

Graphical Abstract

Keywords:

• Carbonic anhydrases
• coumarins
• benzoxazoles
• antiproliferative agents
• docking

Acknowledgements

We thank the Spanish MICINN (PID2020-116460RB-I00, PGC2018-094503-B-C22), the Junta de Andalucía (FQM134), the Gobierno de Canarias (ProID2020010101, ACIISI/FEDER, UE), the Mexican CONACYT (CB-2015/257465) and the Italian Ministry for Education and Science (MIUR), grant PRIN rot. 2017XYBP2R for financial support. M.X.F. thanks Cabildo de Tenerife for a “Agustín de Betancourt” contract and Program FDCAN from Gobierno de Canarias. A.F.-A. thanks the CONACYT (Mexico) for the award of a fellowship. A.P. thanks the EU Social Fund (FSE) and the Canary Islands ACIISI for a predoctoral grant TESIS202001005. We would also like to thank the Servicio de Resonancia Magnética Nuclear, CITIUS (University of Seville) for the performance of NMR experiments.

Disclosure statement

CT Supuran is Editor-in-Chief of the Journal of Enzyme Inhibition and Medicinal Chemistry and he was not involved in the assessment, peer review or decision-making process of this paper. The authors have no relevant affiliations of financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.