Design, synthesis, and biological investigation of selective human carbonic anhydrase II, IX, and XII inhibitors using 7-aryl/heteroaryl triazolopyrimidines bearing a sulfanilamide scaffold

Romagnoli, Romeo, De Ventura, Tiziano, Manfredini, Stefano, Baldini, Erika, Supuran, Claudiu T., Nocentini, Alessio, Brancale, Andrea, Varricchio, Carmine ORCID: https://orcid.org/0000-0002-1673-4768, Bortolozzi, Roberta, Manfreda, Lorenzo and Viola, Giampietro 2023. Design, synthesis, and biological investigation of selective human carbonic anhydrase II, IX, and XII inhibitors using 7-aryl/heteroaryl triazolopyrimidines bearing a sulfanilamide scaffold. Journal of Enzyme Inhibition and Medicinal Chemistry 38 (1) , 2270180. 10.1080/14756366.2023.2270180

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Abstract

A novel library of human carbonic anhydrase (hCA) inhibitors based on the 2-sulfanilamido[1,2,4]triazolo[1,5-a]pyrimidine skeleton modified at its 7-position was prepared by an efficient convergent procedure. These derivatives were evaluated in vitro for their inhibition properties against a representative panel of hCA isoforms (hCA I, II, IV, IX, and XII). The target tumour-associated isoforms hCA IX and XII were potently inhibited with KIs in the low nanomolar range of 5–96 nM and 4–72 nM, respectively. Compounds 1d, 1j, 1v, and 1x were the most potent hCA IX inhibitors with KIs of 5.1, 8.6, 4.7, and 5.1 nM, respectively. Along with derivatives 1d and 1j, compounds 1r and 1ab potently inhibited hCA XII isoform with KIs in a single-digit nanomolar range of 8.8, 5.4, 4.3, and 9.0 nM, respectively. Compounds 1e, 1m, and 1p exhibited the best selectivity against hCA IX and hCA XII isoforms over off-target hCA II, with selectivity indexes ranging from 5 to 14.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Pharmacy
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by-nc/4.0/, Start Date: 2023-10-18
Publisher:	Taylor and Francis Group
ISSN:	1475-6366
Date of First Compliant Deposit:	18 December 2025
Date of Acceptance:	7 October 2023
Last Modified:	18 Dec 2025 09:45
URI:	https://orca.cardiff.ac.uk/id/eprint/183331

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