4-Arylbenzenesulfonamides as Human Carbonic Anhydrase Inhibitors (hCAIs): Synthesis by Pd Nanocatalyst-Mediated Suzuki–Miyaura Reaction, Enzyme Inhibition, and X-ray Crystallographic Studies

Cornelio, Benedetta; Laronze-Cochard, Marie; Ceruso, Mariangela; Ferraroni, Marta; Rance, Graham A.; Carta, Fabrizio; Khlobystov, Andrei N.; Fontana, Antonella; Supuran, Claudiu T.; Sapi, Janos

Abstract

Benzenesulfonamides bearing various substituted (hetero)aryl rings in the para-position were prepared by palladium nanoparticle-catalyzed Suzuki–Miyaura cross-coupling reactions and evaluated as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors against isoforms hCA I, II, IX, and XII. Most of the prepared sulfonamides showed low inhibition against hCA I isoform, whereas the other cytosolic isoenzyme, hCA II, was strongly affected. The major part of these new derivatives acted as potent inhibitors of the tumor-associated isoform hCA XII. An opposite trend was observed for phenyl, naphthyl, and various heteroaryl substituted benzenesulfonamides which displayed subnanomolar hCA IX inhibition while poorly inhibiting the other tumor-associated isoform hCA XII. The inhibition potency and influence of the partially restricted aryl–aryl bond rotation on the activity/selectivity were rationalized by means of X-ray crystallography of the adducts of hCA II with several 4-arylbenzenesulfonamides.

Citation

Cornelio, B., Laronze-Cochard, M., Ceruso, M., Ferraroni, M., Rance, G. A., Carta, F., …Sapi, J. (2016). 4-Arylbenzenesulfonamides as Human Carbonic Anhydrase Inhibitors (hCAIs): Synthesis by Pd Nanocatalyst-Mediated Suzuki–Miyaura Reaction, Enzyme Inhibition, and X-ray Crystallographic Studies. Journal of Medicinal Chemistry, 59(2), 721-732. https://doi.org/10.1021/acs.jmedchem.5b01771

• Journal Article Type: Article
• Acceptance Date: Jan 7, 2016
• Online Publication Date: Jan 15, 2016
• Publication Date: Jan 28, 2016
• Deposit Date: Aug 18, 2020
• Publicly Available Date: Sep 14, 2020
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 59
• Issue: 2
• Pages: 721-732
• DOI: https://doi.org/10.1021/acs.jmedchem.5b01771
• Keywords: Molecular Medicine; Drug Discovery
• Public URL: https://nottingham-repository.worktribe.com/output/4842962
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01771
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry,copyright© American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01771