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J Med Chem. 2016 Jan 28;59(2):721-32. doi: 10.1021/acs.jmedchem.5b01771. Epub 2016 Jan 15.

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

Author information

1
Institut de Chimie Moléculaire de Reims, CNRS UMR 7312, Université de Reims Champagne-Ardenne, UFR Pharmacie, 51 Rue Cognacq-Jay, F-51096 Reims Cedex, France.
2
Dipartimento di Farmacia, Università "G. d'Annunzio" , Via dei Vestini, I-66100 Chieti, Italy.
3
Dipartimento di Chimica Ugo Schiff, Università degli Studi di Firenze , Via della Lastruccia 3, I-50019 Sesto Fiorentino, Firenze, Italy.
4
School of Chemistry, University of Nottingham , University Park, Nottingham, NG7 2RD, U.K.
5
Nottingham Nanotechnology and Nanoscience Centre, University of Nottingham , University Park, Nottingham, NG7 2RD, U.K.
6
Neurofarba Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze , Via U. Schiff 6, I-50019 Sesto Fiorentino, Firenze, Italy.

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.

PMID:
26741028
DOI:
10.1021/acs.jmedchem.5b01771
[Indexed for MEDLINE]

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