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BioMed Research International
Volume 2014 (2014), Article ID 523210, 11 pages
http://dx.doi.org/10.1155/2014/523210
Research Article

Hydrophobic Substituents of the Phenylmethylsulfamide Moiety Can Be Used for the Development of New Selective Carbonic Anhydrase Inhibitors

1Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Naples, Italy
2Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia
3Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Room 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy
4Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy

Received 28 February 2014; Accepted 13 April 2014; Published 2 September 2014

Academic Editor: Mariya Al-Rashida

Copyright © 2014 Giuseppina De Simone et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

A new series of compounds containing a sulfamide moiety as zinc-binding group (ZBG) has been synthesized and tested for determining inhibitory properties against four human carbonic anhydrase (hCA) isoforms, namely, CAs I, II, IX, and XII. The X-ray structure of the cytosolic dominant isoform hCA II in complex with the best inhibitor of the series has also been determined providing further insights into sulfamide binding mechanism and confirming that such zinc-binding group, if opportunely derivatized, can be usefully exploited for obtaining new potent and selective CAIs. The analysis of the structure also suggests that for drug design purposes the but-2-yn-1-yloxy moiety tail emerges as a very interesting substituent of the phenylmethylsulfamide moiety due to its capability to establish strong van der Waals interactions with a hydrophobic cleft on the hCA II surface, delimited by residues Phe131, Val135, Pro202, and Leu204. Indeed, the complementarity of this tail with the cleft suggests that different substituents could be used to discriminate between isoforms having clefts with different sizes.