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Natural Product-Based Phenols as Novel Probes for Mycobacterial and Fungal Carbonic Anhydrases

Davis, Rohan A., Hofmann, Andreas, Osman, Asiah, Hall, Rebecca A., Mühlschlegel, Fritz A., Vullo, Daniela, Innocenti, Alessio, Supuran, Claudiu T., Poulsen, Sally-Ann (2011) Natural Product-Based Phenols as Novel Probes for Mycobacterial and Fungal Carbonic Anhydrases. Journal of Medicinal Chemistry, 54 (6). pp. 1682-1692. ISSN 0022-2623. (doi:10.1021/jm1013242) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Official URL
http://dx.doi.org/10.1021/jm1013242

Abstract

In order to discover novel probes that may help in the investigation and control of infectious diseases through a new mechanism of action, we have evaluated a library of phenol-based natural products (NPs) for enzyme inhibition against four recently characterized pathogen ?-family carbonic anhydrases (CAs). These include CAs from Mycobacterium tuberculosis, Candida albicans, and Cryptococcus neoformans as well as ?-family human CA I and CA II for comparison. Many of the NPs selectively inhibited the mycobacterial and fungal ?-CAs, with the two best performing compounds displaying submicromolar inhibition with a preference for fungal over human CA inhibition of more than 2 orders of magnitude. These compounds provide the first example of non-sulfonamide inhibitors that display ? over ? CA enzyme selectivity. Structural characterization of the library compounds in complex with human CA II revealed a novel binding mode whereby a methyl ester interacts via a water molecule with the active site zinc.

Item Type: Article
DOI/Identification number: 10.1021/jm1013242
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences > Biomedical Research Group
Depositing User: Sue Davies
Date Deposited: 08 Mar 2012 14:04 UTC
Last Modified: 29 May 2019 08:52 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/29005 (The current URI for this page, for reference purposes)
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