Natural Product-Based Phenols as Novel Probes for Mycobacterial and Fungal Carbonic Anhydrases
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In order to discover novel probes that may help in the investigation and control of infectious diseases through a new mechanismof 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 R-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 ߠover R 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.
Journal of Medicinal Chemistry
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright 2011 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm1013242.
Biologically Active Molecules