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J Med Chem. 2011 Mar 24;54(6):1682-92. doi: 10.1021/jm1013242. Epub 2011 Feb 18.

Natural product-based phenols as novel probes for mycobacterial and fungal carbonic anhydrases.

Author information

1
Eskitis Institute, Griffith University, Nathan, Queensland 4111, Australia.

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 β-family carbonic anhydrases (CAs). These include CAs from Mycobacterium tuberculosis, Candida albicans, and Cryptococcus neoformans as well as α-family human CA I and CA II for comparison. Many of the NPs selectively inhibited the mycobacterial and fungal β-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 β over α 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.

PMID:
21332115
DOI:
10.1021/jm1013242
[Indexed for MEDLINE]

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