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

Rohan A. Davis | Zendy; Andreas Hofmann | Zendy; Asiah Osman | Zendy; Rebecca A. Hall | Zendy; Fritz A. Mühlschlegel | Zendy; Daniela Vullo | Zendy; Alessio Innocenti | Zendy; Claudiu T. Supuran | Zendy; SallyAnn Poulsen | Zendy

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

Author(s) -

Rohan A. Davis,

Andreas Hofmann,

Asiah Osman,

Rebecca A. Hall,

Fritz A. Mühlschlegel,

Daniela Vullo,

Alessio Innocenti,

Claudiu T. Supuran,

SallyAnn Poulsen

Publication year - 2011

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/jm1013242

Subject(s) - chemistry , cryptococcus neoformans , candida albicans , enzyme , biochemistry , natural product , mycobacterium tuberculosis , active site , human pathogen , carbonic anhydrase , mechanism of action , stereochemistry , microbiology and biotechnology , tuberculosis , in vitro , gene , biology , pathology , medicine

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.

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