Document Report Card

ID: ALA1687921

Journal: J Med Chem

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

Authors: Davis RA, Hofmann A, Osman A, Hall RA, Mühlschlegel FA, Vullo D, Innocenti A, Supuran CT, Poulsen SA.

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.

CiteXplore: 21332115

DOI: 10.1021/jm1013242