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

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Davis RA, Hofmann A, Osman A, Hall RA, Muhlschlegel FA, Vullo D, Innocenti A, Supuran CT, Poulsen SA

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

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

PubMed ID

21332115 [ View in PubMed

]

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

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Acetazolamide	Carbonic anhydrase 1	Ki (nM)	250	N/A	N/A	Details
Acetazolamide	Carbonic anhydrase 2	Ki (nM)	12	N/A	N/A	Details
Topiramate	Carbonic anhydrase 1	Ki (nM)	250	N/A	N/A	Details
Topiramate	Carbonic anhydrase 2	Ki (nM)	10	N/A	N/A	Details
Zonisamide	Carbonic anhydrase 1	Ki (nM)	56	N/A	N/A	Details
Zonisamide	Carbonic anhydrase 2	Ki (nM)	35	N/A	N/A	Details