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

Research output: Contribution to journalArticlepeer-review

Authors

  • Rohan A Davis
  • Andreas Hofmann
  • Asiah Osman
  • Fritz A Mühlschlegel
  • Daniela Vullo
  • Alessio Innocenti
  • Claudiu T Supuran
  • Sally-Ann Poulsen

Colleges, School and Institutes

External organisations

  • University of Kent
  • Griffith University
  • E Kent Hosp NHS Trust
  • Sez INFN Firenze

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.

Details

Original languageEnglish
Pages (from-to)1682-92
Number of pages11
JournalJournal of Medicinal Chemistry
Volume54
Issue number6
Publication statusPublished - 24 Mar 2011

Keywords

  • Anti-Bacterial Agents, Antifungal Agents, Biological Agents, Candida albicans, Carbonic Anhydrase I, Carbonic Anhydrase II, Carbonic Anhydrase Inhibitors, Carbonic Anhydrases, Catalytic Domain, Cryptococcus neoformans, Crystallography, X-Ray, Humans, Hydrogen Bonding, Isoenzymes, Models, Molecular, Molecular Structure, Mycobacterium tuberculosis, Phenols, Protein Binding, Small Molecule Libraries

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