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

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

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)


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


  • 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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