Acetazolamide-based fungal chitinase inhibitors

Alexander W. Schuettelkopf, Ludovic Gros, David E. Blair, Julie A. Frearson, Daan M. F. van Aalten, Ian H. Gilbert

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    Abstract

    Chitin is an essential structural component of the fungal cell wall. Chitinases are thought to be important for fungal cell wall remodelling, and inhibition of these enzymes has been proposed as a potential strategy for development of novel anti-fungals. The fungal pathogen Aspergillus fumigatus possesses two distinct multi-gene chitinase families. Here we explore acetazolamide as a chemical scaffold for the inhibition of an A. fumigatus 'plant-type' chitinase. A co-crystal structure of AfChiA1 with acetazolamide was used to guide synthesis and screening of acetazolamide analogues that yielded SAR in agreement with these structural data. Although acetazolamide and its analogues are weak inhibitors of the enzyme, they have a high ligand efficiency and as such are interesting leads for future inhibitor development. (C) 2010 Elsevier Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)8334-8340
    Number of pages7
    JournalBioorganic & Medicinal Chemistry
    Volume18
    Issue number23
    DOIs
    Publication statusPublished - 1 Dec 2010

    Keywords

    • Chitinase
    • Aspergillus fumigatus
    • SCREENING-BASED DISCOVERY
    • SACCHAROMYCES-CEREVISIAE
    • INVASIVE ASPERGILLOSIS
    • CRYSTAL-STRUCTURES
    • PROTEIN
    • GROWTH
    • ALLOSAMIDIN
    • HEVAMINE
    • COMPLEX
    • CELL

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