Acetazolamide-based fungal chitinase inhibitors.
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.
University of Dundee, Sir James Black Centre, UK.
Alexander W
AW
Schüttelkopf
Ludovic
L
Gros
David E
DE
Blair
Julie A
JA
Frearson
Daan M F
DM
van Aalten
Ian H
IH
Gilbert
D000086:Acetazolamide / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000201:enzymology; D001665:Binding Sites; D002688:Chitinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D002688:Chitinases; D000086:Acetazolamide