University of Dundee, Sir James Black Centre, UK.
Bioorg Med Chem. 2010 Dec 1;18(23):8334-40. doi: 10.1016/j.bmc.2010.09.062. Epub 2010 Oct 8.
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.
几丁质是真菌细胞壁的重要结构成分。几丁质酶被认为对真菌细胞壁重塑很重要，抑制这些酶已被提议作为开发新型抗真菌药物的潜在策略。真菌病原体烟曲霉拥有两个截然不同的多基因几丁质酶家族。在这里，我们研究了乙酰唑胺作为抑制烟曲霉“植物型”几丁质酶的化学支架。AfChiA1 与乙酰唑胺的共晶结构用于指导合成和筛选乙酰唑胺类似物，这些类似物的 SAR 与这些结构数据一致。尽管乙酰唑胺及其类似物是该酶的弱抑制剂，但它们具有较高的配体效率，因此是未来抑制剂开发的有趣先导物。
