Synthetic and Crystallographic Studies of a New Inhibitor Series Targeting Bacillus anthracis Dihydrofolate Reductase

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• 作者：Jennifer M. Beierlein ; Kathleen M. Frey ; David B. Bolstad ; Phillip M. Pelphrey ; Tammy M. Joska ; Adrienne E. Smith ; Nigel D. Priestley ; Dennis L. Wright ; Amy C. Anderson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：December 11, 2008
• 年：2008
• 卷：51
• 期：23
• 页码：7532-7540
• 全文大小：441K
• 年卷期：v.51,no.23(December 11, 2008)
• ISSN：1520-4804

文摘

Bacillus anthracis, the causative agent of anthrax, poses a significant biodefense danger. Serious limitations in approved therapeutics and the generation of resistance have produced a compelling need for new therapeutic agents against this organism. Bacillus anthracis is known to be insensitive to the clinically used antifolate, trimethoprim, because of a lack of potency against the dihydrofolate reductase enzyme. Herein, we describe a novel lead series of B. anthracis dihydrofolate reductase inhibitors characterized by an extended trimethoprim-like scaffold. The best lead compound adds only 22 Da to the molecular weight and is 82-fold more potent than trimethoprim. An X-ray crystal structure of this lead compound bound to B. anthracis dihydrofolate reductase in the presence of NADPH was determined to 2.25 Å resolution. The structure reveals several features that can be exploited for further development of this lead series.