Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines

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• 作者：Thanh Lam ; Mark T. Hilgers ; Mark L. Cunningham ; Bryan P. Kwan ; Kirk J. Nelson ; Vickie Brown-Driver ; Voon Ong ; Michael Trzoss ; Grayson Hough ; Karen Joy Shaw ; John Finn
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 13, 2014
• 年：2014
• 卷：57
• 期：3
• 页码：651-668
• 全文大小：957K
• ISSN：1520-4804

文摘

A new series of dihydrofolate reductase (DHFR) inhibitors, the 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines, were designed and optimized for antibacterial potency and enzyme selectivity. The most potent inhibitors in this series contained a five-membered heterocycle at the 2-position of the benzimidazole, leading to highly potent and selective compounds that exploit the differences in the size of a binding pocket adjacent to the NADPH cofactor between the bacterial and human DHFR enzymes. Typical of these compounds is 7-((2-thiazol-2-yl)benzimidazol-1-yl)-2,4 diaminoquinazoline, which is a potent inhibitor of S. aureus DHFR (K_i = 0.002 nM) with 46700-fold selectivity over human DHFR. This compound also has high antibacterial potency on Gram-positive bacteria with an MIC versus wild type S. aureus of 0.0125 渭g/mL and a MIC versus trimethoprim-resistant S. aureus of 0.25 渭g/mL. In vivo efficacy versus a S. aureus septicemia was demonstrated, highlighting the potential of this new series.