Coumarin-Based Inhibitors of Bacillus anthracis and Staphylococcus aureus Replicative DNA Helicase: Chemical Optimization, Biological Evaluation, and Antibacterial Activities

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• 作者：Bing Li ; Ramdas Pai ; Ming Di ; Daniel Aiello ; Marjorie H. Barnes ; Michelle M. Butler ; Tommy F. Tashjian ; Norton P. Peet ; Terry L. Bowlin ; Donald T. Moir
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 27, 2012
• 年：2012
• 卷：55
• 期：24
• 页码：10896-10908
• 全文大小：454K
• 年卷期：v.55,no.24(December 27, 2012)
• ISSN：1520-4804

文摘

The increasing prevalence of drug-resistant bacterial infections demands the development of new antibacterials that are not subject to existing mechanisms of resistance. Previously, we described coumarin-based inhibitors of an underexploited bacterial target, namely the replicative helicase. Here we report the synthesis and evaluation of optimized coumarin-based inhibitors with 9鈥?8-fold increased potency against Staphylococcus aureus (Sa) and Bacillus anthracis (Ba) helicases. Compounds 20 and 22 provided the best potency, with IC₅₀ values of 3 and 1 渭M, respectively, against the DNA duplex strand-unwinding activities of both B. anthracis and S. aureus helicases without affecting the single strand DNA-stimulated ATPase activity. Selectivity index (SI = CC₅₀/MIC) values against S. aureus and B. anthracis for compound 20 were 33 and 66 and for compound 22 were 20 and 40, respectively. In addition, compounds 20 and 22 demonstrated potent antibacterial activity against multiple ciprofloxacin-resistant MRSA strains, with MIC values ranging between 0.5 and 4.2 渭g/mL.