Structure−Activity Relationships for a Series of Quinoline-Based Compounds Active against Replicating and Nonreplicating Mycobacterium tuberculosis

详细信息    查看全文

• 作者：Annamaria Lilienkampf^&#8224 ; ; Jialin Mao^&#8224 ; ^‡ ; ; Baojie Wan^‡ ; ; Yuehong Wang^‡ ; ; Scott G. Franzblau*^‡ ; ; Alan P. Koz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：April 9, 2009
• 年：2009
• 卷：52
• 期：7
• 页码：2109-2118
• 全文大小：193K
• 年卷期：v.52,no.7(April 9, 2009)
• ISSN：1520-4804

文摘

Tuberculosis (TB) remains as a global pandemic that is aggravated by a lack of health care, the spread of HIV, and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. New anti-TB drugs are urgently required to shorten the long 6−12 month treatment regimen and to battle drug-resistant Mtb strains. We have identified several potent quinoline-based anti-TB compounds, bearing an isoxazole containing side-chain. The most potent compounds, 7g and 13, exhibited submicromolar activity against the replicating bacteria (R-TB), with minimum inhibitory concentrations (MICs) of 0.77 and 0.95 μM, respectively. In general, these compounds also had micromolar activity against the nonreplicating persistent bacteria (NRP-TB) and did not show toxicity on Vero cells up to 128 μM concentration. Compounds 7g and 13 were shown to retain their anti-TB activity against rifampin, isoniazid, and streptomycin resistant Mtb strains. The results suggest that quinoline−isoxazole-based anti-TB compounds are promising leads for new TB drug development.