Discovery of Selective Menaquinone Biosynthesis Inhibitors against Mycobacterium tuberculosis

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• 作者：Joy Debnath ; Shajila Siricilla ; Bajoie Wan ; Dean C. Crick ; Anne J. Lenaerts ; Scott G. Franzblau ; Michio Kurosu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 26, 2012
• 年：2012
• 卷：55
• 期：8
• 页码：3739-3755
• 全文大小：785K
• 年卷期：v.55,no.8(April 26, 2012)
• ISSN：1520-4804

文摘

Aurachin RE (1) is a strong antibiotic that was recently found to possess 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) and bacterial electron transport inhibitory activities. Aurachin RE is the only molecule in a series of aurachin natural products that has the chiral center in the alkyl side chain at C9鈥?position. To identify selective MenA inhibitors against Mycobacterium tuberculosis, a series of chiral molecules were designed based on the structures of previously identified MenA inhibitors and 1. The synthesized molecules were evaluated in in vitro assays, including MenA enzyme and bacterial growth inhibitory assays. We could identify novel MenA inhibitors that showed significant increase in potency of killing nonreplicating M. tuberculosis in the low oxygen recovery assay (LORA) without inhibiting other Gram-positive bacterial growth even at high concentrations. The MenA inhibitors reported here are useful new pharmacophores for the development of selective antimycobacterial agents with strong activity against nonreplicating M. tuberculosis.