Synthesis, screening and docking analysis of hispolon analogs as potential antitubercular agents

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• 作者：Neduri V. Balaji^a ; Bollikolla Hari Babu^a ; ^{dr.b.haribabu@gmail.com} ; Gottumukkala V. Subbaraju^b ; Kurre Purna Nagasree^c ; Muthyala Murali Krishna Kumar^c ; ^{drmmkau@gmail.com}
• 关键词：Hispolons ; Antitubercular ; Ketoacyl synthase docking analysis
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：27
• 期：1
• 页码：11-15
• 全文大小：750 K
• 卷排序：27

文摘

A series of 20 hispolons/dihydrohispolons were synthesized and characterized by spectral data. These compounds were subjected to in vitro antitubercular activity screening against Mycobacterium tuberculosis (H37Rv) strain. The synthesized compounds showed varied antitubercular activity ranging from 100 to 1.6 μg/mL. Among the screened compounds, four compounds (H1, H2, H3 and H15) have shown moderate activity with MIC 25 μg/mL. Potent activities were observed for the dihydrohispolon derivative H14 (MIC 1.6 μg/mL) followed by H13 (6.25 μg/mL) and H17 (12.5 μg/mL), H19 (3.125 μg/ML). Docking simulations gave good insights on the possible interactions between the tested compounds and β-keto acyl synthase enzyme (mtbFabH). Drug-inhibitor combination studies showed no synergism with the drugs targeting mycolic acid biosynthesis (isoniazid, ethambutol and thiolactomycin, a specific inhibitor of KAS-B enzyme) but showed significant synergism with other drugs including rifampicin and ciprofloxacin ascertaining the drug target for hispolons as inhibition of mycolic acid biosynthesis, probably via mtbFabH.