Synthesis of highly potent novel anti-tubercular isoniazid analogues with preliminary pharmacokinetic evaluation

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• 作者：Addepalli Venkata Ramani ; Arumalla Monika ; Vadlamani Lakshmi Indira ; Gopisetti Karyavardhi ; Jangala Venkatesh ; Variam Ullas Jeankumar ; Thimmappa H. Manjashetty ; Perumal Yogeeswari ; Dharmarajan Sriram ; ^{drdsriram@yahoo.com} ; ^{dsriram@bits-hyderabad.ac.in}
• 关键词：Isoniazid analogue ; Anti-TB activity ; Anti-mycobacterial activity ; Tuberculosis
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 April, 2012
• 卷：22
• 期：8
• 页码：2764-2767
• 文件大小：389 K

摘要

Thirty two novel isoniazid analogues were prepared by one-pot three component condensations of isoniazid (INH), 3-mercaptopropionic acid and various aryl/heteroaryl aldehydes. The synthesized compounds were evaluated for their anti-TB activity against Mycobacterium tuberculosis H37Rv (MTB) and cytotoxicity. Among the compounds, compound N-(2-(4-(benzyloxy) phenyl)-4-oxo-1,3-thiazinan-3-yl) isonicotinamide (17) inhibited MTB with MIC of 0.12 渭M and was three times more potent than INH. The main pharmacokinetic parameters after intravenous administration (10 mg/kg body weight) in male Wistar rats viz. t_陆, K_el, mean plasma clearance and mean volume of distribution were found to be 1.14 卤 0.20 h, 0.62 卤 0.10 h^鈭?, 22.48 卤 0.16 mL/kg/min and 1.99 卤 0.49 L, respectively. The systemic absorption was slow after oral administration (50 mg/kg body weight). The peak plasma concentration was found to be 1.31 卤 0.06 渭g/mL attained in 3 h. The bioavailability was found to be 16.7%.