Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2018-11-03 , DOI: 10.1016/j.bmcl.2018.11.002
T.G. Shruthi , Sumesh Eswaran , Prasad Shivarudraiah , Shridhar Narayanan , Sangeetha Subramanian
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Tuberculosis is the infectious disease caused by mycobacterium tuberculosis (Mtb), responsible for the utmost number of deaths annually across the world. Herein, twenty-one new substituted 1,2,4-oxadiazol-3-ylmethyl-piperazin-1-yl-quinoline derivatives were designed and synthesized through multistep synthesis followed by in vitro evaluation of their antitubercular potential against Mtb WT H37Rv. The compound QD-18 was found to be promising with MIC value of 0.5 µg/ml and QD-19 to QD-21 were also remarkable with MIC value of 0.25 µg/ml. Additionally, we have carried out experiments to confirm the metabolic stability, cytotoxicity and pharmacokinetics of these compounds along with kill kinetics of QD-18. These compounds were found to be orally bioavailable and highly effective. Altogether, these results indicate that QD-18, QD-19, QD-20 and QD-21 are promising lead compounds for the development of a novel chemical class of antitubercular drugs.
中文翻译:
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带有1,2,4-恶二唑基团的新喹啉衍生物的合成,抗结核研究和生物学评估
结核病是由结核分枝杆菌(Mtb)引起的传染病,它是全世界每年死亡人数最多的原因。在此,设计和合成了二十一种新的取代的1,2,4-恶二唑-3-基甲基-哌嗪-1-基-喹啉衍生物,并通过多步合成,然后对其抗Mtb WT H37Rv的抗结核潜力进行了体外评估。发现化合物QD-18的MIC值为0.5 µg / ml很有前景,而QD-19至QD-21的MIC值为0.25 µg / ml也很引人注目。此外,我们进行了实验,以确认这些化合物的代谢稳定性,细胞毒性和药代动力学,以及对它们的杀灭动力学。QD-18。发现这些化合物是口服生物利用的并且是高度有效的。总而言之,这些结果表明QD-18,QD-19,QD-20和QD-21是用于开发新型化学类抗结核药物的有前途的先导化合物。