Molecular Diversity ( IF 3.9 ) Pub Date : 2019-09-10 , DOI: 10.1007/s11030-019-09990-z Ashutosh Prasad Tiwari 1 , B Sridhar 2 , Helena I Boshoff 3 , Kriti Arora 3 , G Gautham Shenoy 1 , K E Vandana 4 , G Varadaraj Bhat 1
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Abstract
Diphenyl ether derivatives inhibit mycobacterial cell wall synthesis by inhibiting an enzyme, enoyl-acyl carrier protein reductase (InhA), which catalyses the last step in the fatty acid synthesis cycle of genus Mycobacterium. To select and validate a protein crystal structure of enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis for designing inhibitors using molecular modelling, a cross-docking and correlation study was performed. A series of novel 1-(3-(3-hydroxy-4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) ethan-1-ones were synthesized from this model and screened for their antitubercular activity against M. tuberculosis H37Rv. Compound PYN-8 showed good antitubercular activity on M. tuberculosis H37Rv (MIC = 4–7 µM) and Mycobacterium bovis (% inhibition at 10 µM = 95.91%). Cytotoxicity of all the synthesized derivatives was assessed using various cell lines, and they were found to be safe. Structure of PYN-8 was also confirmed by single-crystal X-ray diffraction. The molecular modelling studies also corroborated the biological activity of the compounds. Further, in silico findings revealed that all these tested compounds exhibited good ADME properties and drug likeness and thus may be considered as potential candidates for further drug development.
Graphic abstract
中文翻译：
作为潜在抗结核药物的新型二苯醚衍生物的设计、合成、计算机模拟和体外评估。
抽象的
二苯醚衍生物通过抑制烯酰基载体蛋白还原酶 (InhA) 来抑制分枝杆菌细胞壁合成，该酶催化分枝杆菌属脂肪酸合成循环的最后一步。为了选择和验证结核分枝杆菌烯酰-酰基载体蛋白还原酶的蛋白质晶体结构，以使用分子模型设计抑制剂，进行了交叉对接和相关研究。由此模型合成了一系列新型1-(3-(3-羟基-4-苯氧基苯基)-5-苯基-4,5-二氢-1H-吡唑-1-基)乙烷-1-酮并进行了筛选它们对结核分枝杆菌H37Rv 具有抗结核活性。化合物PYN-8对结核分枝杆菌H37Rv (MIC = 4–7 µM) 和牛分枝杆菌(10 µM 时的抑制百分比 = 95.91%) 显示出良好的抗结核活性。使用各种细胞系评估所有合成衍生物的细胞毒性，发现它们是安全的。 PYN-8的结构也通过单晶X射线衍射得到证实。分子模型研究还证实了这些化合物的生物活性。此外，计算机结果显示，所有这些测试化合物均表现出良好的 ADME 特性和药物相似性，因此可被视为进一步药物开发的潜在候选者。
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