Saharan Vanita D, Mahajan Supriya S
Department of Pharmaceutical Chemistry, C.U. Shah College of Pharmacy, S.N.D.T. Women's University, Sir Vithaldas Vidyavihar, Juhu Tara Road, Santacruz (West), Mumbai 400049, India.
Department of Pharmaceutical Chemistry, C.U. Shah College of Pharmacy, S.N.D.T. Women's University, Sir Vithaldas Vidyavihar, Juhu Tara Road, Santacruz (West), Mumbai 400049, India.
Bioorg Med Chem Lett. 2017 Feb 15;27(4):808-815. doi: 10.1016/j.bmcl.2017.01.026. Epub 2017 Jan 11.
The enoyl acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (MTB) is an attractive target for developing novel antitubercular agents. A series of gallic acid formazans, were computationally designed and docked into the active site of InhA to understand their binding mode and potential to inhibit InhA. Nine compounds from the designed series were identified as potential InhA inhibitors, on the basis of good Glide score. These compounds were synthesized in the laboratory and evaluated for in vitro antitubercular activity against drug-sensitive and multi-drug resistant strains of MTB. Out of nine compounds, three compounds exhibited the most promising MIC of <2μM against the sensitive strain of MTB, H37Rv. The compounds were evaluated against five resistant strains of MTB. Most of the compounds exhibited activity superior to the standard, linezolid, against all these resistant strains. The mechanism of action of these compounds was concluded to be InhA inhibition, through InhA enzyme inhibition study. Insignificant cytotoxicity of these compounds was observed on RAW 264.7 cell line. Inactivity of all these compounds against gram positive and gram negative bacteria indicated their specificity against MTB. The compounds were further analyzed for ADME properties and showed potential as good oral drug candidates. The results clearly identified some novel, selective and specific InhA inhibitors against sensitive and resistant strains of MTB.
结核分枝杆菌（MTB）的烯酰基载体蛋白还原酶（InhA）是开发新型抗结核药物的一个有吸引力的靶点。通过计算机设计了一系列没食子酸甲臜，并将其对接至InhA的活性位点，以了解它们的结合模式及抑制InhA的潜力。基于良好的Glide评分，从设计系列中鉴定出9种化合物作为潜在的InhA抑制剂。这些化合物在实验室中合成，并针对MTB的药物敏感和多药耐药菌株进行了体外抗结核活性评估。在这9种化合物中，有3种化合物对MTB敏感菌株H37Rv表现出最有前景的最低抑菌浓度（MIC）<2μM。对5种MTB耐药菌株对这些化合物进行了评估。大多数化合物对所有这些耐药菌株表现出优于标准药物利奈唑胺的活性。通过InhA酶抑制研究得出这些化合物的作用机制为抑制InhA。在RAW 264.7细胞系上观察到这些化合物的细胞毒性不显著。所有这些化合物对革兰氏阳性和革兰氏阴性细菌均无活性，表明它们对MTB具有特异性。对这些化合物的吸收、分布、代谢和排泄（ADME）特性进行了进一步分析，结果表明它们有潜力成为良好的口服药物候选物。结果清楚地鉴定出了一些针对MTB敏感和耐药菌株的新型、选择性和特异性InhA抑制剂。
