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Discovery of hydrazone containing thiadiazoles as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors.
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2020-01-07 , DOI: 10.1016/j.ejmech.2020.112035
Hilal Doğan 1 , Şengül Dilem Doğan 2 , Miyase Gözde Gündüz 3 , Vagolu Siva Krishna 4 , Christian Lherbet 5 , Dharmarajan Sriram 4 , Onur Şahin 6 , Emin Sarıpınar 7
Affiliation  

Tuberculosis, caused by Mycobacterium tuberculosis, is a serious infectious disease and remains a global health problem. There is an increasing need for the discovery of novel therapeutic agents for its treatment due to the emerging multi-drug resistance. Herein, we present the rational design and the synthesis of eighteen new thiadiazolylhidrazones (TDHs) which were synthesized by intramolecular oxidative N-S bond formation reaction of 2-benzylidene-N-(phenylcarbamothioyl)hydrazine-1-carboximidamide derivatives by phenyliodine(III) bis(trifluoroacetate) (PIFA) under mild conditions. The compounds were characterized by various spectral techniques including FTIR, 1H NMR, 13C NMR and HRMS. Furthermore, the proposed structure of TDH12 was resolved by single-crystal X-ray analysis. The compounds were evaluated for their in vitro antitubercular activity against M. tuberculosis H37Rv. Among them, some compounds exhibited remarkable antimycobacterial activity, MIC = 0.78-6.25 μg/mL, with low cytotoxicity. Additionally, the most active compounds were screened for their biological activities against M. tuberculosis in the nutrient starvation model. Enzyme inhibition assays and molecular docking studies revealed enoyl acyl carrier protein reductase (InhA) as the possible target enzyme of the compounds to show their antitubercular activities.

中文翻译:

发现了含th的噻二唑类作为结核分枝杆菌生长和烯酰基酰基载体蛋白还原酶(InhA)抑制剂。

由结核分枝杆菌引起的结核病是一种严重的传染病,仍然是全球性的健康问题。由于新兴的多药耐药性,越来越需要发现用于其治疗的新型治疗剂。在这里,我们提出合理的设计和十八个新的噻二氮杂ly酮(TDHs)的合成,该TDHs是通过2-碘亚甲基-N-(苯基氨基甲硫酰基)肼-1-羧酰亚胺酰胺衍生物与苯基碘(III)bis(III)的分子内氧化NS键形成反应合成的三氟乙酸盐(PIFA)在温和的条件下使用。通过多种光谱技术对化合物进行表征,包括FTIR,1H NMR,13C NMR和HRMS。此外,通过单晶X射线分析解析了提出的TDH12的结构。评价化合物对结核分枝杆菌H37Rv的体外抗结核活性。其中,一些化合物表现出显着的抗分枝杆菌活性,MIC = 0.78-6.25μg/ mL,细胞毒性低。此外,在营养饥饿模型中筛选了活性最高的化合物抗结核分枝杆菌的生物学活性。酶抑制试验和分子对接研究表明,烯酰基酰基载体蛋白还原酶(InhA)是化合物显示其抗结核活性的可能靶酶。营养不足模型中的结核病。酶抑制试验和分子对接研究表明,烯酰基酰基载体蛋白还原酶(InhA)是化合物显示其抗结核活性的可能靶酶。营养不足模型中的结核病。酶抑制试验和分子对接研究表明,烯酰基酰基载体蛋白还原酶(InhA)是化合物显示其抗结核活性的可能靶酶。
更新日期:2020-01-07
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