Dhumal Sambhaji T, Deshmukh Amarsinh R, Bhosle Manisha R, Khedkar Vijay M, Nawale Laxman U, Sarkar Dhiman, Mane Ramrao A
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, India.
Combi Chem-Bio Resource Centre, CSIR-National Chemical Laboratory, Pune 411008, India.
Bioorg Med Chem Lett. 2016 Aug 1;26(15):3646-51. doi: 10.1016/j.bmcl.2016.05.093. Epub 2016 Jun 1.
In search of more potent and safe new antitubercular agents, here new 2-pyridinyl substituted thiazolyl-5-aryl-1,3,4-oxadiazoles (6a-o), have been designed and synthesized using thionicotinamide as a starting, following novel multistep synthetic route. An intermediate, pyridinyl substituted thiazolyl acid hydrazide (4) when condensed with benzoic acids/nicotinic acids (5a-o) in the presence of silica supported POCl3 yielded better to excellent yields of the title compounds. All the synthesized compounds (6a-o) and intermediate acid hydrazide (4) have been screened for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra (MTB) and Mycobacterium bovis BCG. Amongst them, 6f, 6j, 6l and 6o have revealed promising activity against M. bovis BCG at concentrations less than 3μg/mL. These compounds have shown low cytotoxicity (CC50: >100μg/mL) towards four human cancer cell lines. Molecular docking study has also been performed against mycobacterial enoyl reductase (InhA) enzyme to gain an insight into the binding modes of these molecules and recorded good binding affinity. The ADME properties the title products have also been analyzed.
为了寻找更有效且安全的新型抗结核药物，本文以硫代烟酰胺为起始原料，按照新颖的多步合成路线，设计并合成了新型的2-吡啶基取代的噻唑基-5-芳基-1,3,4-恶二唑（6a-o）。中间体吡啶基取代的噻唑基酰肼（4）在硅胶负载的POCl3存在下与苯甲酸/烟酸（5a-o）缩合，得到了产率良好至优异的目标化合物。对所有合成的化合物（6a-o）和中间体酰肼（4）进行了针对结核分枝杆菌H37Ra（MTB）和牛分枝杆菌卡介苗的体外抗结核活性筛选。其中，6f、6j、6l和6o在浓度低于3μg/mL时对牛分枝杆菌卡介苗显示出有前景的活性。这些化合物对四种人类癌细胞系表现出低细胞毒性（CC50：>100μg/mL）。还针对分枝杆菌烯酰还原酶（InhA）进行了分子对接研究，以深入了解这些分子的结合模式，并记录到良好的结合亲和力。此外，还分析了目标产物的ADME性质。
