Tawari Nilesh R, Bag Seema, Raju Archana, Lele Arundhati C, Bairwa Ranjeet, Ray Mukti Kanta, Rajan M G R, Nawale Laxman U, Sarkar Dhiman, Degani Mariam S
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India.
Radiation Medicine Center, Bhabha Atomic Research Centre, Tata Memorial Hospital Annex, Parel, Mumbai 400012, India.
Future Med Chem. 2015;7(8):979-88. doi: 10.4155/fmc.15.48.
A series of 2,4-diamino-s-triazines was designed, with potential for activity against Mycobacterium tuberculosis (Mtb) dihydrofolate reductase enzyme, on the basis of virtual screening results and structure-based drug design.
The compounds were evaluated against Mtb (H37Rv) and their cytotoxicity was assessed using VERO cell lines. Of particular note, two compounds were found to have the most promising antituberculosis activity (6b minimum inhibitory concentration: 1.76 μM and 6i minimum inhibitory concentration: 1.57 μM) along with low cytotoxicity (CC50: >300 μM). The enzyme assay results of these two indicated significant inhibition of Mtb dihydrofolate reductase along with selectivity. Selected derivatives were tested against dormant tubercle bacilli in vivo and ex vivo indicating potential inhibition.
This study provides promising antituberculosis dihydrofolate reductase inhibitors that can act as potential leads for further development.
基于虚拟筛选结果和基于结构的药物设计，设计了一系列2,4-二氨基-s-三嗪，它们具有抗结核分枝杆菌（Mtb）二氢叶酸还原酶的活性潜力。
对这些化合物进行了抗结核分枝杆菌（H37Rv）评估，并使用VERO细胞系评估了它们的细胞毒性。特别值得注意的是，发现两种化合物具有最有前景的抗结核活性（6b的最低抑菌浓度：1.76 μM，6i的最低抑菌浓度：1.57 μM），同时细胞毒性较低（CC50：>300 μM）。这两种化合物的酶分析结果表明对结核分枝杆菌二氢叶酸还原酶有显著抑制作用且具有选择性。对选定的衍生物进行了体内和体外针对休眠结核杆菌的测试，表明有潜在抑制作用。
本研究提供了有前景的抗结核二氢叶酸还原酶抑制剂，可作为进一步开发的潜在先导化合物。
