Malapati Prasanthi, Siva Krishna Vagolu, Nallangi Radhika, Meda Nikhila, Reshma Srilakshmi Rudraraju, Sriram Dharmarajan
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, India.
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, India.
Bioorg Med Chem. 2018 Jan 1;26(1):177-190. doi: 10.1016/j.bmc.2017.11.031. Epub 2017 Nov 21.
Mycobacterium tuberculosis glutamate racemase is an essential enzyme involved in peptidoglycan synthesis and conserved in most bacteria. Small molecule inhibitors were reported on other bacterial species whereas in M. tuberculosis it wasn't explored much. In this study we have screened in house compound library using fluorescence thermal shift assay and enzyme inhibition assay, form this (1-(3-(benzo[d]thiazol-2-yl)phenyl)-3-(p-tolyl)thiourea) was identified as lead compound with IC 19.47 ± 0.81 μM. Further lead optimization by synthesis resulted in twenty-three compounds, of which Compound 25 has shown more efficacy compared to lead 1 showing non-competitive mode of inhibition with IC 1.32 ± 0.43 μM. It also showed significant activity (represented in log reduction) in nutrient starved dormant M. tuberculosis model (2.1), M. tuberculosis biofilm assay (2.0) and in vivo M. marinum infected zebrafish model (3.5).
结核分枝杆菌谷氨酸消旋酶是一种参与肽聚糖合成的必需酶，在大多数细菌中保守存在。其他细菌物种已有小分子抑制剂的报道，而在结核分枝杆菌中对此研究较少。在本研究中，我们使用荧光热位移测定法和酶抑制测定法筛选了内部化合物库，从中鉴定出（1-(3-(苯并[d]噻唑-2-基)苯基)-3-(对甲苯基)硫脲）作为先导化合物，其IC为19.47±0.81μM。通过合成进行进一步的先导优化产生了23种化合物，其中化合物25与先导化合物1相比显示出更高的效力，表现出非竞争性抑制模式，IC为1.32±0.43μM。它在营养饥饿的休眠结核分枝杆菌模型（2.1）、结核分枝杆菌生物膜测定（2.0）和体内海鱼分枝杆菌感染的斑马鱼模型（3.5）中也显示出显著活性（以对数减少表示）。
