Devi Parthiban Brindha, Samala Ganesh, Sridevi Jonnalagadda Padma, Saxena Shalini, Alvala Mallika, Salina Elena G, Sriram Dharmarajan, Yogeeswari Perumal
Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad-500078 (India).
ChemMedChem. 2014 Nov;9(11):2538-47. doi: 10.1002/cmdc.201402171. Epub 2014 Aug 22.
The pantothenate biosynthetic pathway is essential for the persistent growth and virulence of Mycobacterium tuberculosis (Mtb) and one of the enzymes in the pathway, pantothenate synthetase (PS, EC: 6.3.2.1), encoded by the panC gene, has become an appropriate target for new therapeutics to treat tuberculosis. Herein, we report nanomolar thiazolidine inhibitors of Mtb PS developed by a rational inhibitor design approach. The thiazolidine compounds were discovered by using energy-based pharmacophore modelling and subsequent in vitro screening, which resulted in compounds with a half maximal inhibitory concentration (IC50) value of (1.12 ± 0.12) μM. These compounds were subsequently optimised by a combination of modelling and synthetic chemistry. Hit expansion of the lead by chemical synthesis led to an improved inhibitor with an IC50 value of 350 nM and an Mtb minimum inhibitory concentration (MIC) of 1.55 μM. Some of these compounds also showed good activity against dormant Mtb cells.
泛酸生物合成途径对于结核分枝杆菌（Mtb）的持续生长和毒力至关重要，该途径中的一种酶——由panC基因编码的泛酸合成酶（PS，EC：6.3.2.1），已成为治疗结核病新疗法的合适靶点。在此，我们报告了通过合理的抑制剂设计方法开发的Mtb PS的纳摩尔级噻唑烷抑制剂。噻唑烷化合物是通过基于能量的药效团建模和随后的体外筛选发现的，筛选出的化合物半数最大抑制浓度（IC50）值为（1.12±0.12）μM。随后通过建模和合成化学相结合的方法对这些化合物进行了优化。通过化学合成对先导化合物进行命中扩展，得到了一种改进的抑制剂，其IC50值为350 nM，Mtb最低抑菌浓度（MIC）为1.55 μM。其中一些化合物对休眠的Mtb细胞也表现出良好的活性。
