Samala Ganesh, Devi Parthiban Brindha, Saxena Shalini, Meda Nikhila, Yogeeswari Perumal, Sriram Dharmarajan
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Hyderabad 500078, India.
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Hyderabad 500078, India.
Bioorg Med Chem. 2016 Mar 15;24(6):1298-307. doi: 10.1016/j.bmc.2016.01.059. Epub 2016 Feb 2.
In the present study, we have designed imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazole derivatives from earlier reported imidazo[1,2-a]pyridine based Mycobacterium tuberculosis (MTB) pantothenate synthetase (PS) inhibitors. We synthesized thirty compounds and they were evaluated for MTB PS inhibition study, in vitro anti-TB activities against replicative and non-replicative MTB, in vivo activity using Mycobacterium marinum infected Zebra fish and cytotoxicity against RAW 264.7 cell line. Among them compound 2-methyl-N'-(4-phenoxybenzoyl)benzo[d]imidazo[2,1-b]thiazole-3-carbohydrazide (5bc) emerged as potent compound active against MTB PS with IC50 of 0.53±0.13 μM, MIC of 3.53 μM, 2.1 log reduction against nutrient starved MTB, with 33% cytotoxicity at 50 μM. It also showed 1.5 log reduction of M. marinum load in Zebra fish at 10mg/kg.
在本研究中，我们基于先前报道的咪唑并[1,2 - a]吡啶类结核分枝杆菌（MTB）泛酸合成酶（PS）抑制剂设计了咪唑并[2,1 - b]噻唑和苯并[d]咪唑并[2,1 - b]噻唑衍生物。我们合成了30种化合物，并对它们进行了MTB PS抑制研究、针对增殖型和非增殖型MTB的体外抗结核活性研究、使用海分枝杆菌感染的斑马鱼进行体内活性研究以及对RAW 264.7细胞系的细胞毒性研究。其中，化合物2 - 甲基 - N' - (4 - 苯氧基苯甲酰基)苯并[d]咪唑并[2,1 - b]噻唑 - 3 - 碳酰肼（5bc）成为对MTB PS具有活性的强效化合物，其IC50为0.53±0.13 μM，MIC为3.53 μM，对营养饥饿的MTB有2.1个对数级的降低，在50 μM时细胞毒性为33%。在10mg/kg剂量下，它还使斑马鱼体内的海分枝杆菌载量降低了1.5个对数级。
