Benzothiazinone-piperazine derivatives as efficient Mycobacterium tuberculosis DNA gyrase inhibitors

Manoj Chandran, Janupally Renuka, Jonnalagadda Padma Sridevi, Ganesh S. Pedgaonkar, Vanaparthi Asmitha, Perumal Yogeeswari, Dharmarajan Sriram
2015 International Journal of Mycobacteriology  
Tuberculosis DNA gyrase Supercoiling Minimum inhibitory concentration A B S T R A C T Background and objectives: Bacterial DNA topoisomerases are unique in maintaining the DNA topology for cell viability. Mycobacterium tuberculosis (MTB) DNA gyrase, a sole type II topoisomerase has a larger scope as a target for developing novel therapeutics. In this study, an effort was made towards the design and synthesis of benzothiazinone-piperazine hybrid analogues to obtain the possibility of it to lead
more » ... lity of it to lead development through the molecular hybridization technique. Methods: A five-step scheme was followed to obtain a series of 36 benzothiazinone-piperazine derivatives and to evaluate them for MTB DNA gyrase inhibition, antimycobacterial and cytotoxicity studies. Results: Compound N-(4-chlorophenyl)-4-(6-nitro-4-oxo-4H-benzo[e][1,3]thiazin-2-yl)piperazine-1-carbothioamide (18) showed greater inhibitory potential with an IC 50 of 0.51 ± 0.16 lM in the DNA supercoiling assay of MTB with a moderate anti-tubercular activity of 4.41 lM. The compound even passed the safety profile of eukaryotic cell cytotoxicity with a 1.81% inhibition in the RAW 264.7 cell line at 100 lM concentration. Conclusions: This study describes the discovery of benzothiazinone as gyrase inhibitors with potent MTB MIC and inhibitory profiles of the gyrase enzyme with less cytotoxic effect. Furthermore, it is believed that this class of compounds has the potential to be further developed as an anti-TB drug candidate. I n t e r n a t i o n a l J o u r n a l o f M y c o b a c t e r i o l o g y 4 ( 2 0 1 5 ) 1 0 4 -1 1 5 H O S T E D BY Av ai la bl e at w w w . s c i e n c e di r e c t .c om ScienceDirect j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / I J M Y C O
doi:10.1016/j.ijmyco.2015.02.002 pmid:26972878 fatcat:ujqcxlvksjapvjs4sdmbbmaj5a