Efficacy Study Of Potential Anti-tubercular Molecules: In-vitro and Ex-vivo Laxman Nawale, Navnath Rode, Amol Sonawane, Vijay Khedkar, Manisha Arkile, Amar Yeware, Ramesh. A. Joshi, Anjali. P. Likhite, Rohini Joshi, Dhiman Sarkar National Repository of Small Molecules, National Chemical Laboratory, Pune 411008 Dose Dependent Effect of NR Inhibitors on Wayne's Dormancy Model Introduction Tuberculosis: Infectious disease caused by the bacillus Mycobacterium tuberculosis Second leading infectious killer after HIV/AIDS In 2013, 8.6 million TB cases were reported out of which 1.3 million died Emergence of Multi-drug resistant TB (MDR-TB) and extremely drug resistant TB (XDR) for which no drugs are available. Latency being a cause of recurring TB infection is a major problem in eradication of TB Dose Dependent Effect of Inhibitors against Active M. tuberculosis H37Ra Mycobacterium tuberculosis Courtesy: Alicia Johnson -Human not animals were source of Tuberculosis (TB): Study Need: Discovery of new antitubercular molecules against active and latent forms Reasons: M.tuberculosis bacilli possess a well characterized nitrate metabolic pathway which plays important role in pathogenesis (Khan et. al. 2012) Increased NarGHJI activity during dormancy induced by oxygen limitation (Khan et. al. 2008) Nitrate reduction is directly proportional to the number of M.tuberculosis bacilli in culture (Sarkar et. al. (2012) In vitro and ex-vivo whole cell based assay protocols are already developed for screening diverse compound library (Khan et. al(2012), Singh et al(2005). We have already screened selected libraries from a stock of ~7500 samples available in NRM Effect of Inhibitors on M. tuberculosis H37Ra within Macrophage Efficacy in Intracellular Environment Nitrate reductase Energy Metabolism - D.Sarkar, “Int J antimicrob. agents, 2008 Results Screening of different Anti-tubercular Molecules against M. tuberculosis H37Ra to Identify as Potential Drug Cytotoxic Effect of Inhibitors against human cancer cell lines In vitro and ex vivo effect of representative inhibitors against M. tuberculosis H37Ra Prospects of Compounds Low cytotoxicity in human cancer cell lines, gram positive and gram negative bacteria Solubility >500 µM Easy and low cost synthesis Identification of novel anti-tubercular molecules from synthetic, natural and nanoparticle class of compounds Novelty of work MIC’s are as low as the frontline anti-tubercular drug’s used in DOTS and the Stop TB Strategy recommended by WHO and IPR protected by NCL-CSIR Conclusions A set of 55 compounds have been identified as potential anti-tubercular inhibitors Compounds are efficacious against intracellular M. tuberculosis as well as M. tuberculosis H37Ra residing within macrophage Cytotoxicity is nil up to 100 µg/ml for human cancer cell lines The non-toxic properties prove that they can be used as potential anti-tubercular inhibitors Acknowledgements Authors are thankful to Director, NCL, Pune, India for providing financial assistance through an In-house project. Disclosure: Compounds IPR protected by NCL-CSIR Feb 28, 2014