title: Identification of New Molecular Entities (NMEs) as Potential Leads against Tuberculosis from Open Source Compound Repository.
abstract: The purpose of this study was to provide a number of diverse and promising early-lead compounds that will feed into the drug discovery pipeline for developing new antitubercular agents. The results from the phenotypic screening of the open-source compound library against Mycobacterium smegmatis and Mycobacterium bovis (BCG) with hit validation against M. tuberculosis (H37Rv) have identified novel potent hit compounds. To determine their druglikeness, a systematic analysis of physicochemical properties of the hit compounds has been performed using cheminformatics tools. The hit molecules were analysed by clustering based on their chemical finger prints and structural similarity determining their chemical diversity. The hit compound library is also filtered for druglikeness based on the physicochemical descriptors following Lipinski filters. The robust filtration of hits followed by secondary screening against BCG, H37Rv and cytotoxicity evaluation has identified 12 compounds with potential against H37Rv (MIC range 0.4 to 12.5 μM). Furthermore in cytotoxicity assays, 12 compounds displayed low cytotoxicity against liver and lung cells providing high therapeutic index > 50. To avoid any variations in activity due to the route of chemical synthesis, the hit compounds were re synthesized independently and confirmed for their potential against H37Rv. Taken together, the hits reported here provides copious potential starting points for generation of new leads eventually adds to drug discovery pipeline against tuberculosis.
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad - 500 007, India.
authors.forename: Sudha Sravanti
authors.initials: SS
authors.lastname: Kotapalli
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad - 500 007, India.
authors.forename: Sri Satya Anila
authors.initials: SS
authors.lastname: Nallam
authors.affiliation: Division of Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad - 500 007, India.
authors.forename: Lavanya
authors.initials: L
authors.lastname: Nadella
authors.affiliation: Syngene International Ltd., Biocon park, Bangalore - 560 099, India.
authors.forename: Tanmay
authors.initials: T
authors.lastname: Banerjee
authors.affiliation: Division of Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad - 500 007, India.
authors.forename: Haridas B
authors.initials: HB
authors.lastname: Rode
authors.affiliation: Division of Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad - 500 007, India.
authors.forename: Prathama S
authors.initials: PS
authors.lastname: Mainkar
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad - 500 007, India.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Ummanni
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D056945:Hep G2 Cells; D006801:Humans; D009163:Mycobacterium bovis / Q000254:growth & development; D020102:Mycobacterium smegmatis / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000254:growth & development*; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents