title: Repurposing of a drug scaffold: Identification of novel sila analogues of rimonabant as potent antitubercular agents.
abstract: The structural similarity between an MmpL3 inhibitor BM212, and a cannabinoid receptor modulator rimonabant, prompted us to investigate the anti-tubercular activity of rimonabant and its analogues. Further optimization, particularly through incorporation of silicon into the scaffold, resulted in new compounds with significant improvement in anti-tubercular activity against Mycobacterium tuberculosis (H37Rv). The sila analogue 18a was found to be the most potent antimycobacterial compound (MIC, 31 ng/mL) from this series with an excellent selectivity index.
authors.affiliation: CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411008, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110 025, India.
authors.forename: Remya
authors.initials: R
authors.lastname: Ramesh
authors.affiliation: CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411008, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110 025, India.
authors.forename: Rahul D
authors.initials: RD
authors.lastname: Shingare
authors.affiliation: CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411008, India.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110 025, India.
authors.forename: Amitesh
authors.initials: A
authors.lastname: Anand
authors.affiliation: CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India.
authors.forename: Swetha
authors.initials: S
authors.lastname: B
authors.affiliation: Incozen Therapeutics Pvt. Ltd., Alexandria Knowledge Park, Turkapally, Rangareddy, 500078, India.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Veeraraghavan
authors.affiliation: Incozen Therapeutics Pvt. Ltd., Alexandria Knowledge Park, Turkapally, Rangareddy, 500078, India.
authors.forename: Srikant
authors.initials: S
authors.lastname: Viswanadha
authors.affiliation: CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110 025, India.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Ummanni
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110 025, India.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Gokhale
authors.affiliation: CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411008, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110 025, India. Electronic address: ds.reddy@ncl.res.in.
authors.forename: D
authors.initials: D
authors.lastname: Srinivasa Reddy
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D058492:Drug Repositioning; D056945:Hep G2 Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000077285:Rimonabant; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D010880:Piperidines; D011720:Pyrazoles; D000077285:Rimonabant
keywords: BM212; Drug repurposing; MmpL3 inhibitor; Rimonabant; Sila analogue; Tuberculosis