title: Synthesis of new verapamil analogues and their evaluation in combination with rifampicin against Mycobacterium tuberculosis and molecular docking studies in the binding site of efflux protein Rv1258c.
abstract: New verapamil analogues were synthesized and their inhibitory activities against Mycobacterium tuberculosis H37Rv determined in vitro alone and in combination with rifampicin (RIF). Some analogues showed comparable activity to verapamil and exhibited better synergies with RIF. Molecular docking studies of the binding sites of Rv1258c, a M. tuberculosis efflux protein previously implicated in intrinsic resistance to RIF, suggested a potential rationale for the superior synergistic interactions observed with some analogues.
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Kawaljit
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Malkeet
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Elumalai
authors.initials: E
authors.lastname: Pavadai
authors.affiliation: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Division of Medical Microbiology, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Krupa
authors.initials: K
authors.lastname: Naran
authors.affiliation: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Division of Medical Microbiology, University of Cape Town, Rondebosch 7701, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Digby F
authors.initials: DF
authors.lastname: Warner
authors.affiliation: Centre for World Health and Medicine, Saint Louis University, USA.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Ruminski
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa. Electronic address: Kelly.Chibale@uct.ac.za.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D012293:Rifampin / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C519050:Rv1258c protein, Mycobacterium tuberculosis; D014700:Verapamil; D012293:Rifampin
keywords: Efflux pump; Rifampicin; Rv1258c; Tuberculosis; Verapamil