title: Design, Synthesis, and Evaluation of Novel Hybrid Efflux Pump Inhibitors for Use against Mycobacterium tuberculosis.
abstract: Efflux pumps are considered a major potential contributor to the development of various forms of resistance in Mycobacterium tuberculosis leading to the emergence of multidrug-resistant tuberculosis (TB). Verapamil (VER) and tricyclic chemosensitizers such as the phenothiazines are known to possess efflux pump inhibition properties and have demonstrated significant efficacy in various TB disease models. Novel hybrid molecules based on fusion of the VER substructure with various tricyclic, as well as nontricyclic, chemosensitizer cores or their structural motifs are described. These hybrid compounds were evaluated in vitro and ex vivo individually for their intrinsic activity and in combination for their potentiating potential with the frontline anti-TB drugs, rifampin and isoniazid. In addition, efflux pump inhibition was assessed in an ethidium bromide assay. This study led to the identification of novel compounds, termed hybrid efflux pump inhibitors, with intrinsic antimycobacterial activities (MIC90≤ 3.17 μg/mL) and intracellular activity in macrophages at a low concentration (≤6.25 μg/mL).
authors.affiliation: Department of Chemistry, 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.
authors.forename: Kawaljit
authors.initials: K
authors.lastname: Singh
authors.affiliation: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Department of Pathology, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Krupa
authors.initials: K
authors.lastname: Naran
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy and Immunology, Saint Louis University , 1100 South Grand Boulevard, St. Louis, Missouri 63104, United States.
authors.forename: Fahreta
authors.initials: F
authors.lastname: Hamzabegovic
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy and Immunology, Saint Louis University , 1100 South Grand Boulevard, St. Louis, Missouri 63104, United States.|Department of Molecular Biology, Saint Louis University , 1100 South Grand Boulevard, St. Louis, Missouri 63104, United States.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hoft
authors.affiliation: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Department of Pathology, 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 , 1100 South Grand Boulevard, St. Louis, Missouri 63104, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Ruminski
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy and Immunology, Saint Louis University , 1100 South Grand Boulevard, St. Louis, Missouri 63104, United States.
authors.forename: Getahun
authors.initials: G
authors.lastname: Abate
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.|Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Rondebosch 7701, South Africa.|South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014376:Tuberculosis / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D026901:Membrane Transport Proteins
keywords: adjunctive agents; chemosensitizers; ethidium bromide; macrophages; thioridazine; verapamil