Design, Synthesis, and Evaluation of Novel Hybrid Efflux Pump Inhibitors for Use against Mycobacterium tuberculosis
| Autor: | Malkeet Kumar, Getahun Abate, Digby F. Warner, Daniel F. Hoft, Kelly Chibale, Kawaljit Singh, Krupa Naran, Peter G. Ruminski, Fahreta Hamzabegovic |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.drug_class Antitubercular Agents Chemosensitizer Microbial Sensitivity Tests Biology Pharmacology Antimycobacterial Mycobacterium tuberculosis 03 medical and health sciences chemistry.chemical_compound Bacterial Proteins medicine Humans Tuberculosis chemistry.chemical_classification Isoniazid Membrane Transport Proteins biology.organism_classification In vitro 030104 developmental biology Infectious Diseases chemistry Biochemistry Drug Design Efflux Ethidium bromide Tricyclic medicine.drug |
| Zdroj: | ACS Infectious Diseases. 2:714-725 |
| ISSN: | 2373-8227 |
| DOI: | 10.1021/acsinfecdis.6b00111 |
| Popis: | 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 ≤... |
| Databáze: | OpenAIRE |
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