title: Structural Simplification of Bedaquiline: the Discovery of 3-(4-(N,N-Dimethylaminomethyl)phenyl)quinoline-Derived Antitubercular Lead Compounds.
abstract: Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub-microgram per mL concentrations against both sensitive and multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC-ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower-cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non-ATP synthase related targets.
authors: State Key Laboratory of Bioactive Substances and Function ofNatural Medicine, Institute of Materia Medica, Peking Union Medical College andChinese Academy of Medical Sciences, Beijing, 100050, China.|Beijing Key Laboratory of Active Substances Discovery and DrugabilityEvaluation, Institute of Materia Medica, Peking Union Medical College andChinese Academy of Medical Sciences, Beijing, 100050, China.
authors: Chunxian
authors: C
authors: He
authors: Department of Structural Biology, Max Planck Institute of Biophysics, Max-von-Laue-Str. 3, 60438, Frankfurt am Main, Germany.
authors: Laura
authors: L
authors: Preiss
authors: Department of Pharmacology, Beijing Tuberculosis and Thoracic TumorResearch Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing, 101149, China.
authors: Bin
authors: B
authors: Wang
authors: Department of Pharmacology, Beijing Tuberculosis and Thoracic TumorResearch Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing, 101149, China.
authors: Lei
authors: L
authors: Fu
authors: Beijing Key Laboratory of Active Substances Discovery and DrugabilityEvaluation, Institute of Materia Medica, Peking Union Medical College andChinese Academy of Medical Sciences, Beijing, 100050, China.
authors: Hui
authors: H
authors: Wen
authors: Beijing Key Laboratory of Active Substances Discovery and DrugabilityEvaluation, Institute of Materia Medica, Peking Union Medical College andChinese Academy of Medical Sciences, Beijing, 100050, China.
authors: Xiang
authors: X
authors: Zhang
authors: Beijing Key Laboratory of Active Substances Discovery and DrugabilityEvaluation, Institute of Materia Medica, Peking Union Medical College andChinese Academy of Medical Sciences, Beijing, 100050, China.
authors: Huaqing
authors: H
authors: Cui
authors: Department of Structural Biology, Max Planck Institute of Biophysics, Max-von-Laue-Str. 3, 60438, Frankfurt am Main, Germany.|Department of Life Sciences, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
authors: Thomas
authors: T
authors: Meier
authors: State Key Laboratory of Bioactive Substances and Function ofNatural Medicine, Institute of Materia Medica, Peking Union Medical College andChinese Academy of Medical Sciences, Beijing, 100050, China.
authors: Dali
authors: D
authors: Yin
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D064687:Diarylquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; D011804:Quinolines; C493870:bedaquiline; C037219:quinoline
keywords: ATP synthase; Mycobacterium tuberculosis; bedaquiline; multidrug resistance; pulmonary tuberculosis