title: Design and Stereochemical Research (DFT, ECD and Crystal Structure) of Novel Bedaquiline Analogs as Potent Antituberculosis Agents.
abstract: A series of bedaquiline analogs containing H-bond donors were designed as anti-Mycobacterium tuberculosis drugs. A pair of diastereoisomers (R/S- and S/S-isomers) was selected from these designed compounds for synthetic and stereochemical research. The title compounds were synthesized from chiral precursors for the first time and the absolute configurations (ACs) were determined by electronic circular dichroism (ECD) with quantum chemical calculations. Moreover, a single crystal of the S/S compound was obtained for X-ray diffraction analysis, and the crystal structure showed high consistency with the geometry, confirming the reliability of ACs obtained by ECD analyses and theoretical simulation. Furthermore, the effect of stereochemistry on the anti-tuberculosis activity was investigated. The MICs of the R/S- and S/S-isomers against Mycobacterium phlei 1180 are 9.6 and 32.1 μg·mL(-1), respectively. Finally, molecular docking was carried out to evaluate the inhibitory nature and binding mode differences between diastereoisomers.
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, China. gengyiding86@163.com.
authors.forename: Yiding
authors.initials: Y
authors.lastname: Geng
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, China. xt_llw@163.com.
authors.forename: Linwei
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, China. chengjun871@163.com.
authors.forename: Chengjun
authors.initials: C
authors.lastname: Wu
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, China. c420491898@163.com.
authors.forename: Yumeng
authors.initials: Y
authors.lastname: Chi
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, China. spencerleo@163.com.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China. shxuwei8720@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, China. suntiemin@126.com.
authors.forename: Tiemin
authors.initials: T
authors.lastname: Sun
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D064687:Diarylquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; C493870:bedaquiline; D000251:Adenosine Triphosphatases
keywords: DFT; ECD; X-ray diffraction; absolute configuration; anti-tuberculosis; docking