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Molecules 2016, 21(7), 875; doi:10.3390/molecules21070875

Design and Stereochemical Research (DFT, ECD and Crystal Structure) of Novel Bedaquiline Analogs as Potent Antituberculosis Agents

Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, China
School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 22 May 2016 / Revised: 20 June 2016 / Accepted: 29 June 2016 / Published: 4 July 2016
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [2682 KB, uploaded 4 July 2016]   |  


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. View Full-Text
Keywords: anti-tuberculosis; absolute configuration; DFT; ECD; X-ray diffraction; docking anti-tuberculosis; absolute configuration; DFT; ECD; X-ray diffraction; docking

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Geng, Y.; Li, L.; Wu, C.; Chi, Y.; Li, Z.; Xu, W.; Sun, T. Design and Stereochemical Research (DFT, ECD and Crystal Structure) of Novel Bedaquiline Analogs as Potent Antituberculosis Agents. Molecules 2016, 21, 875.

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