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Design, Synthesis and Biological Evaluation of Anti-tuberculosis Agents based on Bedaquiline Structure

Author(s):

Chengjun Wu*, Jinghan Luo, Mengtong Wu, Fanzhen Meng, Zhiqiang Cai, Yu Chen and Tiemin Sun   Pages 1 - 12 ( 12 )

Abstract:


Background: Bedaquiline is a novel anti-tuberculosis drug that inhibits Mycobacterial ATP synthase. However, It studies have been found that bedaquiline has serious side effects due to high lipophilicity. Recently, the complete structure of ATP synthase was first reported in the journal of Science.

Objective: The study aimed to design, synthesis and biological evaluation of anti-tuberculosis agents based on Bedaquiline structure.

Methods: The mode of action of bedaquiline and ATP synthase was determined by molecular docking, and a series of low lipophilic bedaquiline derivatives were synthesized. The inhibiting activities of bedaquiline derivatives towards Mycobacterium phlei 1180 and Mycobacterium tuberculosis H37Rv were evaluated in vitro. A docking study was carried out to elucidate the structure-activity relationship of the obtained compounds. The predicted ADMET properties of synthesized compounds were also analyzed.

Results: The compounds 5c3, 6a1, and 6d3 showed good inhibitory activities (MIC=15.62 ug.mL-1). At the same time, the compounds 5c3, 6a1, and 6d3 also showed good drug-like properties through molecular docking and ADMET properties prediction.

Conclusion: The results of in vitro anti-tuberculosis activity assays, docking studies and ADMET predictions indicate that the synthesized compounds have potential antifungal activity, with compounds 6a1 being further optimized and developed as lead compounds.

Keywords:

Bedaquiline derivatives, Anti-tuberculosis, ATP synthase, Molecular docking?ADMET

Affiliation:

Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR, Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR, Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR, Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR, College of Petrochemical Engineering, Shenyang University of Technology, Liaoyang 111003, College of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016



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