Background: Bedaquiline is a novel anti-tuberculosis drug that inhibits Mycobacterial
ATP synthase. However, studies have 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
Objective: The study aimed to design, synthesise and carry out biological evaluation of antituberculosis
agents based on the structure of bedaquiline.
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 inhibitory
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 structureactivity
relationship of the obtained compounds. The predicted ADMET properties of the 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.