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

Abstract

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 Science. 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.

Proton Pumping ATPases: Rotational Catalysis, Physiological Roles in Oral Pathogenic Bacteria, and Inhibitors

“…More recently, it was reported that bedaquiline analogs and other compounds binding to the bedaquiline binding site display more potent antituberculosis activity and/or less toxicity to mammals than bedaquiline. 83,84) These inhibitors could be potential candidates for antidental caries agents.…”

Design and synthesis of leucylaniline derivatives as leucyl-tRNA synthetase inhibitors

“…181-182 1C. (S)-2-amino-N-(3-(N-cyclohexyl-N-ethylsulfamoyl)phenyl)-4-methylpentanamide (22). To a solution of (S)-2-Boc-amino-N-(4-(N-(furan-2-ylmethyl)sulfamoyl)phenyl)-4-methylpentanamide (0.6 g, 0.0013 mol) in DCM, TFA (0.45 g, 0.004 mol) was added at room temperature and the mixture was stirred for 4 h. Later, it was washed with saturated NaHCO 3 solution and followed by brine solution.…”

“…In related literature reports, it has been observed that the heterocyclic structure can generate hydrogen bonds with protein receptors, thereby increasing the activity of compounds. [21][22][23] Based on the key role of leucine and benzamide in various antibacterial drugs, we designed and synthesized a series of new leucine aniline derivatives. We hope to have a good structure-activity relationship.…”