1. Design, synthesis, biological evaluation, structure-activity relationship, and toxicity of clinafloxacin-azole conjugates as novel antitubercular agents
- Author
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Ren Zhenghong, Xuemei Tang, Jie Liu, Jianyong Wei, Da-Cheng Yang, Li Fan, and Xu Xingran
- Subjects
Azoles ,Staphylococcus aureus ,Clinical Biochemistry ,Antitubercular Agents ,Pharmaceutical Science ,Microbial Sensitivity Tests ,01 natural sciences ,Biochemistry ,HeLa ,Structure-Activity Relationship ,Minimum inhibitory concentration ,chemistry.chemical_compound ,Salmonella ,Drug Discovery ,Escherichia coli ,Humans ,Structure–activity relationship ,Bioassay ,Molecular Biology ,chemistry.chemical_classification ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Mycobacterium tuberculosis ,biology.organism_classification ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Drug Design ,Pseudomonas aeruginosa ,Molecular Medicine ,Azole ,Antibacterial activity ,Clinafloxacin ,Fluoroquinolones ,HeLa Cells - Abstract
Based on the advantages of azole molecules and fluoroquinolone drugs, we designed and synthesized 34 clinafloxacin-azole conjugates using fragment-based drug design and drug combination principles. The in vitro activities of the synthesized conjugates against Mycobacterium tuberculosis (H37Rv), Hela cell as well as Gram-positive and Gram-negative bacteria were assayed. The bioassay results revealed that most of the target molecules had anti-tuberculosis (anti-TB) activity, of which 14 compounds had very strong anti-TB activity [minimum inhibitory concentration (MIC) 2 μM]. In addition, the compounds with strong activity towards H37Rv had weak activity towards Gram-negative and Gram-positive bacteria, showing obvious selectivity towards H37Rv. Predicted toxicity data indicated that 27 molecules were less toxic or equivalent to that of the original drug (clinafloxacin). Especially, it is demonstrated that compound TM2l exhibited the strongest anti-TB activity (MIC = 0.29 μM), low antibacterial activity, negligible toxicity, and good drug-likeness values, which can be considered as an ideal lead molecule for future optimization.
- Published
- 2019