首页|TAG-Assisted Liquid-Phase Synthesis and Structure Activity Relationship of Macolacin-Based Side-to-Tail Cyclopeptides Antibiotic
TAG-Assisted Liquid-Phase Synthesis and Structure Activity Relationship of Macolacin-Based Side-to-Tail Cyclopeptides Antibiotic
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TAG-assisted peptide synthesis technology enables optimal conservation of Fmoc amino acid raw materials and chemical solvents while eliminating the need for intricate chromatographic purification processes.This work presents a 4,4'-diphenylphosphonoxy di-phenylcarbinol tag-mediated liquid-phase synthesis approach for preparing side-to-tail cyclopeptides macolacin which has strong ac-tivity against gram-negative bacteria,and its 15 analogues containing four N-methylation modified cyclopeptides,as well as an inves-tigation of their structure-activity relationship(SAR).The synthesis of macolacin analogues primarily focuses on the modifications of the N-methylation group of Ile-7 and the tail fatty acyl chain of macolacin.The incorporation of N-methylation for Ile-7,along with the dihalogenated or monohalogenated benzoic acids for tail modification,exhibited remarkable antibacterial efficacy and minimal hepa-tocellular toxicity in vitro.The present study identified an N-methylation-modified antimicrobial cyclopeptide Ma14 that exhibits rapid bactericidal efficacy against A.baumanii,etc.,while showing reduced hepatocellular toxicity.Molecular docking simulations were conducted to investigate the binding of cyclopeptides to the outer membrane protein BamA of A.baumannii.The findings demon-strated the stable binding interactions of the cyclopeptides with the BamA protein and then presented a novel approach to explain the bacteriostatic mechanism of macolacin-based cyclopeptide antibiotics.
Shanxi Provincial Key Laboratory of Drug Synthesis and Novel Pharmaceutical Preparation Technology,School of Pharmacy,Shanxi Medical University,Taiyuan,Shanxi 030001,China
Medicinal Basic Research Innovation Center of Chronic Kidney Disease,Ministry of Education,Shanxi Medical University,Taiyuan,Shanxi 030001,China
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