Synthesis and antibacterial activity of amino acid substituted phenyl ether pleuromutilin derivatives
Objective The objective of this study was to design and synthesize pleuromutilin derivatives in order to discover new compounds that exhibit broad-spectrum antibacterial activity,high efficiency,and safety.Methods The starting material used for the synthesis of the pleuromutilin derivatives was the natural product pleuromutilin.Three aminophenyl ether pleuromutilin derivatives and eight amino acid substituted phenyl ether pleuromutilin derivatives were synthesized.Activity tests,preliminary druggability evaluations,and molecular docking studies were conducted.Results Eleven novel pleuromutilin derivatives were designed and synthesized.The structures of these derivatives were confirmed using NMR,ESI-MS,and HRMS.Most of the compounds exhibited better antibacterial activity against standard Staphylococcus aureus and standard Escherichia coli compared to lefamulin.Additionally,these compounds demonstrated low cytotoxic activity(IC50＞10 pmol/L)and their physicochemical properties were accurately predicted.The results of the molecular docking studies indicated that the aminophenyl ether and amino acid modifications in the side chains of the compounds enabled the formation of more hydrogen bond interactions with the nucleotides in the binding cavity.Conclusion The modification of pleuromutilin antibiotics with aminophenols and amino acids was beneficial in improving their antibacterial activity and physicochemical properties.
PleuromutilinStructure modification of natural productsAntibacterial activityMolecular dockingCytotoxic activity
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维普
