Design, Synthesis And Biological Activities Of Clarithromycin Carbamate Derivatives Against Resistant Bacteria

When macrolides introduced fatty or aromatic side chains,they could get to ribonucleotide binding site at P or A position in peptidy tunnel,binding to them by hydrogen bond.As a result,target compounds had antibacterial activity against resistant S.pneumoniae.Based on the above thoughts,a series of novel 14-membered macrolide derivatives were designed and synthesized from clarithromycin as a lead compound through the introduction of side chains at C-4" position of its skeleton. Their structures were confirmed by MS,IR and ~1H NMR spectra.In addition,the synthetic routes for the series were successfully established and had such features as high yields,simple operations and mild conditions.In vitro antibacterial activity of the target compounds F1～F15 was determined by using the tube dilution method.The results were as follows:①all of the target compounds had excellent activity against sensitive S.pneumoniae(MIC＜0.125μg/mL) and Staphylococcus aureus(MIC＜0.5μg/mL).②Some target compounds had good activity against resistant S.pneumoniae A22072(mefA),S.pneumoniae B5 (ermB) and mixing S.pneumoniae A+B14(ermB+mefA).Among them,target compounds F7 had potent antibacterial activity against resistant S.pneumoniae B5 (ermB),S.pneumoniae A22072(mefA) and mixing S.pneumoniae A+B14(ermB +mefA),MIC value were 0.125μg/mL,0.25μg/mL and 1μg/mL one by one.Through the analysis of target compounds about structure-function relationship, we got some conclusions as follows:First,compounds with hydroxyl group or amino group that could bind with ribosome,had good antibacterial activity against sensitive and resistant bacteria.Secondly,when electrophilic group of benzene ring at C-4" position of compounds was para position,target compounds had potent antibacterial activity,such as compounds F6,F7,F8,etc.Thirdly,when the interval of two carbamoyl groups at C-4" position of compounds was three carbon atom,target compounds had more excellent antibacterial activity against resistant S.pneumoniae than those compounds that the interval of two carbamoyl groups was five carbon atom at C-4" position.