摘要Natural products are the important sources in cardiovascular drug development.In this study,twenty-nine buthutin derivatives were designed,synthesized,and evaluated for their NHE-1 inhibition and protective effects on cardiomyo-cyte injury.The structure of the newly synthesized compounds had been confirmed by 1H-NMR,13C-NMR,and HR-ESI-MS spectra.Among all target compounds at 1 μM,compounds 9d,9f,9k,9m,and 9n,with a protection ratio exceed-ing 30％,exerted stronger protective effects on H9c2 cardiomyocyte than positive control dexrazoxane and buthutin A.Meanwhile,compounds 9k,9m,and 9o showed the significant NHE-1 inhibitory activities on H9c2 cardiomyocyte,all with a dpHi/min value less than 0.23.What is more,compounds 9k,9m,9o and buthutin A all exhibited the speci-ficity on NHE-1 inhibition.Molecular modelling studies suggested the ability of compounds 9m and 9o to estab-lish interactions with three hydrogen bonds to Asp267 and Glu346 of NHE-1,but also the ability with much lower CDOCKER energies than positive control cariporide and buthutin A.The structure-activity relationship(SAR)studies suggested that the presences of amide group,four-carbon linker,and para hydroxyl benzene ring were advantageous pharmacophores for above two pharmacological actions.This research would open new avenues for developing amide-guanidine-based cardioprotective agents.