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In this study, to enhance its cardioprotection, the triphenylphosphonium\u2010based modification of trimetazidine was conducted to deliver it specifically to mitochondria. Fifteen triphenylphosphonium (TPP) conjugated trimetazidine analogs were designed and synthesized. Their protective effects were evaluated <jats:italic>in\u2005vivo<\/jats:italic> using a <jats:italic>tert<\/jats:italic>\u2010butyl hydroperoxide (<jats:italic>t<\/jats:italic>\u2010BHP) induced zebrafish injury model. Structure\u2010activity relationship correlations revealed the best way to couple the TPP moiety to trimetazidine, and led to a new conjugate (<jats:bold>18a<\/jats:bold>) with enhanced therapeutic properties. Compared to trimetazidine, <jats:bold>18a<\/jats:bold> effectively protects against heart injury in the zebrafish model at a much lower concentration. Further study in <jats:italic>t<\/jats:italic>\u2010BHP treated zebrafish and H9c2 cells demonstrated that <jats:bold>18a<\/jats:bold> protects against cardiomyocyte death and damage by inhibiting excessive production of ROS, maintaining mitochondrial morphology, and preventing mitochondrial dysfunction. Consequently, <jats:bold>18a<\/jats:bold> can be regarded as a potential therapeutic agent for cardioprotection.<\/jats:p>","DOI":"10.1002\/cbdv.202200445","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T13:02:51Z","timestamp":1655470971000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and <i>in\u2005Vivo<\/i> Evaluation of Triphenylphosphonium Conjugated Trimetazidine with Enhanced Cardioprotection and Ability to Restore Mitochondrial Function"],"prefix":"10.1002","volume":"19","author":[{"given":"E","family":"Ou","sequence":"first","affiliation":[{"name":"School of Biomedical and Pharmaceutical Sciences Guangdong University of Technology  Guangzhou 510006 P. R. 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