| ORIGINAL ARTICLE |
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Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents |
| Yuan Liu1, Fa-Qi Wang1, Xin-Hao Hua1, Shu-Han Yang1, Li-Ning Wang2, Yun-Sheng Xu1, Chen-Yue Shao1, Xiang-Bo Gou1, Yu-Ming Liu1 |
1. Department of Pharmacy Engineering, Tianjin University of Technology, Tianjin, 300384, People's Republic of China;
2. College of Traditional Chinese Medicine, Tianjin Univerisity of Traditional Chinese Medicine, Tianjin, 300193, People's Republic of China |
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Abstract 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 cardiomyocyte 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 exceeding 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 specificity on NHE-1 inhibition. Molecular modelling studies suggested the ability of compounds 9m and 9o to establish 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.
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| Keywords
Buthus martensii
Amide-guanidine derivatives
Cardioprotective agents
NHE-1
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| Fund:This work was financially supported by the National Natural Science Foundation of China (NSFC) Youth Project (No. 82204397). |
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Corresponding Authors:
Xiang-Bo Gou, E-mail:gouxiangbo@163.com;Yu-Ming Liu, E-mail:coumarin1968@hotmail.com
E-mail: gouxiangbo@163.com;coumarin1968@hotmail.com
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Issue Date: 17 May 2025
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