Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents

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 compound...

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Main Authors: Yuan Liu, Fa-Qi Wang, Xin-Hao Hua, Shu-Han Yang, Li-Ning Wang, Yun-Sheng Xu, Chen-Yue Shao, Xiang-Bo Gou, Yu-Ming Liu
Format: Article
Language:English
Published: SpringerOpen 2025-02-01
Series:Natural Products and Bioprospecting
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Online Access:https://doi.org/10.1007/s13659-025-00497-9
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author Yuan Liu
Fa-Qi Wang
Xin-Hao Hua
Shu-Han Yang
Li-Ning Wang
Yun-Sheng Xu
Chen-Yue Shao
Xiang-Bo Gou
Yu-Ming Liu
author_facet Yuan Liu
Fa-Qi Wang
Xin-Hao Hua
Shu-Han Yang
Li-Ning Wang
Yun-Sheng Xu
Chen-Yue Shao
Xiang-Bo Gou
Yu-Ming Liu
author_sort Yuan Liu
collection DOAJ
description 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. Graphical Abstract
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spelling doaj-art-9ed5328de7f24c26898d99e55b33a1f82025-02-09T12:59:47ZengSpringerOpenNatural Products and Bioprospecting2192-21952192-22092025-02-0115111410.1007/s13659-025-00497-9Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agentsYuan Liu0Fa-Qi Wang1Xin-Hao Hua2Shu-Han Yang3Li-Ning Wang4Yun-Sheng Xu5Chen-Yue Shao6Xiang-Bo Gou7Yu-Ming Liu8Department of Pharmacy Engineering, Tianjin University of TechnologyDepartment of Pharmacy Engineering, Tianjin University of TechnologyDepartment of Pharmacy Engineering, Tianjin University of TechnologyDepartment of Pharmacy Engineering, Tianjin University of TechnologyCollege of Traditional Chinese Medicine, Tianjin Univerisity of Traditional Chinese MedicineDepartment of Pharmacy Engineering, Tianjin University of TechnologyDepartment of Pharmacy Engineering, Tianjin University of TechnologyDepartment of Pharmacy Engineering, Tianjin University of TechnologyDepartment of Pharmacy Engineering, Tianjin University of TechnologyAbstract 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. Graphical Abstracthttps://doi.org/10.1007/s13659-025-00497-9Buthus martensiiAmide-guanidine derivativesCardioprotective agentsNHE-1
spellingShingle Yuan Liu
Fa-Qi Wang
Xin-Hao Hua
Shu-Han Yang
Li-Ning Wang
Yun-Sheng Xu
Chen-Yue Shao
Xiang-Bo Gou
Yu-Ming Liu
Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents
Natural Products and Bioprospecting
Buthus martensii
Amide-guanidine derivatives
Cardioprotective agents
NHE-1
title Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents
title_full Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents
title_fullStr Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents
title_full_unstemmed Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents
title_short Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents
title_sort design synthesis and biological evaluation of buthutin derivatives as cardioprotective agents
topic Buthus martensii
Amide-guanidine derivatives
Cardioprotective agents
NHE-1
url https://doi.org/10.1007/s13659-025-00497-9
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