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...
Saved in:
Main Authors: | , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
SpringerOpen
2025-02-01
|
Series: | Natural Products and Bioprospecting |
Subjects: | |
Online Access: | https://doi.org/10.1007/s13659-025-00497-9 |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
_version_ | 1823861487107571712 |
---|---|
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 |
format | Article |
id | doaj-art-9ed5328de7f24c26898d99e55b33a1f8 |
institution | Kabale University |
issn | 2192-2195 2192-2209 |
language | English |
publishDate | 2025-02-01 |
publisher | SpringerOpen |
record_format | Article |
series | Natural Products and Bioprospecting |
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 |
work_keys_str_mv | AT yuanliu designsynthesisandbiologicalevaluationofbuthutinderivativesascardioprotectiveagents AT faqiwang designsynthesisandbiologicalevaluationofbuthutinderivativesascardioprotectiveagents AT xinhaohua designsynthesisandbiologicalevaluationofbuthutinderivativesascardioprotectiveagents AT shuhanyang designsynthesisandbiologicalevaluationofbuthutinderivativesascardioprotectiveagents AT liningwang designsynthesisandbiologicalevaluationofbuthutinderivativesascardioprotectiveagents AT yunshengxu designsynthesisandbiologicalevaluationofbuthutinderivativesascardioprotectiveagents AT chenyueshao designsynthesisandbiologicalevaluationofbuthutinderivativesascardioprotectiveagents AT xiangbogou designsynthesisandbiologicalevaluationofbuthutinderivativesascardioprotectiveagents AT yumingliu designsynthesisandbiologicalevaluationofbuthutinderivativesascardioprotectiveagents |