Bis(7)-harmine derivatives as potential multi-target anti-Alzheimer agents
IntroductionThe multi-targeted ligands (MTDL) strategy has been recognized as a promising Approach for the development of effective treatments against Alzheimer’s disease (AD), due to the presence of multiple pathological mechanisms in AD. In this study, a series of bis(7)-harmine derivatives were d...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2025.1545908/full |
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| author | Hongtao Du Hongtao Du Hongtao Du Fang Ma Fang Ma Yuanyuan Cao Miaoyan Bai Xinyi Gao Ziyi Yang Yang Xu Yan Yan Yan Yan |
| author_facet | Hongtao Du Hongtao Du Hongtao Du Fang Ma Fang Ma Yuanyuan Cao Miaoyan Bai Xinyi Gao Ziyi Yang Yang Xu Yan Yan Yan Yan |
| author_sort | Hongtao Du |
| collection | DOAJ |
| description | IntroductionThe multi-targeted ligands (MTDL) strategy has been recognized as a promising Approach for the development of effective treatments against Alzheimer’s disease (AD), due to the presence of multiple pathological mechanisms in AD. In this study, a series of bis(7)-harmine derivatives were designed and synthesized as multifunctional drugs for the treatment of AD.MethodsThe derivatives were synthesized by chemical methods and their structure was confirmed by nuclear magnetic resonance (NMR). The Ellman’s assay was utilized to assess the inhibitory potential of derivatives against hAChE and hBuChE. The inhibitory activity of these derivatives on both hMAO-A and hMAO-B was assessed using a fluorescence-based method. The thioflavin T (Th-T) fluorescence assay was used to assess the inhibition of Aβ1−42 self-aggregation. The cytotoxicity was evaluated using the MTT assay. The Surflex-Dock program in Sybyl-X2.0 Software was employed for molecular docking.ResultsIn vitro studies revealed that numerous synthesized compounds exhibited potent inhibitory activity against hAChE, and hMAO-B (IC50 < 1 μM), as well as Aβ1−42 aggregation (IC50 < 20 μM). Importantly, the multitarget compounds 6d, 8c, and 8d exhibited remarkable efficacy in simultaneously mitigating Aβ-induced toxicity in SH−SY5Y cells while demonstrating minimal cytotoxicity. Furthermore, predicted ADMET results suggested that 6d, 8c, and 8d possessed favorable pharmacokinetic properties and demonstrated low toxicity levels. Additionally, molecular docking studies of 6d within the activesites of hAChE, hMAO-B, and Aβ1−42 elucidated the inhibition mechanism.Discussion and conclusionBased on these findings, it is evident that 6d, 8c, and 8d hold potential as promising multi-functional drugs for AD treatment. |
| format | Article |
| id | doaj-art-340fb71f10af49c3b22c768faf99b95d |
| institution | Kabale University |
| issn | 2296-2646 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Chemistry |
| spelling | doaj-art-340fb71f10af49c3b22c768faf99b95d2025-01-29T06:45:41ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462025-01-011310.3389/fchem.2025.15459081545908Bis(7)-harmine derivatives as potential multi-target anti-Alzheimer agentsHongtao Du0Hongtao Du1Hongtao Du2Fang Ma3Fang Ma4Yuanyuan Cao5Miaoyan Bai6Xinyi Gao7Ziyi Yang8Yang Xu9Yan Yan10Yan Yan11Shaanxi Key Laboratory of Chinese Jujube, College of Life Sciences, Yan’an University, Yan’an, Shaanxi, ChinaShaanxi Qi Yuan Kang Bo Biotechnology Co., Ltd., Tongchuan, Shaanxi, ChinaCollege of Life Science, Xinyang Normal University, Xinyang, ChinaShaanxi Key Laboratory of Chinese Jujube, College of Life Sciences, Yan’an University, Yan’an, Shaanxi, ChinaShaanxi Qi Yuan Kang Bo Biotechnology Co., Ltd., Tongchuan, Shaanxi, ChinaShaanxi Key Laboratory of Chinese Jujube, College of Life Sciences, Yan’an University, Yan’an, Shaanxi, ChinaShaanxi Key Laboratory of Chinese Jujube, College of Life Sciences, Yan’an University, Yan’an, Shaanxi, ChinaShaanxi Key Laboratory of Chinese Jujube, College of Life Sciences, Yan’an University, Yan’an, Shaanxi, ChinaShaanxi Key Laboratory of Chinese Jujube, College of Life Sciences, Yan’an University, Yan’an, Shaanxi, ChinaShaanxi Key Laboratory of Chinese Jujube, College of Life Sciences, Yan’an University, Yan’an, Shaanxi, ChinaShaanxi Key Laboratory of Chinese Jujube, College of Life Sciences, Yan’an University, Yan’an, Shaanxi, ChinaNorthwest A&F University, Xianyang, Shaanxi, ChinaIntroductionThe multi-targeted ligands (MTDL) strategy has been recognized as a promising Approach for the development of effective treatments against Alzheimer’s disease (AD), due to the presence of multiple pathological mechanisms in AD. In this study, a series of bis(7)-harmine derivatives were designed and synthesized as multifunctional drugs for the treatment of AD.MethodsThe derivatives were synthesized by chemical methods and their structure was confirmed by nuclear magnetic resonance (NMR). The Ellman’s assay was utilized to assess the inhibitory potential of derivatives against hAChE and hBuChE. The inhibitory activity of these derivatives on both hMAO-A and hMAO-B was assessed using a fluorescence-based method. The thioflavin T (Th-T) fluorescence assay was used to assess the inhibition of Aβ1−42 self-aggregation. The cytotoxicity was evaluated using the MTT assay. The Surflex-Dock program in Sybyl-X2.0 Software was employed for molecular docking.ResultsIn vitro studies revealed that numerous synthesized compounds exhibited potent inhibitory activity against hAChE, and hMAO-B (IC50 < 1 μM), as well as Aβ1−42 aggregation (IC50 < 20 μM). Importantly, the multitarget compounds 6d, 8c, and 8d exhibited remarkable efficacy in simultaneously mitigating Aβ-induced toxicity in SH−SY5Y cells while demonstrating minimal cytotoxicity. Furthermore, predicted ADMET results suggested that 6d, 8c, and 8d possessed favorable pharmacokinetic properties and demonstrated low toxicity levels. Additionally, molecular docking studies of 6d within the activesites of hAChE, hMAO-B, and Aβ1−42 elucidated the inhibition mechanism.Discussion and conclusionBased on these findings, it is evident that 6d, 8c, and 8d hold potential as promising multi-functional drugs for AD treatment.https://www.frontiersin.org/articles/10.3389/fchem.2025.1545908/fullAlzheimer’s diseaseharmineacetylcholinesterasemonoamine oxidaseamyloid peptide (Aβ) |
| spellingShingle | Hongtao Du Hongtao Du Hongtao Du Fang Ma Fang Ma Yuanyuan Cao Miaoyan Bai Xinyi Gao Ziyi Yang Yang Xu Yan Yan Yan Yan Bis(7)-harmine derivatives as potential multi-target anti-Alzheimer agents Frontiers in Chemistry Alzheimer’s disease harmine acetylcholinesterase monoamine oxidase amyloid peptide (Aβ) |
| title | Bis(7)-harmine derivatives as potential multi-target anti-Alzheimer agents |
| title_full | Bis(7)-harmine derivatives as potential multi-target anti-Alzheimer agents |
| title_fullStr | Bis(7)-harmine derivatives as potential multi-target anti-Alzheimer agents |
| title_full_unstemmed | Bis(7)-harmine derivatives as potential multi-target anti-Alzheimer agents |
| title_short | Bis(7)-harmine derivatives as potential multi-target anti-Alzheimer agents |
| title_sort | bis 7 harmine derivatives as potential multi target anti alzheimer agents |
| topic | Alzheimer’s disease harmine acetylcholinesterase monoamine oxidase amyloid peptide (Aβ) |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2025.1545908/full |
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