Design, Synthesis, and Pharmacological Evaluation of Novel Tacrine Derivatives as Multi-target ANTI-Alzheimer's Agents In Rat Models.

Remya R S, Ramalakshmi N, Muralidharan P, Nalini C N
{"title":"Design, Synthesis, and Pharmacological Evaluation of Novel Tacrine Derivatives as Multi-target ANTI-Alzheimer's Agents In Rat Models.","authors":"Remya R S,&nbsp;Ramalakshmi N,&nbsp;Muralidharan P,&nbsp;Nalini C N","doi":"10.2174/1871524923666230908094645","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease is a progressive neurodegenerative disorder for which no curative drugs are available and treatment available is just palliative.</p><p><strong>Objectives: </strong>Current research focused on design of Tacrine-Flavone hybrids as multitargeted cholinesterase and monoamine oxidase B inhibitors.</p><p><strong>Methods: </strong>A total of 10 Tacrine- Flavone hybrids were designed, synthesized and characterized. The in vitro neurotoxicity and hepatotoxicity of the synthesized compounds determined using SHSY5Y cell line and HEPG2 cell line. One most active compound (AF1) with least toxicity in in vitro studies was chosen for in vivo studies. Acute and subacute toxicity of the novel compound AF1 conducted on Wistar rats according to OECD guideline 423 and 407. The LD50 value of the novel compound calculated according to Finney's method using Probit analysis. Anti-Alzheimer's activity studies conducted on male Wistar rats. Behavioral studies conducted and AChE and MAO-B activity determined in rat brain.</p><p><strong>Results and discussion: </strong>All the compounds exhibited good inhibitory effect on MAO B and AChE. The neurotoxicity studies of the active compound AF1 did not show toxicity up to 100μg. The hepatotoxicity study of the most active compound AF1, showed the compound to be safe up to 200μg. The LD 50 value of the novel compound after a single oral administration was found to be 64 mg/kg bodyweight in rats. Subacute toxicity studies did not show any remarkable toxicity in the vital organs up to 40 mg/kg. Activity studies showed comparable results with standard at 20 mg/kg.</p><p><strong>Conclusion: </strong>The results showed that the novel Tacrine-Flavone hybrids are multitarget-directed ligands, which are safe and active compared to tacrine and can be a promising lead molecule for further study.</p>","PeriodicalId":93930,"journal":{"name":"Central nervous system agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Central nervous system agents in medicinal chemistry","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2174/1871524923666230908094645","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Alzheimer's disease is a progressive neurodegenerative disorder for which no curative drugs are available and treatment available is just palliative.

Objectives: Current research focused on design of Tacrine-Flavone hybrids as multitargeted cholinesterase and monoamine oxidase B inhibitors.

Methods: A total of 10 Tacrine- Flavone hybrids were designed, synthesized and characterized. The in vitro neurotoxicity and hepatotoxicity of the synthesized compounds determined using SHSY5Y cell line and HEPG2 cell line. One most active compound (AF1) with least toxicity in in vitro studies was chosen for in vivo studies. Acute and subacute toxicity of the novel compound AF1 conducted on Wistar rats according to OECD guideline 423 and 407. The LD50 value of the novel compound calculated according to Finney's method using Probit analysis. Anti-Alzheimer's activity studies conducted on male Wistar rats. Behavioral studies conducted and AChE and MAO-B activity determined in rat brain.

Results and discussion: All the compounds exhibited good inhibitory effect on MAO B and AChE. The neurotoxicity studies of the active compound AF1 did not show toxicity up to 100μg. The hepatotoxicity study of the most active compound AF1, showed the compound to be safe up to 200μg. The LD 50 value of the novel compound after a single oral administration was found to be 64 mg/kg bodyweight in rats. Subacute toxicity studies did not show any remarkable toxicity in the vital organs up to 40 mg/kg. Activity studies showed comparable results with standard at 20 mg/kg.

Conclusion: The results showed that the novel Tacrine-Flavone hybrids are multitarget-directed ligands, which are safe and active compared to tacrine and can be a promising lead molecule for further study.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
新型Tacrine衍生物作为多靶点抗阿尔茨海默病药物在大鼠模型中的设计、合成和药理学评价。
背景:阿尔茨海默病是一种进行性神经退行性疾病,目前尚无治疗药物,只能进行姑息治疗。目的:目前的研究重点是设计Tacrine Flavone杂交体作为多靶向胆碱酯酶和单胺氧化酶B抑制剂。方法:设计、合成并鉴定了10个Tacrine-Flavone杂合物。用SHSY5Y细胞系和HEPG2细胞系测定合成化合物的体外神经毒性和肝毒性。选择一种在体外研究中毒性最小的活性最高的化合物(AF1)进行体内研究。根据OECD指南423和407对Wistar大鼠进行的新型化合物AF1的急性和亚急性毒性。根据Finney方法使用Probit分析计算出新化合物的LD50值。对雄性Wistar大鼠进行的抗阿尔茨海默病活性研究。进行了行为研究,并测定了大鼠大脑中AChE和MAO-B的活性。结果与讨论:所有化合物对MAOB和AChE均有良好的抑制作用。活性化合物AF1的神经毒性研究没有显示高达100μg的毒性。对最具活性的化合物AF1的肝毒性研究表明,该化合物在200μg以下是安全的。在大鼠中发现新化合物在单次口服给药后的LD50值为64mg/kg体重。亚急性毒性研究未显示高达40 mg/kg的重要器官有任何显著毒性。活性研究显示,在20mg/kg的浓度下,其结果与标准品相当。结论:结果表明,新的Tacrine Flavone杂化物是多靶点定向配体,与Tacrine相比,它是安全和活性的,可以作为进一步研究的先导分子。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
Lead Phytomolecules for Treating Parkinson's Disease. Phthalates Induced Neurotoxicity: A Mechanistic Approach. The Importance of Stem Cells in the Treatment of Neuropathic Pain. Neuroprotective Effect of Naturally Occurring Flavonoids. Antidepressant Potential of Hispidulin Present in S. barbata D. Don: Mechanistic Insights through Neurochemical and Behavioral Assessments.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1