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Development of novel carbazole derivatives with effective multifunctional action against Alzheimer's diseases: Design, synthesis, in silico, in vitro and in vivo investigation.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2019-12-28 , DOI: 10.1016/j.bioorg.2019.103524 Chandra Bhushan Mishra 1 , Siddharth Gusain 1 , Shruti Shalini 1 , Shikha Kumari 1 , Amresh Prakash 2 , Namrata Kumari 2 , Anita Kumari Yadav 1 , Jyoti Kumari 1 , Kundan Kumar 2 , Manisha Tiwari 1
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2019-12-28 , DOI: 10.1016/j.bioorg.2019.103524 Chandra Bhushan Mishra 1 , Siddharth Gusain 1 , Shruti Shalini 1 , Shikha Kumari 1 , Amresh Prakash 2 , Namrata Kumari 2 , Anita Kumari Yadav 1 , Jyoti Kumari 1 , Kundan Kumar 2 , Manisha Tiwari 1
Affiliation
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Carbazole based novel multifunctional agents has been rationally designed and synthesized as potential anti-Alzheimer agents. Multi-functional activity of these derivatives have been assessed by performing various in-vitro assays and these compounds appeared to be potent AChE inhibitors, Aβ aggregation inhibitors, anti-oxidant and neuroprotective agents. Among the entire series, MT-1 and MT-6 were most potent multifunctional agents which displayed effective and selective AChE inhibition, Aβ disaggregation, anti-oxidant and metal chelation action. Neuroprotective activity of MT-6 has been examined against H2O2 induced toxicity in SHSY-5Y cells and they have shown effective neuroprotection. Additionally, MT-6 did not display any significant toxicity in SHSY-5Y cells, indicating its non-toxic nature. Molecular docking and MD simulation studies have been also performed to explore molecular level interaction with AChE and Aβ. Finally, MT-6 was evaluated against scopolamine induced dementia model of mice and this compound actively improved memory deficit and cognition impairment in scopolamine treated mice. Thus, novel carbazole derivative MT-6 has been explored as an effective and safe multifunctional agent against AD and this molecule may be used as a suitable lead for development of effective anti-Alzheimer agents in future.
中文翻译：
具有对阿尔茨海默氏病有效的多功能作用的新型咔唑衍生物的开发：设计，合成，计算机模拟，体外和体内研究。
基于咔唑的新型多功能药物已被合理地设计和合成为潜在的抗阿尔茨海默病药物。这些衍生物的多功能活性已通过进行各种体外测定来评估，这些化合物似乎是有效的AChE抑制剂，Aβ聚集抑制剂，抗氧化剂和神经保护剂。在整个系列中，MT-1和MT-6是最有效的多功能试剂，显示出有效和选择性的AChE抑制，Aβ分解，抗氧化剂和金属螯合作用。已经检查了MT-6的神经保护活性，以对抗H2O2诱导的SHSY-5Y细胞毒性，并且它们已经显示出有效的神经保护作用。此外，MT-6在SHSY-5Y细胞中未显示任何明显的毒性，表明其无毒性质。还进行了分子对接和MD模拟研究，以探索与AChE和Aβ的分子水平相互作用。最后，针对东碱诱导的痴呆症模型对MT-6进行了评估，该化合物可有效改善东mice碱治疗的小鼠的记忆障碍和认知障碍。因此，已经开发了新型咔唑衍生物MT-6作为抗AD的有效和安全的多功能剂，并且该分子可以用作将来开发有效的抗阿尔茨海默氏剂的合适的先导。
更新日期：2019-12-29
中文翻译：
具有对阿尔茨海默氏病有效的多功能作用的新型咔唑衍生物的开发：设计，合成，计算机模拟，体外和体内研究。
基于咔唑的新型多功能药物已被合理地设计和合成为潜在的抗阿尔茨海默病药物。这些衍生物的多功能活性已通过进行各种体外测定来评估，这些化合物似乎是有效的AChE抑制剂，Aβ聚集抑制剂，抗氧化剂和神经保护剂。在整个系列中，MT-1和MT-6是最有效的多功能试剂，显示出有效和选择性的AChE抑制，Aβ分解，抗氧化剂和金属螯合作用。已经检查了MT-6的神经保护活性，以对抗H2O2诱导的SHSY-5Y细胞毒性，并且它们已经显示出有效的神经保护作用。此外，MT-6在SHSY-5Y细胞中未显示任何明显的毒性，表明其无毒性质。还进行了分子对接和MD模拟研究，以探索与AChE和Aβ的分子水平相互作用。最后，针对东碱诱导的痴呆症模型对MT-6进行了评估，该化合物可有效改善东mice碱治疗的小鼠的记忆障碍和认知障碍。因此，已经开发了新型咔唑衍生物MT-6作为抗AD的有效和安全的多功能剂，并且该分子可以用作将来开发有效的抗阿尔茨海默氏剂的合适的先导。
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