Dimethylquinoxaline 衍生物中的取代基编排：一种用于寻找合适的 CDK5 抑制剂作为阿尔茨海默氏症潜在疗法的工具,Chemistry & Biodiversity

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Dimethylquinoxaline 衍生物中的取代基编排：一种用于寻找合适的 CDK5 抑制剂作为阿尔茨海默氏症潜在疗法的工具
Chemistry & Biodiversity ( IF 2.3 ) Pub Date : 2022-08-19 , DOI: 10.1002/cbdv.202200116
Arvind Kumar Jain ₁ , Arindam Gupta ₂ , C Karthikeyan ₃ , Piyush Trivedi _{1,

4} , Anita Dutt Konar _{1,

5,

6}

Affiliation

发现一组由 6,7 二甲基喹喔啉组成的新杂环类似物（化合物I – IX ）对受体 GSK3β（化合物IV – V ）具有活性（Chem. Biodiversity 2021 , 18 , e2100364）。为了在本文中调节有效的 CDK5 抑制剂，我们的假设支持从相同的喹喔啉系列中找出合适的衍生物，因为这两个靶标 GSK3β 和 CDK5 彼此具有结构相似性。与我们合成化合物I – IX的目标一致, 结合使用光谱技术对它们进行了表征，并评估了它们对 CDK5 的活性。我们的分析反映出，在密度泛函理论 (DFT) 计算和分子模型研究的支持下，相邻的烷氧基/羟基官能团衍生物即化合物III和VI是该系列中最有效的（微摩尔）衍生物。此外，化合物I - IX的功效, 在 CMGC 家族的其他几个成员中进行了监测，即 DYRK1A、CLK1 和 CK1δ，这些成员已知直接参与 Tau 的过度磷酸化。但不幸的是，我们的喹喔啉系列在所有目标中均不活跃。简而言之，进一步优化这些智能核，不仅会导致发现新的药效团，而且还会对激酶库具有显着的选择性，从而为设计针对阿尔茨海默氏症的潜在疗法制定一个独特的路线图。

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Substituent Orchestration in Dimethylquinoxaline Derivatives: A Tool for Fishing Out Appropriate CDK5 Inhibitors as Potential Therapeutics for Alzheimer's

A set of new heterocyclic analogs (Compounds I–IX), comprising of 6,7 dimethyl Quinoxalines were found to be active against the receptor GSK3β (Compounds IV–V) (Chem. Biodiversity 2021, 18, e2100364). In an effort to modulate effective CDK5 inhibitors herein our hypothesis underpinned to fish out an appropriate derivative from the same quinoxaline series, as these two targets GSK3β and CDK5 shared structural resemblance with each other. Aligned to the goal we have synthesized Compounds I–IX, characterized them using a combination of spectroscopic techniques and evaluated their activities against CDK5. Our analysis reflected that the adjacently located alkoxy/hydroxy functionality derivatives namely Compounds III and VI, to be the most potent (micromolar) amongst others in the series, backed by Density Functional Theory (DFT) calculations and molecular modelling studies. Also, the efficacy of the Compounds I–IX, were monitored in few other members of the CMGC family namely DYRK1A, CLK1and CK1δ that have been known to be directly involved in hyperphosphorylation of Tau. But unfortunately in none of the targets, our quinoxaline series were active. In a nut shell further optimisation of these intelligent nucleus, would not only lead to the discovery of novel pharmacophores, but also marked selectivity against a pool of kinases, thereby implementing a distinct roadmap towards the design of potential therapeutics against Alzheimer's.

更新日期：2022-08-19

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