Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer’s Agents,ACS Chemical Neuroscience

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Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer’s Agents
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-10-19 , DOI: 10.1021/acschemneuro.0c00448
Dushyant V Patel ₁ , Nirav R Patel ₁ , Ashish M Kanhed ₂ , Divya M Teli ₃ , Kishan B Patel ₁ , Pallav M Gandhi ₁ , Sagar P Patel ₁ , Bharat N Chaudhary ₁ , Dharti B Shah ₁ , Navnit K Prajapati ₁ , Kirti V Patel ₁ , Mange Ram Yadav _{1,

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Affiliation

The inadequate clinical efficacy of the present anti-Alzheimer’s disease (AD) drugs and their low impact on the progression of Alzheimer’s disease in patients have revised the research focus from single targets to multitarget-directed ligands. A novel series of substituted triazinoindole derivatives were obtained by introducing various substituents on the indole ring for the development of multitarget-directed ligands as anti-AD agents. The experimental data indicated that some of these compounds exhibited significant anti-AD properties. Among them, 8-(piperidin-1-yl)-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino[5,6-b]indol-3-amine (60), the most potent cholinesterase inhibitor (AChE, IC₅₀ value of 0.32 μM; BuChE, IC₅₀ value of 0.21 μM), was also found to possess significant self-mediated Aβ_1–42 aggregation inhibitory activity (54% at 25 μM concentration). Additionally, compound 60 showed strong antioxidant activity. In the PAMPA assay, compound 60 exhibited blood-brain barrier penetrating ability. An acute toxicity study in rats demonstrated no sign of toxicity at doses up to 2000 mg/kg. Furthermore, compound 60 significantly restored the cognitive deficits in the scopolamine-induced mice model and Aβ_1–42-induced rat model. In the in silico ADMET prediction studies, the compound satisfied all the parameters of CNS acting drugs. These results highlighted the potential of compound 60 to be a promising multitarget-directed ligand for the development of potential anti-AD drugs.

中文翻译：

对三嗪并吲哚类化合物作为潜在的新型多靶标定向抗阿尔茨海默氏病药物的进一步研究

目前的抗阿尔茨海默氏病（AD）药物的临床疗效不足，以及它们对患者阿尔茨海默氏病进展的影响很小，已经将研究重点从单一靶标改为了多靶标定向配体。通过在吲哚环上引入各种取代基以开发多靶标配体作为抗AD剂，可获得一系列新的取代的三嗪并吲哚衍生物。实验数据表明这些化合物中的一些表现出显着的抗AD特性。其中，8-（哌啶-1-基） - ñ - （6-（吡咯烷-1-基）己基）-5- ħ - [1,2,4]三嗪并[5,6- b ]吲哚-3-胺（60），最有效的胆碱酯酶抑制剂（AChE，IC ₅₀值为0.32μM; 还发现BuChE的IC ₅₀值为0.21μM）具有显着的自我介导的_Aβ1–42聚集抑制活性（在25μM浓度下为54％）。另外，化合物60显示出强的抗氧化剂活性。在PAMPA测定中，化合物60表现出血脑屏障穿透能力。在大鼠中进行的一项急性毒性研究表明，至多2000 mg / kg的剂量，均无毒性迹象。此外，化合物60可显着恢复东pol碱诱导的小鼠模型和_Aβ1–42诱导的大鼠模型的认知缺陷。在计算机上通过ADMET预测研究，该化合物满足中枢神经系统作用药物的所有参数。这些结果突出了化合物60作为潜在的抗AD药物开发的有希望的多靶标定向配体的潜力。

更新日期：2020-11-04

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