Abstract

To confront a disease like Alzheimer’s disease having complex pathogenesis, development of multitarget-directed ligands has emerged as a promising drug discovery approach. In our endeavor towards the development of multitarget-directed ligands for Alzheimer’s disease, a series of indoloquinoxaline derivatives were designed and synthesized. In vitro cholinesterase inhibition studies revealed that all the synthesized compounds exhibited moderate to good cholinesterase inhibitory activity. 6-(6-(Piperidin-1-yl)hexyl)-6H-indolo[2,3-b]quinoxaline 9f was identified as the most potent and selective BuChE inhibitor (IC₅₀ = 0.96 µM, selectivity index = 0.17) that possessed 2 fold higher BuChE inhibitory activity compared to the commercially approved reference drug donepezil (IC₅₀ = 1.87 µM). Moreover, compound 9f is also endowed with self-induced Aβ_1-42 aggregation inhibitory activity (51.24% inhibition at 50 μM concentration). Some of the compounds of the series also displayed moderate anti-oxidant activity. To perceive a putative binding mode of the compound 9f, molecular docking studies were carried out, and the results pointed out significant interactions of compound 9f with the enzymes in the binding sites of cholinesterases as well as Aβ_1-42. Additionally, compound 9f exhibited favorable in silico ADMET properties. Put together these findings project compound 9f as a potential multitarget-directed ligand in the direction of developing novel anti-AD drugs.

Communicated by Ramaswamy H. Sarma

摘要

为了对抗阿尔茨海默病等具有复杂发病机制的疾病，多靶点定向配体的开发已成为一种有前途的药物发现方法。在我们致力于开发针对阿尔茨海默病的多靶点定向配体的过程中，设计并合成了一系列吲哚喹喔啉衍生物。体外胆碱酯酶抑制研究表明，所有合成的化合物都表现出中等至良好的胆碱酯酶抑制活性。6-(6-(Piperidin-1-yl)hexyl)-6 H -indolo[2,3- b ]quinoxaline 9f被确定为最有效和选择性的 BuChE 抑制剂 (IC _{50= 0.96 µM，选择性指数 = 0.17)，与商业批准的参考药物多奈哌齐 (IC 50} = 1.87 µM)相比，BuChE 抑制活性高出 2 倍。此外，化合物9f还具有自诱导 Aβ _1-42聚集抑制活性（在 50 μM 浓度下抑制 51.24%）。该系列的一些化合物也显示出适度的抗氧化活性。为了解化合物9f的推定结合模式，进行了分子对接研究，结果表明化合物9f与胆碱酯酶结合位点中的酶以及 Aβ _1-42存在显着的相互作用。此外，化合物9f表现出良好的硅 ADMET 性能。将这些发现结合起来，将化合物9f作为一种潜在的多靶点定向配体，朝着开发新型抗 AD 药物的方向发展。

由 Ramaswamy H. Sarma 传达