Indoloquinoxaline derivatives as promising multi-functional anti-Alzheimer agents

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 mu M, selectivity index = 0.17) that possessed 2 fold higher BuChE inhibitory activity compared to the commercially approved reference drug donepezil (IC50 = 1.87 mu M). Moreover, compound 9f is also endowed with self-induced A beta(1-42) aggregation inhibitory activity (51.24% inhibition at 50 mu M 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 A beta(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

Automated summary

To confront the complex pathogenesis of Alzheimer's disease, the development of multitarget-directed ligands has emerged as a promising approach. In this study, a series of indoloquinoxaline derivatives were designed and synthesized for Alzheimer's disease. The synthesized compounds exhibited moderate to good cholinesterase inhibitory activity and compound 9f was identified as the most potent and selective BuChE inhibitor. Compound 9f also showed self-induced Aβ(1-42) aggregation inhibitory activity and favorable in silico ADMET properties. These findings suggest that compound 9f has potential as a multitarget-directed ligand for developing novel anti-AD drugs.