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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)-6 H -indolo[2,3- b ]quinoxaline  9f  was identified as the most potent and selective BuChE inhibitor (IC 50  = 0.96 µM, selectivity index = 0.17) that possessed 2 fold higher BuChE inhibitory activity compared to the commercially approved reference drug donepezil (IC 50  = 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

Indoloquinoxaline derivatives as promising multi-functional anti-Alzheimer agents