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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.

The multifaceted nature of Alzheimer's disease (AD) demands treatment with multitarget-directed ligands (MTDLs) to confront the key pathological aberrations. A novel series of triazinoindole derivatives were designed and synthesized. In vitro studies revealed that all the compounds showed moderate to good anticholinesterase activity; the most active compound 23e showed an IC 50 value of 0.56 ± 0.02 μM for AChE and an IC 50 value of 1.17 ± 0.09 μM for BuChE. These derivatives are also endowed with potent antioxidant activity. To understand the plausible binding mode of the compound 23e , molecular docking studies and molecular dynamics simulation studies were performed, and the results indicated significant interactions of 23e within the active sites of AChE as well as BuChE. Compound 23e successfully diminished H 2 O 2 -induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H 2 O 2 as well as Aβ-induced toxicity in SH-SY5Y cells in a concentration dependent manner. Furthermore, it did not show any significant toxicity in neuronal SH-SY5Y cells in the cytotoxicity assay. Compound 23e did not show any acute toxicity in rats at doses up to 2000 mg/kg, and it significantly reversed scopolamine-induced memory deficit in mice model. Additionally, compound 23e showed notable in silico ADMET properties. Taken collectively, these findings project compound 23e as a potential balanced MTDL in the evolution process of novel anti-AD drugs.

In the past few decades, the cholinergic theory of Alzheimer's disease has been promoted as a crucial tool for the creation of new drugs. In this study, a series of novel quinazolinone scaffold were synthesized, docked and predicted for their ADMET studies for cholinesterase inhibitors against Alzheimer's disease. Docking study were performed, using Autodock 4.2 for the synthesized compounds 4a-c and were observed to be well accommodated in the active site of AChE compared to standard Donepezil. Compounds 4d-f were most suggested novel quinazolinone derivative that the inhibitor exhibited two hydrogen bonding interactions with AChE. In-silico drug-likeness and pharmacokinetic properties was predicted using Swiss ADME, pkCSM software. All synthesized compounds 4a-f having better pharmacokinetic profile for potential to act as a cholinesterase inhibitors against Alzheimer's disease. [ABSTRACT FROM AUTHOR]