Novel Multitarget Directed Triazinoindole Derivatives as Anti-Alzheimer Agents.

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 showed an IC value of 0.56 ± 0.02 μM for AChE and an IC 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 , molecular docking studies and molecular dynamics simulation studies were performed, and the results indicated significant interactions of within the active sites of AChE as well as BuChE. Compound successfully diminished HO-induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against HO 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 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 showed notable in silico ADMET properties. Taken collectively, these findings project compound as a potential balanced MTDL in the evolution process of novel anti-AD drugs.