Novel Multitarget Directed Triazinoindole Derivatives as Anti-Alzheimer Agents

Abstract

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 <b>23e</b> showed an IC₅₀ value of 0.56 ± 0.02 μM for AChE and an IC₅₀ 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 <b>23e</b>, molecular docking studies and molecular dynamics simulation studies were performed, and the results indicated significant interactions of <b>23e</b> within the active sites of AChE as well as BuChE. Compound <b>23e</b> successfully diminished H₂O₂-induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H₂O₂ 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 <b>23e</b> 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 <b>23e</b> showed notable in silico ADMET properties. Taken collectively, these findings project compound <b>23e</b> as a potential balanced MTDL in the evolution process of novel anti-AD drugs.