Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer's Agents.

The inadequate clinical efficacy of the present anti-Alzheimer's disease (AD) drugs and their low impact on the progression of Alzheimer's disease in patients have revised the research focus from single targets to multitarget-directed ligands. A novel series of substituted triazinoindole derivatives were obtained by introducing various substituents on the indole ring for the development of multitarget-directed ligands as anti-AD agents. The experimental data indicated that some of these compounds exhibited significant anti-AD properties. Among them, 8-(piperidin-1-yl)--(6-(pyrrolidin-1-yl)hexyl)-5-[1,2,4]triazino[5,6-]indol-3-amine (), the most potent cholinesterase inhibitor (AChE, IC value of 0.32 μM; BuChE, IC value of 0.21 μM), was also found to possess significant self-mediated Aβ aggregation inhibitory activity (54% at 25 μM concentration). Additionally, compound showed strong antioxidant activity. In the PAMPA assay, compound exhibited blood-brain barrier penetrating ability. An acute toxicity study in rats demonstrated no sign of toxicity at doses up to 2000 mg/kg. Furthermore, compound significantly restored the cognitive deficits in the scopolamine-induced mice model and Aβ-induced rat model. In the ADMET prediction studies, the compound satisfied all the parameters of CNS acting drugs. These results highlighted the potential of compound to be a promising multitarget-directed ligand for the development of potential anti-AD drugs.