Based on the biochemical understanding of Alzheimer's disease, here, we report the design, synthesis, and biological screening of a series of compounds against this neuro-disorder. Adopting the multitarget approach, the catalytic processes of BACE-1 and AChE were targeted, and thereby, compounds 15, 22, 25, 26, 27, and 30 were identified with IC50 in the submicromolar range against these two enzymes. Further, compounds 15 and 25 displayed more than 50% inhibition of β-amyloid aggregation. Implying their physiological use, the compounds exhibited appreciable biological membrane permeability as observed through the parallel artificial membrane permeability experiment. Supporting these results, treatment of the mice with the test compounds reversed their scopolamine-affected memory impairment, where the highest healing effect was seen in the case of compound 25. Overall, the combination of molecular modeling and experimental studies provided highly effective molecules against Alzheimer's disease.
© 2024 The Authors. Published by American Chemical Society.