👤 Mohamed S Nafie

Alzheimer's disease (AD) is a neurodegenerative condition characterized by significant synaptic loss and neuronal death in brain regions critical for cognitive functions. The disease is characterized by the formation of amyloid plaques, which are extracellular constructs consisting mainly of aggregated Aβ42. The latter is a peptide formed by the proteolytic cleavage of β-amyloid precursor protein (APP) by two enzymes, β- and γ-secretase. Therefore, inhibition of the aspartic protease β-secretase (BACE1) is considered a promising therapeutic approach for the treatment and prevention of Alzheimer's disease. Unfortunately, a limited number of β-secretase inhibitors have reached human trials and eventually failed due to inconclusive therapeutic and/or safety profiles. In this study, we developed drug-like molecules with a β-secretase inhibitory activity using a fragment growing strategy on isocytosine and acyl guanidine warheads. Our approach is based on optimizing the hydrophobic part of the molecules to obtain a conformationally restrained scaffold complementary to the hydrophobic pockets within the enzyme active site. We developed 32 compounds with promising Show less

The development of multitargeted therapeutics has evolved as a promising strategy to identify efficient therapeutics for neurological disorders. We report herein new quinolinone hybrids as dual inhibitors of acetylcholinesterase (AChE) and Aβ aggregation that function as multitargeted ligands for Alzheimer's disease. The quinoline hybrids ( Show less