Design and Neuroprotective Screening of Imidazole Derivatives As Multi-Target Agents for Alzheimer’s Disease

Alzheimer disease (AD) is a multifactorial, complicated pathology that requires therapeutic treatments that extend beyond the single-target approach. The present study used a rational multi-target directed ligand (MTDL) to create new imidazole-based hybrids that would simultaneously target the primary and secondary pathological processes of AD. On the basis of in silico target validation, molecular docking and pharmacophore modeling, a targeted library of 25 compounds was prepared using a hybrid pharmacophore and bioisosteric replacement method. The main structural differences were considered in the imidazole core, linker (piperazine, amide, oxime ether) and aromatic (phenyl, benzimidazole) cap. Functional activities such as microtubule stabilization, anti-inflammatory, antioxidant and metal chelation and the primary target inhibition (acetylcholinesterase/AChE, butyrylcholinesterase/BuChE, b-secretase/BACE-1) were selectively filtered in the compounds. IMZ-15 with a benzimidazole cap, an oxime ether linker, and -CF3 substituent became the lead candidate. It showed potent and balanced inhibition of AChE (IC50 = 65.4 nM) and BACE-1 (IC50 = 0.52 uM), marked microtubule-stabilizing action, strong anti-inflammatory and metal-chelating effect, and outstanding neuroprotective effects against oxidative and amyloid- beta insults. More importantly, IMZ-15 was not cytotoxic at 100 uM, which shows a large therapeutic index. These findings support the use of the MTDL strategy, which makes IMZ-15 a highly prospects and multi-functional neuroprotective agent that is worth investigating to treat Alzheimer disease.