Design, synthesis, and evaluation of novel benzofuran and pyrazole-based derivatives as dual AChE/BuChE inhibitors with antioxidant properties for Alzheimer's disease management

Abstract

As a complicated neurodegenerative disorder with several clinical hallmarks, Alzheimer's disease (AD) requires multi-target treatment medicines to address multiple elements of disease progression. In this study, we reported two novel series of compounds: benzofuran-based donepezil analogs (9a-i) and their pyrazole-based counterparts (11a-i) as potential dual inhibitors of AChE and BuChE with additional antioxidant properties, aiming to address multiple pathological aspects of AD simultaneously. The design strategy employed bioisosteric replacement, substituting donepezil's indanone motif with a benzofuran ring in series (9a-i) to maintain crucial hydrogen bonding interactions with the Phe295 residue in the enzyme's active site. Subsequently, the benzofuran ring underwent cleavage, yielding pyrazole-tethered hydroxyphenyl derivatives (11a-i). The biological evaluation revealed that benzofuran-based derivative 9g exhibited exceptional efficacy against both AChE and BuChE, with IC₅₀ values of 0.39 and 0.51 μg/ml, respectively, although it lacked antioxidant activity. Compound 11f demonstrated dual inhibition of AChE (IC₅₀ = 1.24 μg/ml) and BuChE (IC₅₀ = 1.85 μg/ml) while also displaying strong DPPH free radical scavenging activity (IC₅₀ = 3.15 μg/ml). In vivo toxicity studies on compound 11f revealed a favorable safety profile, with no signs of toxicity or adverse events in acute oral toxicity tests in male Wistar rats. Chronic administration of 11f resulted in negligible differences in blood profiles, hepatic enzymes, urea, creatinine, and albumin levels compared to the control group. Histopathological examination of hepatic and kidney tissues from treated rats showed normal histology without damage. In silico molecular docking analysis was performed to rationalize the design approaches and support the experimental findings. This study provides valuable insights into the development of multi-target compounds for potential Alzheimer's disease treatment.

Keywords: AChE; Alzheimer's disease; Benzofuran; BuChE; DPPH; Pyrazole.