Novel quinazolinone Derivatives: Design, synthesis and in vivo evaluation as potential agents targeting Alzheimer disease

Abstract

Since Alzheimer disease is one of the most prevalent types of dementia with a high mortality and disability rate, so development of multi-target drugs becomes the major strategy for battling AD. This study shows the development of a series of quinazolinone based derivatives as novel, multifunctional anti-AD drugs that exhibit both cholinesterase inhibitoryand anti-inflammatory properties. The preliminary results of the in vitro AChE inhibition activity showed that compounds 4b, 5a, 6f, 6h and 7b were better represented for further evaluation. Furthermore, in-vivo AChE inhibition activity and behavior Morris water maze test against donepezil as reference drug were evaluated. Additionally, hippocampal inflammatory markers; TNF-α, NFĸB, IL-1β and IL-6 and antioxidant markers; SOD and MDA were assessed to evaluate the efficacy of quinazolinone derivatives against AD hallmarks. The results showed that 6f, 6h and 7b have promising anti-acetylcholinesterase, anti-inflammatory and antioxidant activities thus, have a significant effect in treatment of AD. Moreover, Histopathological examination revealed that 6f, 6h and 7b derivatives have neuroprotective effect against neuronal damage caused by induced scopolamine model in mice. Finally, the binding ability of the synthesized derivatives to the target, AChE was investigated through molecular docking which reflected significant interactions to the target based on their docking binding scores. Hence, the newly designed quinazolinone derivatives possess promising anti-acetylcholinesterase activity and challenging for the management of AD in the future.

Keywords: Alzheimer's disease; Anti-cholinesterases; Neuroinflammation; Quinazolinone.