Benzo[ d]imidazole-pyrrolo[1,2- a]pyrazine Hybrids Ameliorate Amyloid Aggregates in the Brain of Alzheimer Transgenic Mice

Abstract

Abnormal assembly of amyloid β (Aβ) in the brain is implicated in Alzheimer's disease (AD) and is associated with cognitive impairments. Since Aβ accumulation occurs in advance of the onset of clinical symptoms, identifying preventable drug candidates regulating Aβ accumulation is regarded as a promising approach in AD therapeutic. Herein, we synthesized eight Yonsei Institute of pharmaceutical sciences Alzheimer's Drug (YIAD) compounds based on 5-benzyl-6-phenylbenzo[4,5]imidazo[1,2-a]pyrrolo[2,1-c]pyrazine structures. Subsequently, YIAD-0203 and YIAD-0205 were selected as effective candidates via thioflavin T assays and gel electrophoresis. The potential therapeutic effect of YIAD-0203 and YIAD-0205 on Aβ aggregates was investigated through an AD transgenic mouse model with five familial AD mutations (5XFAD) by oral gavage. Significant amounts of Aβ plaque and oligomer reduction were observed in the hippocampus region of both 4.3-month-old (early stage of AD) and 6.0-month-old (mid stage of AD) YIAD-0205-treated 5XFAD mice brains when compared to the nontreated brains. The ability of YIAD-0205 to ameliorate Aβ aggregates in the early and mid stages of AD progression supports the notion that YIAD-0205 could be utilized as a reliable scaffold for the development of preventive AD drug candidates.

Keywords: Alzheimer’s disease (AD); aggregate dissociators; aggregation inhibitors; amyloid-β (Aβ); drug candidate scaffold; small molecules.