Ethynyl-1,1’-Biphenyl Derivatives as Amyloid Beta Aggregation Inhibitors

Abstract

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder, with characteristic symptoms including memory loss and cognitive decline. AD is characterized by the formation of dense amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) in the central nervous system (CNS). The amyloid β cascade hypothesis states that an increase in insoluble amyloid β aggregates initiates the neurodegenerative cascade observed in AD. The objective of this project was to design, synthesize and evaluate novel ethynyl-1,1’-biphenyl ring scaffolds in the prevention of Aβ1-40/42 aggregation, through the utilization of medicinal chemistry principles. In this regard, the structure-activity relationship (SAR) data for a library of 17 small molecules based on an ethynyl-1,1’-biphenyl compound library (5a-j, 9a-g and 14) were obtained. Ethynyl-1,1’-biphenyl derivatives (5a-j, 9a-g and 14) with varying steric and electronic properties were synthesized, characterized and screened through anti-Aβ1-40/42 aggregation kinetics study and transmission electron microscopy (TEM) experiments to determine their inhibition profile. Lead candidates were identified, and molecular docking studies were conducted to investigate the binding modes of these lead derivatives to understand their binding interactions in Aβ dimer and oligomer models. The most potent Aβ1-40 inhibitor was 5i (4-(4-ethynylphenyl)pyridine; (Aβ1-40 inhibition: 79%), followed by 5e (4'-ethynyl-(1,1'-biphenyl)-4-ol; (Aβ1-40 inhibition: ~67%). All the ethynyl-1,1’-derivatives were more potent inhibitors of Aβ1-42 aggregation, with compound 9g ((3'-ethynyl-(1,1'-biphenyl)-4-yl)(methyl)sulfane) exhibiting greater inhibitory activity ((Aβ1-42 inhibition: ~87 %), closely followed by 5i (4-(4-ethynylphenyl)pyridine; (Aβ1-40 inhibition: 86 %). These investigations demonstrate that biphenyl ring templates with ethynyl-substituents possess anti-Aβ aggregation properties, which can be useful to study Aβ aggregation and also may serve as useful templates in designing novel class of anti-AD agents.