EVALUATION OF NOVEL ADAMANTANE DERIVATIVES AS POTENTIAL DUAL INHIBITORS OF AMYLOID BETA AND TAU AGGREGATION

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized mainly by memory impairment and global decline in overall cognitive functions. Accumulation of neurofibrillary tangles (NFT), amyloid beta (Aβ) plaques, decline of acetylcholine concentration in the central nervous system along with oxidative stress and mitochondrial dysfunction are believed to be the underlying pathology of AD. AD is the leading cause of dementia across the world, with an aging population and no viable treatment insight, the necessity for developing multi-target treatments has been the main focus of AD research in recent years. We are developing small molecules based on an adamantane ring to target Aβ and tau-aggregation. Adamantane derivatives with various substituents were synthesized. The compounds were characterized by nuclear magnetic resonance spectroscopy and mass spectrometry. Initially test compounds were evaluated for their ability to prevent tau-hexapeptide aggregation using various concentrations of test compounds (1-50 μM range) in a 96-well plate format. The results obtained were compared with reference agents, curcumin and orange G. The Aβ-aggregation inhibition studies were conducted using full length Aβ40 peptide based on a ThT based fluorescence assay. In addition, molecular modeling studies were conducted using the Discovery Studio software to explore the interactions of test compounds with steric zipper assembly of tau-hexapeptide and using the dimer assembly of Aβ-peptide. Our results show that adamantane derivatives exhibit weak to good inhibition of either tau-hexapeptide and or Aβ40 aggregates. The aggregation kinetic studies show that adamantane derivatives are capable of affecting various stages of aggregation including increasing duration of the lag phase, reducing the growth phase and an ability to prevent fibril formation. Computational studies suggest that adamantane derivatives can be modified chemically to develop novel molecules with anti-amyloid aggregation properties. Adamantane moiety has been used by pharmaceutical companies and medicinal chemists for more than 50 years to design novel treatments for various diseases. We synthesized, adamantane based molecules as potential anti-AD agents. By utilizing computational modeling and biological assays, we show that these molecules can inhibit the amyloid beta and tau-hexapeptide aggregation. Preliminary data demonstrates that our novel adamantane derivatives inhibit amyloid beta aggregation.