Biological Activity Studies on Biphenyl Conjugated Systems as Potential Beta-Amyloid Peptide Inhibitors
Project no. 557 · Status: Kapanmış · 2017
Summary
The exact mechanism of Alzheimer’s disease (AD) pathogenesis is not known but studies suggest that Aß aggregation plays an important role in the formation and progression of the disease (Hardy and Selkoe, 2002; Roychaudhuri vd., 2009). Based on the structural properties which are important in the inhibition of amiloid aggregation, the synthesis of 42 compounds were realized and elucidated by spectroscopic methods and elemental analysis. The inhibition of Aß aggregation was evaluated by thioflavine T fluorescence assay and the cholinesterase (ChE) inhibition was analyzed by Ellman’s method. According to the biological activity results, all compounds generally showed inhibitory activity on Aß(1-42) fibril formation and AChE in different ratios, whereas they exhibited generally weak or no inhibitory activity against BuChE. Among the series, diazo-8 was found to be the most effective derivative on inhibition of Aß aggregation (78.39% at 100 µM; 61.36% at 25 µM) by exhibiting activity close to the reference compound curcumin. The diazo series displayed a more effective Aß aggregation inhibition profile than the imine series. The highest activity against AChE was the imine-18 (IC50=5.33±0.08 µ?) and the highest activity against BuChE was the diazo-10 (IC50=2.72±0.15 µ?) which was higher than the reference compound galantamine. It was found that the compounds were selective for AChE. According to the molecular modeling results, for diazo-8, it can be thought that ?-? interaction between the pyridine and Phe20 amino acid and hydrogen bonding between one of the diazo groups and Lys16 amino acid may play a role in Aß inhibitory activity. It can be speculated that imine-18 and diazo-10 derivatives’ highest activity could be due to the interaction with both CAS and PAS regions of the enzyme. The synthesized compounds having both Aß aggregation inhibitory activity and AChE inhibitory activity might be considered as multi-targeted agents for the treatment of AD.