Design, synthesis, metal chelation potential and biological evaluation of pyridine chalcones as multi-target-directed ligands against Alzheimer's disease

Abstract

Two sets of 1-phenyl-3-(pyridinyl) prop‑2-en-1-one analogs, 7a-d and 8a-d were designed by the incorporation of pyridine and chalcone privileged scaffolds with the objective of developing multifunctional molecules for Alzheimer's disease (AD). The structure-based approach was used to evaluate the binding potential of the designed pyridine chalcone series in acetylcholinesterase, prior to synthesis. The hybrid molecules designed from the amalgamation of two privileged scaffolds demonstrated excellent potential for simultaneous inhibition of acetylcholinesterase (AChE) and amyloid beta (Aβ1–42) aggregation in addition to promising radical scavenging activities, metal-chelating properties and inhibitory potential for attenuation of advanced glycation products. The compounds showed mixed inhibition of AChE in enzyme kinetic studies with the most potent compound 8c showing an IC50 value of 0.1 ± 0.01 μM. Compounds of both series exhibited good potential of inhibiting Aβ1–42 aggregation, with compound 8c exhibiting an inhibitory potential of 83.58% after 48 h. The molecules demonstrated moderate to good radical scavenging activity in both DPPH and H2O2 radical scavenging assays, moderate inclination for metal chelation and significant potential to inhibit formation of advanced glycation products. The mechanistic basis of these actions has been probed by experimental and computational techniques that leads to greater understanding of the underlying structural basis for the activities of these promising molecules for holistic treatment of AD. Taken together, this work reveals the multifaceted pleiotropy of the designed molecules, especially the 4-pyridine analogs, with the compounds 8b and 8c demonstrating excellent potential as multi-target directed ligands to address most of the causative pathologies of AD.