Mannich reaction mediated derivatization of chromones and their biological evaluations as putative multipotent ligands for the treatment of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a complex neurological disorder and multiple pathways are associated with its pathology. Currently available single-targeting drugs are found to be ineffective for the treatment of AD, and most of these drugs provide symptomatic relief. The multi-target directed ligand strategy is proposed as an effective approach for the treatment of AD. Herein, we report the design and synthesis of a series of 2-phenyl substituted chromone derivatives and their evaluation against AChE, MAO-B, and β amyloid self-aggregation inhibition. In the series, NS-4 and NS-13 were identified as the potent leads against all the specified targets. NS-4 and NS-13 exhibited balanced multipotent activities against AChE with IC₅₀ values of 3.09 μM, and 0.625 μM and against MAO-B with IC₅₀ values of 19.64 μM and 12.31 μM, respectively. These compounds also displayed 28.5% and 32.2% self-aggregation inhibition potential against Aβ_1–42, respectively. All the compounds were found to be selective for AChE over BuChE. Additionally, NS-4 also exhibited potent BuChE inhibition with an IC₅₀ value of 1.95 μM. Moreover, NS-4 and NS-13 reduced intracellular ROS levels up to 65% against SH-SY5Y cells at 25 μM concentration. The lead compounds were found to be neuroprotective and exhibited no cytotoxicity even at 25 μM concentration. In enzyme kinetic inhibition studies, these compounds showed mixed-type inhibition to AChE. In the computational studies, binding interactions, and orientations of the ligands at the active site of the enzymes were analyzed and these lead compounds were found to be thermodynamically stable inside the active cavity for up to 100 ns.