Investigation of Multifunctional Profile of Dihydroquinazoline Derivatives as Potential Therapeutics for the Alzheimer’s Disease

Abstract

Multi-target Directed ligands represent an innovative strategy in the management of Alzheimer’s disease (AD) by addressing its multifactorial etiology. These agents are designed to simultaneously modulate multiple key targets involved in the disease progression, offering a holistic approach for the effective treatment of AD. The current work presents synthesis and evaluation of novel dihydroquinazoline based multi-targeting agents for the management of Alzheimer’s Disease. Most of the compounds showed good selectivity for AChE and MAO-B and two compounds viz. K2V-9 and K2V-12 emerged as potent inhibitors against both the targets. The compound K2V-9 displayed IC50 values of 1.72 ± 0.01 µM and 0.950 ± 0.52 µM against AChE and MAO-B, respectively. Compound K2V-12 showed IC50 values of 1.10 ± 0.078 µM and 1.68 ± 0.25 µM against AChE and MAO-B, respectively. Moreover, amyloid β self-aggregation inhibition studies were also performed where K2V-9 and K2V-12 showed percentage inhibition of 37.34% and 48.10%, respectively after 48 h. Both the compounds were found to be non-toxic, neuroprotective and showed the capability of reducing ROS levels in SHSY-5Y cells. Reversibility and Kinetic studies of these lead compounds showed that both the molecules cause reversible and mixed type inhibitors against targeted enzymes. In the docking and molecular dynamics simulation studies, K2V-9 and K2V-12 were found to accommodate well in the active cavity with good thermodynamic stability.