Investigation of the multifunctional profile of dihydroquinazoline derivatives as potential therapeutics for Alzheimer's disease

Multitarget 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 the synthesis and evaluation of novel dihydroquinazoline-based multitargeting agents for the management of Alzheimer's disease. Most of the compounds showed good selectivity for AChE and MAO-B, and two compounds, <i>viz.</i>K2V-9 and K2V-12, emerged as potent inhibitors against both the targets. Compound K2V-9 displayed IC₅₀ values of <b>1.72 ± 0.01 μM</b> and <b>0.950 ± 0.52 μM</b> against AChE and MAO-B, respectively. Compound K2V-12 showed IC₅₀ values of <b>1.10 ± 0.078 μM</b> and <b>1.68 ± 0.25 μM</b> against AChE and MAO-B, respectively. Moreover, amyloid β self-aggregation inhibition studies were performed, where K2V-9 and K2V-12 showed percentage inhibitions of 37.34% and 48.10%, respectively, after 48 h. Both compounds were found to be non-toxic and neuroprotective and showed the capability of reducing the ROS levels in SHSY-5Y cells. Reversibility and kinetic studies of these lead compounds showed that both molecules produced reversible and mixed-type of inhibition against the targeted enzymes. In the docking and molecular dynamics simulation studies, K2V-9 and K2V-12 were found to be well accommodated in the active cavity with good thermodynamic stability.