Design, Synthesis, and Biological Investigation of Quinazoline Derivatives as Multitargeting Therapeutics in Alzheimer’s Disease Therapy

Abstract

An efficient and promising method of treating complex neurodegenerative diseases like Alzheimer's disease (AD) is the multitarget-directed approach. Here in this work, a series of quinazoline derivatives (<b>AV-1</b> to <b>AV-21</b>) were rationally designed, synthesized, and biologically evaluated as multitargeted directed ligands against human cholinesterase (hChE) and human β-secretase (hBACE-1) that exhibit moderate to good inhibitory effects. Compounds <b>AV-1</b>, <b>AV-2</b>, and <b>AV-3</b> from the series demonstrated balanced and significant inhibition against these targets. These compounds also displayed excellent blood-brain barrier permeability via the PAMPA-BBB assay. Compound <b>AV-2</b> significantly displaced propidium iodide (PI) from the acetylcholinesterase-peripheral anionic site (AChE-PAS) and was found to be non-neurotoxic at the maximum tested concentration (80 μM) against differentiated SH-SY5Y cell lines. Compound <b>AV-2</b> also prevented AChE- and self-induced Aβ aggregation in the thioflavin T assay. Additionally, compound <b>AV-2</b> significantly ameliorated scopolamine and Aβ-induced cognitive impairments in the <i>in vivo</i> behavioral Y-maze and Morris water maze studies, respectively. The <i>ex vivo</i> and biochemical analysis further revealed good hippocampal AChE inhibition and the antioxidant potential of the compound <b>AV-2</b>. Western blot and immunohistochemical (IHC) analysis of hippocampal brain revealed reduced Aβ, BACE-1, APP/Aβ, and Tau molecular protein expressions levels. The pharmacokinetic analysis of compound <b>AV-2</b> demonstrated significant oral absorption with good bioavailability. The <i>in silico</i> molecular modeling studies of lead compound <b>AV-2</b> moreover demonstrated a reasonable binding profile with AChE and BACE-1 enzymes and stable ligand-protein complexes throughout the 100 ns run. Compound <b>AV-2</b> can be regarded as the lead candidate and could be explored more for AD therapy.