Quinazolinone-triazole hybrids as multi-target-directed ligands for Alzheimer's disease: discovery of potent and selective MAO-B inhibitors with cholinesterase modulating activity.

A new series of quinazolinone-triazole hybrids (QTHs, 5a-n) was designed, synthesized, and evaluated as potential multi-target-directed ligands for Alzheimer's disease. All synthesized compounds were screened against human monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). The obtained results revealed pronounced selectivity toward MAO-B, with IC50 values ranging from 0.65 to 7.51 µM, while exhibiting negligible MAO-A inhibition (IC50 > 40 µM). Compounds 5a, 5d, 5g, 5h, and 5m emerged as the most potent and selective MAO-B inhibitors and were subsequently evaluated for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among them, compound 5h displayed the most favorable biological profile, showing potent inhibition of MAO-B (IC50 = 0.65 µM), AChE (IC50 = 0.084 µM), and BuChE (IC50 = 0.667 µM). In silico ADMET analysis indicated acceptable drug-like properties for the lead compounds. Furthermore, molecular docking studies against MAO-B and AChE revealed favorable binding interactions, while a 500 ns molecular dynamics simulation confirmed the stability of the 5h-MAO-B complex. Collectively, the present findings identify compound 5h as a promising lead candidate and highlight quinazolinone-triazole hybrids as attractive scaffolds for the development of selective MAO-B inhibitors with additional cholinesterase inhibitory activity for Alzheimer's disease treatment.