Alzheimer's disease (AD) is a complex ailment of uncertain origin. The available treatments, restricted to cholinesterase inhibitors and N-methyl-D-aspartate receptor (NMDAR) antagonists, merely relieve symptoms. Given the ineffectiveness of single-target therapies, a more promising approach involves a rational combination of specific targets into a single molecule, aiming to provide more significant benefits in mitigating symptoms and slowing disease progression. Our study focused on the design, synthesis, and biological evaluation of 24 new N-methylpropargylamino-quinazoline derivatives. Initially, in silico techniques were employed to scrutinize the compounds for their oral and central nervous system (CNS) availabilities. In vitro assessments included testing the compounds' effects on cholinesterases, monoamine oxidase A/B (MAO-A/B), NMDAR antagonism, dehydrogenase activity, and glutathione levels. Additionally, selected compounds underwent scrutiny for cytotoxicity on undifferentiated and differentiated neuroblastoma SH-SY5Y cells. Notably, II-6h emerged as the optimal candidate, possessing a selective MAO-B inhibition profile, NMDAR antagonism, an acceptable cytotoxicity profile, and the potential to permeate the blood-brain barrier (BBB). The structure-guided drug design strategy employed in this investigation introduces a novel concept for rational drug discovery, contributing to our understanding of the development of innovative therapeutic agents for treating AD.This study was supported by the Czech Science Foundation No. 22-24384S.