Phenylstyrylpyrimidine derivatives as potential multipotent therapeutics for Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial neurological disorder that affects millions of people worldwide. Despite extensive research efforts, there are currently no effective disease-modifying therapeutics available for the complete cure of AD. In the current study, we have designed and synthesized a series of phenyl-styryl-pyrimidine derivatives as potential multifunctional agents against different targets of AD. The compounds were evaluated for their ability to inhibit acetylcholinesterase (AChE), monoamine oxidase (MAO) and β amyloid aggregation which are associated with the initiation and progression of the disease. Several compounds in the series exhibited potent inhibitory activity against AChE and MAO-B, with IC₅₀ values in the low micromolar range. In particular, two compounds, BV-12 and BV-14, were found to exhibit a multipotent profile and showed non-competitive inhibition against MAO-B with IC₅₀ values of 4.93 ± 0.38 & 7.265 ± 0.82 μM, respectively and AChE inhibition with IC₅₀ values of 7.265 and 9.291 μM, respectively. BV-12 and BV-14 also displayed β amyloid self-aggregation inhibition of 32.98% and 23.25%, respectively. Furthermore, molecular modelling studies revealed that BV-14 displayed a docking score of -11.20 kcal mol^-1 with MAO-B & -6.767 kcal mol^-1 with AChE, forming a stable complex with both proteins. It was concluded that phenyl-styryl-pyrimidine derivatives have the potential to be developed as multitarget directed ligands for the treatment of AD.