Madhav_2023_Eur.J.Med.Chem_254_115354

Multi-target directed ligands (MTDLs) have recently attracted significant interest due to their exceptional effectiveness against multi-factorial Alzheimer's disease. The present work described the development of pyrazine-based MTDLs using multicomponent Petasis reaction for the dual inhibition of tau-aggregation and human acetylcholinesterase (hAChE). The molecular structure of synthesized ligands was validated by (1)H & (13)C NMR and mass spectrometry. The screened compounds were shown to have a strong inhibitory effect at 10 microM concentration against tau-oligomerization and hAChE, but only moderate inhibitory activity against Abeta(42). Among all the compounds, the half-maximal inhibitory concentration (IC(50)) for 21 and 24 against hAChE were 0.71 microM and 1.09 microM, respectively, while they displayed half-maximal effective concentrations (EC(50)) values of 2.21 microM and 2.71 microM for cellular tau-oligomerization, respectively. Additionally, an MTT experiment using tau-expressing SH-SY5Y neuroblastoma cells revealed that 21 was more neuroprotective than the FDA-approved medication donepezil. Furthermore, an MD simulation study was performed to investigate the dynamics and stability of AChE-21 and AChE-24 complexes in an aqueous environment. The MM-PBSA calculations were performed to evaluate the binding of 21 and 24 with AChE, and the relative binding energy was calculated as -870.578 and -875.697 kJ mol(-1), respectively. As a result, the study offered insight into the design of new MTDLs and highlighted 21 as a potential roadblock to the development of anti-AD medications.