Multicomponent Petasis reaction for the identification of pyrazine based multi-target directed anti-Alzheimer?s agents: In-silico design, synthesis, and characterization

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 1H & 13C NMR and mass spectrometry. The screened compounds were shown to have a strong inhibitory effect at 10 mu M concentration against tau-oligomerization and hAChE, but only moderate inhibitory activity against A beta 42. Among all the compounds, the half-maximal inhibitory concentration (IC50) for 21 and 24 against hAChE were 0.71 mu M and 1.09 mu M, respectively, while they displayed half-maximal effective concentrations (EC50) values of 2.21 mu M and 2.71 mu M 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.

Automated summary

The study developed pyrazine-based multi-target directed ligands (MTDLs) through multicomponent Petasis reaction for the simultaneous inhibition of tau-aggregation and human acetylcholinesterase (hAChE) in Alzheimer's disease. The synthesized ligands were structurally validated, and showed strong inhibitory effects against tau-oligomerization and hAChE, with moderate activity against A beta 42. Compound 21 exhibited potential neuroprotective effects and displayed higher binding energy with AChE compared to compound 24. This study provides insights into the design of new MTDLs and identifies compound 21 as a potential obstacle in the development of anti-AD medications.