Synthesis of novel aryl-substituted 2-aminopyridine derivatives by the cascade reaction of 1,1-enediamines with vinamidinium salts to develop novel anti-Alzheimer agents.

Alzheimer's disease (AD), a severe neurodegenerative disorder, imposes socioeconomic burdens and necessitates innovative therapeutic strategies. Current therapeutic interventions are limited and underscore the need for novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), enzymes implicated in the pathogenesis of AD. In this study, we report a novel synthetic strategy for the generation of 2-aminopyridine derivatives via a two-component reaction converging aryl vinamidinium salts with 1,1-enediamines (EDAMs) in a dimethyl sulfoxide (DMSO) solvent system, catalyzed by triethylamine (Et3N). The protocol introduces a rapid, efficient, and scalable synthetic pathway, achieving good to excellent yields while maintaining simplistic workup procedures. Seventeen derivatives were synthesized and subsequently screened for their inhibitory activity against AChE and BChE. The most potent derivative, 3m, exhibited an IC50 value of 34.81 ± 3.71 µM against AChE and 20.66 ± 1.01 µM against BChE compared to positive control donepezil with an IC50 value of 0.079 ± 0.05 µM against AChE and 10.6 ± 2.1 µM against BChE. Also, detailed kinetic studies were undertaken to elucidate their modes of enzymatic inhibition of the most potent compounds against both AChE and BChE. The promising compound was then subjected to molecular docking and dynamics simulations, revealing significant binding affinities and favorable interaction profiles against AChE and BChE. The in silico ADMET assessments further determined the drug-like properties of 3m, suggesting it as a promising candidate for further pre-clinical development.

An efficient route to the synthesis of novel zwitterionic pyridinium-cyanopropenides with 3-heteroaryl-substituted trimethinium salts.

In this study, eight new zwitterionic derivatives were synthesized using a simple design method from the reaction of various 2-substituted 1,3-bis(dimethylamino)-trimethinium salts with malononitrile or ethyl 2-cyanoacetate in excellent yields in the presence of triethylamine in ethanol at reflux. The molecular structures of the new compounds were confirmed by IR, UV/vis, mass, 1H, and 13C NMR spectra as well as by elemental analyses.

A facile and efficient route to one-pot synthesis of new cyclophanes using vinamidinium salts.

In this study, an efficient method for the synthesis of new cyclophanes (5a-f, 6a-g) through the condensation of 1,4-phenylenedimethanamine (3) or 2,3,5,6-tetramethylbenzene-1,4-diamine (4) with 2-substituted vinamidiniums (2a-g) is described. The cyclophane derivatives are obtained in good to excellent yields in the presence of acetic acid in refluxing acetonitrile after 15 h. The structure of new compounds was validated based on their spectral data (1H NMR, 13C NMR, IR) and elemental analysis.

Synthesis of new allylidene amino phenol-containing Schiff bases and metal complex formation using trimethinium salts.

An efficient route for the synthesis of novel Schiff bases from the condensation reaction of 2-substituted 1,3-bis(dimethylamino)-trimethinium salts with diverse aminophenols in the presence of triethylamine in EtOH at reflux is described. Complexes of transition metals with Schiff base ligand (L) 3c, having the donor atom set N2O2, were studied. The ultraviolet spectral behavior of the complexes in DMSO was investigated and the λ max of these compounds was examined. The structure of the new compounds was confirmed based on their spectral data from IR, 1H NMR and 13C NMR, mass spectra, and elemental analysis.