Novel Bis-thiazoles with pyridine and 1,4-Dihydropyridine linkers as potential anti-Alzheimer agents

•Novel bis-thiazoles with pyridine and 1,4-dihydropyridine linkers were developed.•The above were treated with 1-aryl-2-bromoethanone to yield bis-hydrazonothiazole.•All were characterised using 1H, 13C NMR, IR, mass spectroscopy and CHN analysis.•MD against 1EVE showed ligand conformational changes and good binding affinities.•SwissADME was used to prioritize promising candidates for further experimentation. A series of bis-hydrazonothiazoles with pyridine and 1,4-dihydropyridine linkers was synthesized using 2,2′-[(2,6-dimethyl-1,4-dihydropyridine-3,5-diyl)bis(ethan-1-yl-1-ylidene)]bis(hydrazine-1-carbothioamide) and 2,2′-[(2,6-dimethylpyridine-3,5-diyl)bis(ethan-1-yl-1-ylidene)]bis(hydrazine-1-carbothioamide) as starting materials, which were reacted with 1-aryl-2-bromoethanone to form the desired bis-hydrazonothiazoles. Additionally, an alternative synthetic strategy involved the simple oxidation of 1,4-dihydropyridine linkers using a mixture of aqueous sodium nitrite and acetic acid to produce pyridine linkers. The synthesized compounds were subjected to molecular docking studies against the protein 1EVE (one of the AD bio-markers) to evaluate their 3-D orientation, flexibility, and conformational changes upon binding—key factors for optimizing drug design and therapeutic efficacy. The binding affinities of the synthesized compounds ranged from −1.14 to −11.64 kcal/mol, compared to -6.78 to -10.24 kcal/mol for the reference drugs. Statistical analysis revealed no significant difference in binding affinity between Donepezil and compounds 5c, 7a, 7b, and 8a, indicating similar therapeutic potential. Differences in binding affinities among the approved drugs underscored their distinct interaction profiles with the target protein. Molecular docking and SwissADME predictions helped prioritize molecules based on drug-likeness and pharmacokinetic profiles, identifying candidates for in-vivo validation and enhancing the drug development process. Docking ligand 7b into 1EVE protein structure revealed significant conformational differences. The mean of the plane (green) is NCCCCC. [Display omitted]