Design, Synthesis And Bioactivity Of 3,6 - Diarylthiazolotriazine Compounds

Alzheimer’s disease (AD) is one kind of senile dementia, the rate of incidence of the disease was higher than another kind of senile dementia. The physical health of AD patients is seriously injured, and the qualities of their lives are influenced. Most of the AD clinic treatment drugs are reversible acetyleholinestearse (AChE) inhibitors. Unfortunately, all of the drugs used in clinic showed unsatisfactory curative effect and some side effects. So, to find out the novel reversible multi-target spots AChE inhibitors are focused urgently in research and development of new drugs, the applied prospects of the kind of drug will be broad.According to the three-dimensional structure and function of AChE, the structural feature of AChE and the mode of interaction between AChE and the small molecules were analyzed, some small molecules which were designed and synthesized, which based on our previous work were consulted for reference, some computer aided drug design methods, such as molecular docking, some structural modification works of AChE inhibitors were used for reference, a series of 3,6-diaryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives as the target compounds were designed. Molecular docking results displayed that the target compounds can interact with both catalytic active site and peripheral anionic site of AChE, the target compounds were a kind of multi-target spots AChE inhibitors.1-(4-chlorophenyl)ethanone and 1-(4-bromophenyl)ethanone were prepared by Friedel-Crafts acylation reaction of chlorobenzene or bromobenzene,1-(4-ethoxyphenyl)ethanone and 1-(4-ethoxyphenyl)ethanone were synthesized by alkylation reaction of 1-(4-hydrooxyphenyl) ethanone. The key intermediate of the synthetic route 2-aryl-2-oxoacetic acid was prepared by using reduction, elimination reaction, and oxidation reaction under mild condition,1-arylethanone was as raw material.2-aryl-2-oxoacetic acid condensed with thiosemicarbazide in alkaline aqueous solution to obtain 3,4-dihydro-6-aryl-3-thioxo-1,2,4-triazin-5(2H)-ones derivatives. 3,4-dihydro-6-aryl-3-thioxo-1,2,4-triazin-5(2H)-ones acted with substituted a-phenacyl chlorides in acetic acid to obtain twenty-seven 3,6-diaryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones as target compounds. Among above target compounds,6-aryl-3-hydroxyaryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones were later transferred to twenty-seven 6-aryl-3-alkoxylphenyl-7H-thiazolo[3,2-b]- 1,2,4-triazin-7-ones by using Williamson reaction. The structures of all target compounds were preliminarily characterized by MS,1H-NMR and IR spectra. According to the search results of SciFinder, all target compounds were unreported in literature.The AChE inhibitory activities in vitro of the target compounds were evaluated by using Ellman colorimetric assay, the positive control drug was huperzine-A.28 of target compounds exhibited more than 50% inhibition at 10μM.According to the test results of the AChE inhibitory activities of the target compounds, the primary structure-activity relationships were discussed. The FieldTemplater and FieldAlign software were used to analyse the molecular force fields of the target compounds. The field parameters showed interactions between all parts of the compounds and protein. The results of the molecular force field analysis was in accordance with the above-mentioned structure-activity relationships.