Design, Synthesis And Bioactivity Of Thiazolyl Triazine Compounds

Alzheimer’s disease(AD),is one type of senile dementia,can seriously injury the physical health of AD patients,with the aggravation of social aging phenomena,AD gradually become a rigorous and complicated problem clinically and socially.Acetyleholinestearse(ACHE) inhibitors are the most developed groups of drugs approved for AD symptomatic treatment.Unfortunately,all the drugs used in clinic showed insufficiency,searching for new AChE inhibitors is focused urgently in research and development of new drugs.Based on our previous work,3D structures of AChE and interactive binding modes between AChE with some compounds which had been designed and synthesized in our laboratory were analyzed.Using molecular docking strategy,some molecular databases were virtually screened. According to the hit structures,integrating the principles of bioisosterism,hybridization,and structural optimization,a series of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives as the target compounds were designed.Docking results display the target compounds can interact with both central and peripheral binding sites of ACHE,and are highly selective AChE inhibitors with a novel Heterocyclic scaffold.Aryl pyruvic acids which were produced by Erlenmeyer-Pl(o|¨)chl reaction reacted with thiosemicarbazone to give 3,4-dihydro-6-arylmethyl-3-thioxo-1,2,4-triazin-5(2H)-ones as the cyclized products.Condensation of 3,4-dihydro-6-arylmethyl-3-thioxo-1,2,4-triazin-5(2H)-ones with substitutedα-phenacyl chlorides formed 6-arylmethyl-3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones as target compounds.Among above target compounds,6-arylmethyl-3-hydroxyphenyl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones were later transferred to 6-arylmethyl-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,IR,~1H-NMR spectra.According to the search results by SciFinder,all target compounds are unreported in literature.The single crystals of target compounds 6-benzyl-3- { 4-[2-(1 -piperidinyl)-2-oxoethoxy]phenyl }-7H-thiazolo[3,2-b]- 1,2,4-triazin-7-one (L43),6-benzyl-3- { 2-[2-(4-morpholinyl)ethoxy]phenyl } -7H-thiazolo[3,2-b]- 1,2,4-triazin-7-one (L49), 6-benzyl-3- {2-[(2-dimethylamino)-2-oxoethoxy]phenyl) -7H-thiazolo[3,2-b]- 1,2,4-triazin-7-one (L54),and 6-(4-methoxybenzyl)-3- { 2-[(2-diethylamino)-2-oxoethoxy]phenyl } -7H-thiazolo[3,2-b]- 1,2,4-triazin -7-one(L80) were obtained by slow evaporation of solvents at room temperature,and the crystal structures were determined with an X-ray diffractometer.The AChE inhibitory activities in vitro of target compounds were carried out by using Ellman colorimetric assay with huperzine-A as a reference standard.Most of target compounds exhibit more than 50%inhibition at 10μM.The median inhibitory concentration values of some target compounds showed dose-effects relationship in AChE inhibitory activity.In order to understand binding mode in AChE and theoretically guide design of new inhibitors, the quantitative structural activity relationships of the 7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones were performed by using 3D-QSAR approach:comparative molecular field analysis(CoMFA) and comparative molecular similarity indices analysis(CoMSIA).The computed results show that the predicted power of the obtained models is favorable.From analysis of the contour of molecular field in three dimensional spaces,the key features vital to ligand including steric and electrostatic properties were identified and steric properties play an important role.These results demonstrate some useful indications in structural optimization of target compoundsand future design of new molecules.