Synthesis And Biological Activity Of Isoxazolidin And Thiazin Derivatives With1,2,4-triazol

1,2,4-triazole derivatives, for its high efficiency, broad-spectrum, low toxicity, systemic and broad application prospects, attract researchers’ and pharmaceutical companies’ great attention. So far, many kinds of triazole drugs have been used in clinical research.Making changes in the structural skeleton of compounds can create new triazole drugs, introducing N, S, O heteroatoms or heterocyclic to the molecular structure can improve the drugs’ functionality. In order to find new triazole lead compounds which have high biological activities, with the methed of bioactive substructure splicing principle, we combined isoxazolidin ring,1,3-thiazine ring, tert-butyl and1,2,4-triazole ring together in a molecular structure, synthesized two types of new skeleton structure triazole derivatives, while succeed in introducing N, S, O heteroatoms to the target molecule. We hope to screen out some compounds with excellent bioactivity. The thesis’ research results are:1)1,2,4-triazole reacted with1-chloro-3,3-dimethylbutan-2-one to get3,3-dimeth-yl-1-(1H-1,2,4-triazol-1-yl)butan-2-one1. Compound1reacted with aldehydes produced4,4-dimethyl-1-aryl-2-(1H-1,2,4-triazol-1-yl)pent-1-en-3-one2. Then compound2reacted with hydroxylamine hydrochloride produced5-(tert-butyl)-3-aryl-4-(1H-1,2,4-triazol-1-yl)-isoxazolidin-5-ol3. Reaction conditions had been optimized:using ethyl acetate as solution, add reaction materials, the ratio of1,2,4-triazole,1-chloro-3,3-dimethylbutan-2-one, K2CO3, PEG600was1vs1vs1.5vs0.03, after refluxing for4.5h, the yield of substitution reaction was94.2%; using piperidine as catalyst,1mol aldehyde and1.1mol compound1under reflux in toluene for6-8h by aldol condensation, materials could almost react completely with little side reaction; Cyclization reaction using ethanol as solvent, the ratio of compounds2, hydroxylamine, anhydrous sodium acetate was1vs1.3vs1.5, after refluxing for1.5～2.0h could obtain satisfactory results. The compounds3were purified by recrystallization then got3a-3o, new structures were confirmed by1H NMR. Compounds3a-3o were tested for their anti-tumor activities against lung cancer cells in vitro. The bioassay results showed that compounds3d,3i and3o possess promising anti-tumor activities.2) designed and synthesized a series of1,3-thiazine derivatives as NA inhibitors against150-Cavity and430-Cavity double-binding-site. Using ethanol as solution, concentrated hydrochloric acid as catalyst, compounds2reacted with thiourea produced compounds4, the yield of1,3-thiazine cyclization reaction was6.0-13.1%. The structures of compounds4were confirmed by1H NMR. By doing orthogonal experimental design, the optimization method of1,3-thiazine cyclization reaction was as following:DMF as solvent, concentrated sulfuric acid as catalyst, the ratio of compound2and thiourea was1vs1.2,140℃stirring reaction. Under the optimization method, the yield of4-tert-butyl-6-(4-chlorophenyl)-5-(1,2,4-triazol-1-yl)-2-amino-6H-1,3-thiazine was24.1%, which was significantly improved compared to the past method. Compounds4a-4d were tested for NA inhibitory activities in vitro at40μg/mL concentration, they performed normal NA inhibitory activities.3) Compounds4b-4f were tested for herbicidal, insecticidal activities. At2250g ai/ha concentration, the inhibition rate to amaranthus spinosus and chenopodium album of compound4b was90%, it can be developed as erbicide for amaranthus spinosus and chenopodium album. Compounds4b-4f showed some toxic activity to aphis fabae and tetranychus urticae in500mg/L concentration.