Highly Efficient Synthesis And Bioactivity And Structure-Activity Relationship Study Of Spirooxindole And Its Derivatives

Natural source anti-plant virus compounds are one of the important sources of antiphytoviral agents.Due to the limitation of the intrinsic structure and the physicochemical property of natural products,their derivatization is often difficult to achieve.In order to break through the limitation and make the molecular structure more simple and diverse,and drawing on the experience of ?-carboline antiviral inhibitor and the preliminary biological results of tryptophan,this paper intends to systematically carry out research on the diversity-oriented green and efficient new antiphytoviral agents using biosynthesis precursor tryptophan as basic material.The main content of the paper comprises: the design and synthesis of natural pseudo spiro-indole products with the structural diversity,the development of efficient synthetic methods of building spiro-indole molecular skeleton,the study of their anti-plant virus activities and structure-activity relationship.Additionally,the phenanthroindolizidine alkaloids which were synthesized by our group were modified and derivatived based on the prodrug principle.In the synthesis methodology,we developed a Pd-catalyzed cycloisomerization/nucleophilic addition/reduction reaction which provided a simple and efficient method for the synthesis of a wide range of C2-spiropseudoindoxyls which are common structural units in indole alkaloids.A study of the mechanism indicated that this protocol involved a Pd-catalyzed 5-exo-dig nitroalkyne cyclization and internal N–O bond redox process.The anti-virus,fungicidal and insecticidal activity evaluation of representative compounds highlighted the significance of this reaction for the construction of bioactive functionalized spiro-heterocycles.In terms of biological activity,using biosynthesis precursor tryptophan as basic material,we designed and synthesized a series of novel spirooxindole derivatives containing acylhydrazone moiety and first evaluated their biological activities.The results of bioassays indicated that most of the target compounds showed good antiTMV activity both in vitro and in vivo(inactivation,curative,and protection)in the laboratory.Activities of compounds IV-4?IV-5?IV-9-IV-11?IV-16?IV-24?IV-29 were much higher than that of ribavirin(38.2,36.4±0.2,37.5±0.2,and 36.4±0.1% at 500 ?g/mL),especially compound IV-4(48.4,58±0.4,55.2±2.3,and 49.7±0.2% at 500 ?g/mL)exhibited the best antiviral activity.In addition,we were pleased to find that these compounds also showed broad-spectrum of fungicidal activity and insecticidal activity.For instance,most of these derivatives exhibited more than 60% fungicidal activity against Physalospora piricola at 50 mg/kg.Compounds IV-17 and IV-26 displayed excellent insecticidal activities(60% against C.pipiens pallens at 0.25 mg/kg)even at very low concentration.Secondly,we continued to conduct further research on the structure diversity of spirooxindole derived from tryptophan based on hydrogen bonding principle which was used in the drug research and development;we designed a series of spirooxindole-fused hydantoins and thiohydantoins.The results of bioassays indicated that the urea V-22 which was failed to access cyclization displayed best anti-TMV activity(42.3,46.9±2.8,39.8±1.1,49.2±0.3% at 500 ?g/mL)which was higher than ribavirin.The result just turned out that the existence of N-H bond may form hydrogen bond with the target and reasonably enhance the antivirus activities.Meanwhile,most of these compounds displayed broad-spectrum fungicidal activity.Almost all the thiohydantoins exhibit inhibitory effect against Physalospora piricola,Rhizoctonia cerealis and Sclerotinia sclerotiorum.For example,the inhibitory rate of V-8 and V-19 against Physalospora piricola was up to 93.1% at 50 mg/kg;the inhibitory rate of V-6 and V-21 against Sclerotinia sclerotiorum were 90.2% and 96.1% respectively.In order to overcome the drawback of phenanthroindolizidine alkaloids like lowsolubility,instability and high cytotoxicity,we attempt to modify the parent molecule 6-O-desmethylantofine,tylophorine and 14-hydroxyl-tylophorine on the basis of prodrug principle.The phenanthroindolizidine alkaloids were derived as borate,quaternary ammonium salte and dichloroacetylate respectively,the anticancer activity as well as the decomposition kinetics research indicate that our initial design ideas are reasonable.