Nitrogen Thick (even) Synthesis And Biological Activity Of Heterocyclic Compounds Measured

The thesis mainly consists of the following two parts:Part One: Hybrid pharmacophore guided design of TV-substituted arylmethyltetrahydropyridine linked indoles: Synthesis, crystal structure and anticanceractivity studiesIn order to find some potent anticancer activity lead compounds, based onthe hybrid pharmocophore approach, we have chosen the bioactive molecularentities^substituted arylmethyl piperidine-4-one and5-substituted indoles tosuitably combine them through carbon-carbon bond formation for creating newhybrid molecules, a total of42new A^substituted arylmethyl tetrahydropyridinelinked indoles (I广I42) were synthesized, The structural formula of compounds (I)are as follows: The structures of the compounds (I广I42) were characterized by ’H NMR, IR,and elemental analysis, and the crystal structures of two compounds (I35) and (I36)were confirmed by X-ray diffraction.The anticancer activities tests of the compounds (Ij—142) were finished inCentral Research Institute of Shanghai Pharmaceutical (Group) Co., Ltd. andthe Zooblast-molecular Biology Laboratory of Shanghai Normal University. The results indicated that most of these compounds examined were quite effective onall cancer cell lines examined, and the higher cytotoxicity of these compoundsagainst leukemic K562cells was observed. Among them the compounds (1^) and(I31) emerged as the most active compounds of this series, the IC50of them were122uM and1.22uM against leukemic K562cells, respectively, which were lowerthan the anticancer drug of clinical practice5-FU (IC5o=8.56uM). Acridineorange lfuorescence, flow cytometric analysis and cell cycle analysis suggestedthat (I31) induced leukemic K562cell death by apoptosis. In addition, themetabolic stability of compounds (I30) and (I31) in human and rat liver microsomewere studied, and both of them exhibited excellent metabolic stability. Further,effects of compound (I30) and (I31) on the catalytic activities of five maincytochrome P450s (CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2C19) ofhuman liver microsome were assessed, and both of them exhibited nocompetitive inhibition on the catalytic activities of five main drug metabolismenzymes of human liver microsome. All the results indicated that (I30) and (I31)may serve as prototype molecules for further development of a new class ofanti-leukemia agents.Part TWo: Receptor-based hydrogen bond-guided design of cis-Nitenpyramanalogues bearing chiral ester arm: Synthesis, insecticidal activity, docking andmolecular dynamics simulation studiesIn order to search the lead compounds of neonicotinoid insecticides for newpesticide, based on our preliminary research work, especially relying on thesuccessful experience of developing c/^nitenpyram analogues, a new series ofc/^nitenpyram analogues bearing chiral ester arm were designed and synthesized(II广1112，111广1113). The structural formulas of compounds (II) and (III) are asfollows respectively: The structures of the compounds (Ⅱ1～Ⅱ12, Ⅲ1～Ⅲ3) were characterized by ’H NMR, IR, and elemental analysis.The preliminary insecticidal activity tests of compounds (Ⅱ1～Ⅱ12, Ⅲ1～Ⅲ3) were finished in bioassay department, Branch of National Pesticide R&D South Center of Hangzhou. The results indicated that most of the cis-nitenpyram analogues showed excellent insecticidal activities against Nilaparvata lugens and Myzus persicae, whereas analogues (Ⅱ4) and (Ⅲ2) afforded the best in vitro activity, the LC50values of the analogues (Ⅱ4) and (Ⅲ2) were0.148and0.144mg/L，respectively. Structure-activity relationships (SAR) studies showed that the introduction of electronegative oxygen, hydroxyl which function as hydrogen bond donor/acceptor played a critical role on the insecticidal potencies of our designed nitenpyram analogues. In addition, molecular docking and molecular dynamic(MD) simulation revealed that significant hydrogen bonds formed between the newly introduced amino acid ester segment and the basic residue Gln55located within loop D of the target nAChRs was crucial for the good insecticidal potency, the significant hydrogen bond forces and the complementary hydrogen bond actions coexist and cooperate in the molecular recognition process of the analogues and its target nAChRs, which explained the SARs observed in vitro and implied that a new tatic of molecular design developed by us in this paper both practical and feasible.