Design, Synthesis, And Anti-HIV-1Biological Activity Of Novel Piperidine Derivatives Targeting CCR5Receptor

Acquired Immune Deficiency Syndrome (AIDS) disseminate widely on a globalscale that has been a serious threat to human health and life. CCR5is the keycoreceptor of HIV-1into the cells. The study of HIV-1small molecule antagoniststargeting CCR5is one hot spot in the anti-AIDS research field.This dissertation mainly revolves the study of bioactive molecules targetingHIV-1CCR5in three aspects, drug design, systhesis and biological activity assay.First, a reliable pharmacophore model was established with the Hypogen moduleof Discovery Studio2.5program. Then a self-designed small molecule library wasscreened with the pharmacophore model. In view of our laboratory obtained results,1-piperidin-propylamine derivatives were designed as molecular skeleton, and thepharmacophore model was used to predict on the activity.Second, intermediate4-(3-benzyl-1H-pyrazol-5-yl) piperidine was synthesisedwith new systhetic method. The target compounds were synthesized by acylationreaction, Grignard reaction, Claisen condensation and nucleophilic substitution. Thestructure of intermediates and target compounds were confirmed by1H NMR,13CNMR and ESI-MS.In the end, the biological activity of the target compounds was determined usingthe MAGI method. Anti-HIV-1bioactivity of the pyrazol-piperidine-4-carboxamidederivative19g was improved significantly, the IC50is750nmol·L-1and the therapeuticindex reached203. It should be a good lead compound for further research ofanti-HIV-1drug.