Studies On The Design, Synthesis And Biological Activity Of Anti-HIV Drug Targeting PCAF Bromodomain

This thesis includes six parts: (1) A review described the progress in the studies of anti-HIV drugs since the first AIDS patient was reported in 1981; (2) Based on the 3D structure of the PCAF BRD which plays an important role in the gene expression and transcription of HIV-1, eighteen N₁-(nitroaryl)-propane-1,3- diamines derivatives were designed and synthesized as HIV-1 Tat/PCAF BRD association inhibitor for the first time. The interaction between compound 2-2 and the PCAF BRD was disclosed clearly by the 3D structure of PCAF BRD/compound 2-2 complex determined by NMR. Biological activities in vitro (IC₅₀) were determined by ELISA assay and the primary structure activity relationships were concluded; (3) The new methodology of N₁-(electron-drawing substituted aryl)-propane-1,3- diamines derivatives was studied. The 2-[3-(arylamino)-propyl]-isoindole-1,3-diones were synthesized from electron-drawing substituted anilines and N-(3-bromopropyl)phthalimide by N-alkylation under solvent-free condition. These intermediates were easily converted into N₁-(electron-drawing substituted aryl)-propane-1,3- diamines by hydrazinolysis, Biological activities in vitro (IC₅₀) of some new compounds were determined by ELISA assay and the results complement the primary structure activity relationships; (4) Six 3-aryloxy-1-propylamines were synthesized for studying the SAR of HIV-1 Tat/PCAF BRD inhibitors. Substituted 2-nitrophenol reacted with 1,3-dibromopropane to give 3-(2-nitroaryloxy)-1-propylbromides under common heating and microwave irradiation, the reaction rate was accelerated remarkably and the yields were increased under microwave irradiation in comparision with that under common heating. 3-(2-nitroaryloxy)-1-propylbromides were treated with potassium phthalimide to produce 2-[3-(aryloxy)-propyl]- -isoindoline-1, 3-dione. Hydrazinolysis of intermediates yielded target molecules. The inhibition of HIV-1 Tat/PCAF BRD interaction in vitro was determined by ELISA assay, and some influential factors of biological activity were discussed; (5) Based on the 3D structure of PCAF BRD/compound 2-2/ N-ethyl-acetamide triple complex, N₁- (4-methyl-2-nitro-phenyl)-2-acetaminoethyl...