Design,Synthesis And Biological Evaluation Of Tropane And 2-methylpiperazine Derivatives As CCR5 Antagonists

AIDS is an infectious disease of human immune system caused by HIV-1.HIV has claimed 25 million lives worldwide since the disease was found in 1981.The treatment of AIDS is still in progress.Therefore,it is urgent to develop new chemical anti-HIV agents.Recently,Chemokine receptor 5(CCR5)has been found to play a vital role in the HIV-1 entry,and many efforts have paid for discovering novel small molecule antagonists toward CCR5.Based on literature searching and study,118 target compounds within four structural scaffolds were designed and synthesized in this thesis by using strategies including scaffold hopping,fragment assembly and bioisosterism.Some synthesized target compounds showed potent CCR5 inhibitory activity and anti-HIV-1 activity.The second part of the thesis is mainly about 8-azabicyclo[3.2.1]octan derivatives.On the one hand,"Design,synthesis and evaluation of biological activity of 8-(-2-phenylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan derivatives" is the first section of this part.34 target compounds were synthesized starting from the lead compound,Phizer-5,which was suffered from optimization by using the strategy of scaffold hopping.All the compounds were tested for CCR5 antagonistic activities based on calcium mobilization assay.And the preliminary structure-activity relationship(SAR)showed that all the tested compounds displayed some activity.Specifically,compound 1-68 had a superior activity(IC50=0.1μM).And compounds with sulfamide moiety showed better activities.On the other hand,"Design,synthesis and evaluation of biological activity of 8-cyclohexyl-8-azabicyclo[3.2.1]octan derivities" is the second section of this part.21 novel target compounds were design and synthesized through using the strategy of fragment assembly by connecting the 3-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-cyclohexyl 8-azabicyclo[3.2.1]octan moiety of compound 1-68 and the 1-acetyl-N-phenylpiperidine-4-carboxamide moiety of TAK-12 through cyclohexane.Evaluation of CCR5 antagonistic activity and preliminary SAR revealed that most compounds showed moderate to strong activity.The activities of four compounds(1-95:IC50=17nM,1-103:IC50=42nM,1-104:IC50=55nM,1-105:IC50=74nM)were the same order of magnitude to that of maraviroc(IC50=13.1nM).compounds with potent activity were selected for anti-HIV-1 assays and the results showed that the inhibitory rate of compounds 1-95,1-103 and 1-104 were over 60%at the concentration of 10μg/ml.in addition,1-95,1-103,1-104 and 1-105 showed no obvious cytotoxicity in MTT assay.The third part of the thesis is on 2-methylpiperizane derivatives and analogues.The first section of this part is "Design,synthesis and evaluation of biological activity of 2-methyl-N-substitutedphenyl-N’-(N-monosubstitutedaminepropyl)piperazine derivatives and analogues" 44 target compounds were design and synthesized in this section based on rational drug design strategy and compound 23h was used as lead compound.The result of biological evaluation revealed that all the tested compounds showed a limited potency.And the most potent compound was compound 1-90(IC50=1.12μM).Moreover,SAR exhibited that there was slightly different when the basic center was replaced by the 2-methylpiperazine,2,6-dimethylpiperzaine or 1,4-diazepane.The second section of this part is "Design,synthesis and evaluation of biological activity of 2-methyl-N-substitutedbenzyl-N’-(N,N-disubstitutedaminepropyl)piperazine derivatives and analogues." The results of CCR5 assay were that most of compounds displayed potent activity.Six compounds(2-114,2-117,2-119,2-124,2-147and 2-150)showed abetter activities than that of the positive control,maraviroc.Four representative compounds 2-114,2-117,2-147and 2-150 were chosen for anti-HIV-1 assay and the result revealed that the IC50 of compounds 2-114,2-147and 2-150 were less than 100nM and compound 2-147(IC50=31.4nM)had a better activity.In addition,compounds 2-114,2-117,2-147and 2-150 showed no obvious cytotoxicity in MTT assay,which paved the way for further exploring.A metabolic stability assay showed that 2-147 exhibited good stability in rat whole blood.Compounds 2-147 and 2-150 showed 45%and 64%inhibition at concentration of 3μM in hERG assay,which laid a foundation for further studies.