Design And Synthesis Of Anti-HIV Drugs Based On CCR5

Acquired immune deficiency syndrome (AIDS) resulted by HIV was infectious disease that seriously threatened human health. AIDS has resulted in serious endanger to human and society in last twenty years and has been the fourth serious disease in the world. At present, 29 drugs are licensed by the FDA for the treatment of HIV-1 infection in the United States, these agents can favorably influence disease progression, but do not cure HIV infection. The drugs must be maintained long-term, and serious chronic toxicity, therapy fatigue, and drug resistance have become major issues. CCR5 is a coreceptor for HIV entry into target cells and it was found that individuals homozygous for a 32-base pair deletion in the gene for CCR5, which prevents expression of functional receptor on the cell surface, have been identified as being highly resistant to HIV-1 infection, while infected heterozygous individuals showed significantly delayed progression to AIDS. The discovery has led to promising new targets for drug development.Because the crystal structure of transmembrane protein CCR5 was not reported drug design based on ligand was the appropriate way tot find new CCR5 antagonist quickly. A three-dimensional pharmacophore model evaluated effectively based on pyrrolidine- and butane- derived CCR5 antagonists by HypoGen module in catalyst 4.11 soft ware was gained. Active values of 74 molecules in test set tested by hypo1 (R=0.703) indicated hypo1 can afford good test ability and can be used in testing unknown compounds.According to literature polyhydroxy phenol behaved higher bioactivity, piperazin derivatives exhibited good cell infiltration and the structure in the compound virtual screened, N-(3-(4-cinnamoylcyclohexyl)propyl)benzamide derivatives was designed and synthesized and none of them was reported. They were N-(3-(4-cinnamoylcyclohexyl)propyl)-3,4,5-trihydroxybenzamide,N-(3-(4-(3-p-tolylacryloyl)cyclohexyl)propyl)-3,4,5-trihydroxy-benzamide,N-(3-(4-(3-(4-chlorophenyl)a cryloyl)cyclohexyl)propyl)-3,4,5-trihydroxybenzamide,N-(3-(4-(3-(2-chlorophenyl)acryloyl)cyclohexyl)propyl)-3,4,5-trihydroxybenzamide,N-(3-(4-(3-(2-nitrophenyl)acryloyl)cyclohexyl)propyl)-3,4,5-trihydroxy-benzamide,N-(3-(4-(3-(3-hydroxyphenyl)acryloyl)cyclohexyl)propyl)-3,4,5-trihydroxy-benzamide,N-(3-(4-cinnamoylcyclohexyl)propyl)-3,4-dihydroxybenzamide,N-(3-(4-(3-p-tolylacryloyl)cyclohexyl)propyl)-3,4-dihydroxy-benzamide,N-(3-(4-(3-(4-chlorophenyl)acryloyl)cyclohexyl)propyl)-3,4-dihydroxybenzamide,N-(3-(4-(3-(2-chlorophenyl)acryloyl)cyclohexyl)propyl)-3,4-dihydroxybenzamide,N-(3-(4-(3-(2-nitrophenyl)acryloyl)cyclohexyl)propyl)-3,4-dihydroxy-benzamide, and N-(3-(4-(3-(3-hydroxyphenyl)acryloyl)cyclohexyl)propyl)-3,4-dihy droxy-benzamide.