Design, Synthesis And Anti-HIV-1 Activity Evaluation Of CCR5 Small Molecular Antagonists

AIDS is a disease of the human immune system caused by the HIV-1. Treatment with antiretroviral agents, especially with highly active antiretroviral therapy (HAART) has substantially reduced morbidity and mortality significantly. HAART regimens can inhibit the duplication of virus and can hardly eradicate HIV-1 from infected people. There is a need to discover new target for HIV-1 therapy. The researchers found chemokine receptor 5 (CCR5) plays a key role in the HIV-1 entry. Therefore, many efforts have been directed toward discovering novel small-molecule CCR5 antagonists.In our research, we proposed a "Y. shape" pharmacophore model with three hydrophobic domains and one basic center. On the basis of bioisosteric replacement, fragment assembly, and the "Y shape" pharmacophore model, four series of piperazine derivatives and analogs, piperidin-4-ol derivatives, and piperidin-4-carboxyl derivatives were designed.75 new compounds were synthesized. Piperazine derivatives and analogs were tested for CCR5 antagonistic activities based on membrane fusion assay. The results indicated that compound 2-50 (IC50640 nM) showed the best CCR5 antagonistic activities. Piperidin-4-ol derivatives and piperidin-4-carboxyl derivatives were tested for CCR5 antagonistic activities based on calcium mobilization assay. The results showed that the activities of compounds 2-159,2-182,2-183 and 2-192 (IC50 25.73±3.85,35.47±5.67,25.53±5.84, and 26.37±8.43 nM, respectively) were similar to that of maraviroc (IC5025.43±1.35 nM). Some piperazine derivatives and piperidin-4-carboxyl derivatives were also tested in anti-HIV-1 assays. Compounds 2-76, 2-159 and 2-183 were found to be potent (IC500.44,0.073 and 0.094μM, respectively). The above results will provide experimental clues for designing of novel CCR5 antagonists.