Design, Synthesis And Anti-HIV-1 Activity Evaluation As CCR5 Small Molecule Antagonists

AIDS is a disease of the human immune system caused by the HIV-1. Although the antiretroviral therapy (cocktail therapy) has been common practice for the treatment in clinic, the issues of drug resistance, toxicity and severe adverse effects, as well as the long-term costs, make it a need for the development of novel drugs targeting distinct processes in the viral lifecycle. Chemokine Receptor 5 (CCR5) plays a key role in the HIV-1 entry. Therefore, many efforts have been directed toward discovering novel drugs with potent anti-HIV-1 activity, high receptor selectivity and good pharmacokinetic properties.In our research, Sch-351125 and Sch-417690 were chosed as the lead compounds. Taking account of SAR of piperidine- and piperazine-based CCR5 small-molecule antagonists and the attractive features elucidated by docking studies, the nitrogen atom on the piperidine or piperazine ring which was most likely to form a salt bridge with the E283A in TM7 of CCR5 and the substituted aromatic ring which might form hydrophobic interactions with 1198A in TM5 were kept. On the basis of the two key pharmacophores, a series of piperidine-methylene-piperazine and pyrrolidine-piperazine derivatives were designed. 48 New compounds were synthesized and 33 Compounds were tested for membrane fusion activity. Preliminary studies indicated that 3 compounds showed potent inhibitory activities in membrane fusion test and 7 compounds showed moderate inhibitory activities at the concentration of 5μM. The results will provide experimental clues for designing of novel CCR5 antagonists.In addition, quantitative structure activity relationship (QSAR) studies have been carried out on a series of piperidine- and piperazine-based compounds. 3D-QSAR models were established by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. 2D-QSAR models were also developed by using multiple linear regression (MLR) and support vector machine (SVM) methods. All the QSAR models were proved to be reliable by internal and external validation and will probably aid further structural design andoptimization of more potent CCR5 inhibitors.