Design, Synthesis And Activity Evaluation Of CCR5and CXCR4Dual Inhibitors

Acquired Immune Deficiency Syndrome (AIDS), the fatal disease caused byHuman Immunodeficiency Virus-1(HIV-1), has made a great threat to human healthand affected the development of social economy. HIV virus entry into target cells withthe assistance of CCR5or CXCR4co-receptors, thus co-receptor inhibitors couldeffectively block HIV virus infection.In recent years, the CCR5co-receptor inhibitors have been attracted muchattention by a number of multinational pharmaceutical companies and academicinstitutions. A series of small molecule CCR5inhibitors have been designed andsynthesized, a CCR5inhibitor (Pfizer Maraviroc) was approved by FDA in2007.Compared with CCR5inhibitors, CXCR4inhibitors have been rarely investigated. Uptill now, pull bicyclic amines, tetrahydroquinoline benzimidazole amines andguanidines exhibited potent anti-HIV activities. However, CCR5or CXCR4inhibitorsalone have some limitations, a single inhibitor of CCR5and CXCR4is only effectiveto the corresponding virus. In addition, the CCR5inhibitors in clinic require CCR5virus detection before use, and long-term use of CCR5inhibitors may result in virusinfection via CXCR4.In this paper, on the basis of the provious syntheses of3-methyl pyridine benzylquinoline polyamine derivatives and5,6,7,8-tetrahydroquinoline polyaminederivatives as well as the analysis of the structure and structure-activity relationship ofCCR5and CXCR4receptors, a series of novel tetrahydroquinoline amines and otherswere designed and synthesized according to the strategy of splice of segments andgroup transfers, and their anti-HIV activity were also determined.The main work is as follows:1. Ten tetrahydro-quinolin-benzylamino polyamines were synthesized accordingto the AMD070prepared by AnorMED.2. Five tetrahydroquinoline-benzyl guanidine and polyamine dervatives weresynthesized.3. Five tetrahydroquinoline-piperidine formamide dervatives were designed andsynthesized.4. Twenty novle compounds were characterized by mass spectrometry (MS),nuclear magnetic resonance (1H-NMR) and the novelty was confirmed by SciFinderretrieve.5. Tetrahydroquinoline-benzimidazole polyamine dervatives exhibited betteranti-HIV activity (IC50<1μmol/L), but tetrahydroquinoline-benzyl polyamines were not active to CXCR4(IC50>8μmol/L).This study provide references for the further optimizations of bifunctionalinhibitors for CCR5and CXCR4.