Abstract
Hepatitis C virus and chikungunya virus fall into the category of RNA and emerging viruses respectively, which cause serious global health-care problems. More than 400,000 people die from liver diseases related to the hepatitis C virus each year. During the past two years, the U.S. Food and Drug Administration has approved a few drugs for hepatitis C diseace. These therapeutic treatments, however, are expensive and limited by the low sustained virologic response rate, the long duration of treatment, and adverse events. As an emerging disease, chikungunya fever causes a major medical problem nowadays. The term “chikungunya” is a Makonde word for “that which bends up”, which refers to the contorted posture of infected patients suffering from severe joint pain. Unfortunately, current treatments of CHIK fever are for symptoms with no effective licensed vaccine and drug. In this thesis, we report a series of new conjugated compounds were synthesized by chemical methods from imidazole and coumarin derivatives with a –SCH2– linkage. Experimental results indicate that, of the twenty newly synthesized imidazole–coumarin conjugates, three of them exhibited appealing EC50 values (5.1–8.4 μM) and selective indices >20 against hepatitis C virus. Their potency and selectivity were increased substantially by modification of their structure with two factors: imidazole nucleus with a hydrogen atom at the N(1) position and coumarin nucleus with a substituent, such as Cl, F, Br, Me, and OMe. These guidelines provide valuable information for further development of conjugated compounds as anti-viral agents. Moreover, a series of coumarin–guanosine conjugated compounds were designed and synthesized as potential chikungunya virus inhibiting agents. They were obtained by coupling of 6,8-dithioguanosine at its C-6 position with 3-(chloromethyl)coumarin reagents bearing F, Cl, Br, Me, and OMe substituents through a –SCH2– joint. Meanwhile, an organic “dummy” ligand (e.g., methy, benzyl, and naphthylmethyl) or coumarinyl moiety was attached at the C-8 position. Their chemical structures were determined unambiguously by spectroscopic methods. Three of these new conjugates were found to inhibit CHIKV in Vero cells with significant potency (EC50 = 9.9–13.9 μM) and showed low toxicity (CC50 = 96.5–212 μM). Their selectivity index values were 9.37–21.7. By analysis of the data from the anti-viral assays, their structure–activity relationship was derived. It indicates that the coumarin moiety is essential and OMe group is the best for anti-viral activity, as well as the three hydroxyl groups are helpful for hydrophilicity.