Esterification of the Free Carboxylic Group in 3,4-di-O-caffeoylquinic Acid Enhances the Inhibition Activity against Respiratory Syncytial Virus (RSV)

Abstract

Based on molecular docking analysis, nine alkyl 3,4-di-O-caffeoyl- quinates have been designed. Started from 3,4-di- O-caffeoylquinic acid (3,4-DCQA), all the compounds have been synthesized using thionylchloride as coupling reagent with yields of 56%-72%. By applying plaque reduction assay, the anti-respiratory syncytial virus (RSV) activities of all the compounds were evaluated. The IC50 values of all the derivatives were 2.9 to 7.8 times less than that of 3,4-DCQA itself. Isopropyl 3,4-Di-O-caffeoyl quinate (LS-4) was confirmed as the most active compound with IC50 value of 0.3 μM. It was indicated that hydrophobic groups with 2 to 4 carbon chain length were optimal for the enhancement of anti-RSV activity. Interestingly, all the derivatives showed greater cytotoxicity than 3,4-DCQA. Except LS-5, LS-6 and LS-9, all the derivatives have less toxicity than ribavirin. Furthermore, the stabilities of LS-4 in water, artificial gastric juice (AGJ), and artificial intestinal juice were evaluated, respectively. It was shown that LS-4 is stable in AGJ with the hydrolysis rate of 24.9% after 6 hours incubation at 37°C.