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

Abstract

Donghui Wu, Wei Tang, Chao Xia, Laitao Zhang, Ling Zhuang, Pinghua Sun, Nenghua Chen, Cheng Luo, Guocai Wang, Yaolan Li and Heru Chen

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.

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