Synthesis of baicalin carboxylate derivatives and their structure–Activity relationship analysis of their inhibitory activity on BVDV NS5B polymerase

Background: Bovine viral diarrhea virus (BVDV) has a serious impact on the global livestock industry; however, there are no specific therapeutic drugs for BVDV, so the development of anti-BVDV drugs is a research priority. Objectives: To investigate whether baicalin and its ester derivatives are active against BVDV non-structural protein 5B (NS5B). Materials and Methods: We modified the sugar chain part of the structure of baicalin by esterifying the carboxyl group at the 6-position of 7-β-d-glucuronide and by introducing alkyl groups of different lengths. The binding and in vitro activity of the baicalin ester derivatives with BVDV NS5B polymerase was determined using molecular docking, molecular dynamics, Cell Counting Kit-8 (CCK-8) assays, and real-time RT-PCR. Results: The following six baicalin ester derivatives were obtained: baicalin methyl ester, baicalin ethyl ester, baicalin propyl ester, baicalin butyl ester, baicalin hexyl ester, and baicalin heptyl ester. Molecular docking, molecular dynamics, CCK-8 assays, and real-time RT-PCR showed that baicalin and its derivatives could bind to BVDV NS5B polymerase, with baicalin ethyl ester showing the best binding ability and antiviral activity. Conclusion: Baicalin and its ester derivatives exert an inhibitory effect on BVDV by targeting the BVDV NS5B polymerase, and this effect shows a structure–activity relationship. The results provide an important theoretical basis for the further development of anti-BVDV drugs.