Novel betulin dicarboxylic acid ester derivatives as potent antiviral agents: Design, synthesis, biological evaluation, structure-activity relationship and in-silico study
Paweł Pęcak, Beata Orzechowska, Elwira Chrobak, Stanisław Boryczka
Abstract
The search for new methods of antiviral therapy is primarily focused on the use of substances of natural origin. In this context, a triterpene compound, betulin 1, proved to be a good starting point for derivatization. Thirty-eight betulin acid ester derivatives were synthetized, characterized, and tested against DNA and RNA viruses. Several compounds exhibited 4- to 11-fold better activity against Enterovirus E (compound 5 EC50: 10.3 μM) and 3- to 6-fold better activity against Human alphaherpesvirus 1 (HHV-1; compound 3c EC50: 17.2 μM). Time-of-addition experiments showed that most of the active compounds acted in the later steps of the virus replication cycle (e.g., nucleic acid/protein synthesis). Further in-silico analysis confirmed in-vitro data and demonstrated that interactions between HHV-1 DNA polymerase and the most active compound, 3c, were more stable than interactions with the parent non-active betulin 1.