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  3. Novel betulin dicarboxylic acid ester derivatives as potent antiviral agents: Design, synthesis, biological evaluation, structure-activity relationship and in-silico study

Novel betulin dicarboxylic acid ester derivatives as potent antiviral agents: Design, synthesis, biological evaluation, structure-activity relationship and in-silico study

  • Eur J Med Chem. 2021 Dec 5:225:113738. doi: 10.1016/j.ejmech.2021.113738.
Paweł Pęcak 1,  Beata Orzechowska 2,  Elwira Chrobak 3,  Stanisław Boryczka 4
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 4 Jagiellońska Str., 41-200, Sosnowiec, Poland. Electronic address: chemorg@sum.edu.pl.
  • 2 Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Laboratory of Virology, 12 Rudolfa Weigla Str., 53-114, Wrocław, Poland. Electronic address: beata.orzechowska@hirszfeld.pl.
  • 3 Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 4 Jagiellońska Str., 41-200, Sosnowiec, Poland. Electronic address: echrobak@sum.edu.pl.
  • 4 Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 4 Jagiellońska Str., 41-200, Sosnowiec, Poland. Electronic address: boryczka@sum.edu.pl.
PMID: 34425312 DOI: 10.1016/j.ejmech.2021.113738
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.

Keywords

Anti-herpes; Anti-influenza; Antiviral; Betulin; Dicarboxylic acid ester; Docking.

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