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

Autor: Pęcak P; 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., Orzechowska B; 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., Chrobak E; 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., Boryczka S; 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.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2021 Dec 05; Vol. 225, pp. 113738. Date of Electronic Publication: 2021 Aug 06.
DOI: 10.1016/j.ejmech.2021.113738
Abstrakt: 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 EC 50 : 10.3 μM) and 3- to 6-fold better activity against Human alphaherpesvirus 1 (HHV-1; compound 3c EC 50 : 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: