New triazole-substituted triterpene derivatives exhibiting anti-RSV activity: synthesis, biological evaluation, and molecular modeling

Elenilson F da Silva; Krist Helen Antunes Fernandes; Denise Diedrich; Jessica Gotardi; Marcia Silvana Freire Franco; Carlos Henrique Tomich de Paula da Silva; Ana Paula Duarte de Souza; Simone Cristina Baggio Gnoatto

doi:10.3762/bjoc.18.161

New triazole-substituted triterpene derivatives exhibiting anti-RSV activity: synthesis, biological evaluation, and molecular modeling

Beilstein J Org Chem. 2022 Nov 9:18:1524-1531. doi: 10.3762/bjoc.18.161. eCollection 2022.

Affiliations

¹ Phytochemistry and Organic Synthesis Laboratory, School of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
² Clinical and Immunology Laboratory, Biomedical Research Institute, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
³ Laboratory of Computational Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14040-020, Brazil.

^# Contributed equally.

Abstract

Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infections in infants. Currently, ribavirin, a nucleoside analog containing a 1,2,4-triazole-3-carboxamide moiety, is a first-line drug for its treatment, however, its clinical use has been limited due to its side effects. Here, we designed two new nitroaryl-1,2,3-triazole triterpene derivatives as novel anti-RSV drugs. Their anti-RSV and cytotoxic activity were evaluated in vitro, RSV protein F gene effects by RT-PCR and molecular modeling with inosine monophosphate dehydrogenase (IMPDH) were performed. Compound 8 was the best performing compound, with an EC₅₀ value of 0.053 μM, a TI of 11160.37 and it inhibited hRSV protein F gene expression by approximately 65%. Molecular docking showed a top-ranked solution located in the same region occupied by crystallographic ligands in their complex with IMPDH. The results obtained in this study suggest that compound 8 might be a new anti-RSV candidate.

Keywords: antiviral; betulinic acid; bioisosterism; respiratory syncytial virus; triterpene; ursolic acid.

Grants and funding

This work was supported by grants and financial support from Brazilian Agencies CNPq and CAPES. The authors are also grateful to the Graduate Programme in Pharmaceutical Sciences (PPGCF/UFRGS) according to these: Obtenção De Derivados Triterpenos Semissintéticos Com Atividade Antitumoral E Antiviral In Vitro E In Vivo. PhD Thesis 2016, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil. GNSS received CAPES Fellowship.