(+)-fenchol and (−)-isopinocampheol derivatives targeting the entry process of filoviruses

The increasing frequency of filovirus outbreaks in African countries has led to a pressing need for the development of effective antifilovirus agents. In continuation of our previous research on the antifilovirus activity of monoterpenoid derivatives, we synthesized a series of (+)-fenchol and (−)-i...

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Published in:European journal of medicinal chemistry 2024-09, Vol.275, p.116596, Article 116596
Main Authors: Sokolova, Anastasiya S., Baev, Dmitriy S., Mordvinova, Ekaterina D., Yarovaya, Olga I., Volkova, Natalia V., Shcherbakov, Dmitriy N., Okhina, Alina A., Rogachev, Artem D., Shnaider, Tatiana A., Chvileva, Anastasiya S., Nikitina, Tatiana V., Tolstikova, Tatyana G., Salakhutdinov, Nariman F.
Format: Article
Language:English
Subjects:
Ebola virus
Fenchol
Glycoprotein
Isopinocampheol
Lysosomotropic compounds
Marburg virus
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Summary:The increasing frequency of filovirus outbreaks in African countries has led to a pressing need for the development of effective antifilovirus agents. In continuation of our previous research on the antifilovirus activity of monoterpenoid derivatives, we synthesized a series of (+)-fenchol and (−)-isopinocampheol derivatives by varying the type of heterocycle and linker length. Derivatives with an N-alkylpiperazine cycle proved to be the most potent antiviral compounds, with half-maximal inhibitory concentration (IC50) 1.4–20 μМ against Lenti-EboV-GP infection and 11.3–47 μМ against Lenti-MarV-GP infection. Mechanism-of-action experiments revealed that the compounds may exert their action by binding to surface glycoproteins (GPs). It was demonstrated that the binding of the synthesized compounds to the Marburg virus GP is less efficient as compared to the Ebola virus GP. Furthermore, it was shown that the compounds possess lysosomotropic properties. Thus, the antiviral activity may be due to dual effects. This study offers new antiviral agents that are worthy of further exploration. [Display omitted] •Fenchol and isopinocampheol esters as inhibitors of the entry process of filoviruses.•The antiviral activity may also be due to lysosomotropic properties.•Ester 6c, with its broad-spectrum antiviral activity, has good stability in the blood.
ISSN:0223-5234
1768-3254
1768-3254
DOI:10.1016/j.ejmech.2024.116596