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

• 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: Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Chlorocebus aethiops; Dose-Response Relationship, Drug; Ebola virus; Ebolavirus - drug effects; Fenchol; Glycoprotein; Humans; Isopinocampheol; Lysosomotropic compounds; Marburg virus; Marburgvirus - drug effects; Microbial Sensitivity Tests; Molecular Structure; Structure-Activity Relationship; Virus Internalization - drug effects
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116596

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.