Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses
| Autor: | Elena Kazakova, Vadim Makarov, Anna Egorova, Sean Ekins, Michaela Schmidtke, Birgit Jahn |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Cell Survival Stereochemistry Potential candidate Microbial Sensitivity Tests Ring (chemistry) medicine.disease_cause Antiviral Agents 01 natural sciences Article Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Intragastric administration Drug Discovery medicine Animals Humans Isoxazole Oxazoles Enterovirus 030304 developmental biology Pharmacology Mice Inbred BALB C Oxadiazoles 0303 health sciences Dose-Response Relationship Drug Molecular Structure CYP3A4 010405 organic chemistry Organic Chemistry Pleconaril General Medicine 0104 chemical sciences chemistry Rhinovirus HeLa Cells |
| Zdroj: | Eur J Med Chem |
| ISSN: | 0223-5234 |
| Popis: | Today, there are no medicines to treat enterovirus and rhinovirus infections. In the present study, a series of novel pleconaril derivatives with substitutions in the isoxazole and phenyl rings was synthesized and evaluated for their antiviral activity against a panel of pleconaril-sensitive and -resistant enteroviruses. Studies of the structure-activity relationship demonstrate the crucial role of the N,N-dimethylcarbamoyl group in the isoxazole ring for antiviral activity against pleconaril-resistant viruses. In addition, one or two substituents in the phenyl ring directly impact on the spectrum of antienteroviral activity. The 3-(3-methyl-4-(3-(3-N,N-dimethylcarbamoyl-isoxazol-5-yl)propoxy)phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 10g was among the compounds exhibiting the strongest activity against pleconaril-resistant as well as pleconaril-susceptible enteroviruses with IC50 values from 0.02 to 5.25 μM in this series. Compound 10g demonstrated markedly less CYP3A4 induction than pleconaril, was non-mutagenic, and was bioavailable after intragastric administration in mice. These results highlight compound 10g as a promising potential candidate as a broad spectrum enterovirus and rhinovirus inhibitor for further preclinical investigations. |
| Databáze: | OpenAIRE |
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