Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses

  • Eur J Med Chem. 2020 Feb 15:188:112007. doi: 10.1016/j.ejmech.2019.112007.
Anna Egorova  1 ,  Elena Kazakova  1 ,  Birgit Jahn  2 ,  Sean Ekins  3 ,  Vadim Makarov  4 ,  Michaela Schmidtke  5
Affiliations
  • 1. Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, 33-2 Leninsky Prospect, Moscow, 119071, Russia.
  • 2. Jena University Hospital, Department of Medical Microbiology, Section Experimental Virology, Hans-Knöll-Strasse 2, Jena, 07745, Germany.
  • 3. Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, NC27606, USA.
  • 4. Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, 33-2 Leninsky Prospect, Moscow, 119071, Russia. Electronic address: [email protected].
  • 5. Jena University Hospital, Department of Medical Microbiology, Section Experimental Virology, Hans-Knöll-Strasse 2, Jena, 07745, Germany. Electronic address: [email protected].
PMID: 31881489 DOI: 10.1016/j.ejmech.2019.112007
Abstract

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.

Keywords
Antivirals; CYP3A4 induction; Capsid-binding inhibitor; Coxsackie B3 virus; Drug design/discovery; Pharmacokinetics; Resistance; Rhinovirus; Structure-activity relationship analysis.