Discovery of N-benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HCMV)

Sameera Senaweera, Tiffany C. Edwards, Jayakanth Kankanala, Yan Wang, Rajkumar Lalji Sahani, Jiashu Xie, Robert J. Geraghty, Zhengqiang Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Current drugs for treating human cytomegalovirus (HCMV) infections are limited by resistance and treatment-associated toxicities. In developing mechanistically novel HCMV antivirals, we discovered an N-benzyl hydroxypyridone carboxamide antiviral hit (8a) inhibiting HCMV in submicromolar range. We describe herein the structure–activity relationship (SAR) for 8a, and the characterization of potent analogs for cytotoxicity/cytostatic property, the preliminary mechanism of action, and the absorption, distribution, metabolism and excretion (ADME) properties. The SAR revealed a few pharmacophore features conferring optimal antiviral profile, including the 5-OH, the N-1 benzyl, at least one –CH2− in the linker, and a di-halogen substituted phenyl ring in the amide moiety. In the end, we identified numerous analogs with sub-micromolar antiviral potency and good selectivity index. The preliminary mechanism of action characterization used a pUL89-C biochemical endonuclease assay, a virus entry assay, a time-of-addition assay, and a compound withdrawal assay. ADME profiling measuring aqueous solubility, plasma and liver microsomal stability, and parallel artificial membrane permeability assay (PAMPA) permeability demonstrated largely favorable drug-like properties. Together, these studies validate the N-benzyl hydroxypyridone carboxamide as a viable chemotype for potent and mechanistically distinct antivirals against HCMV.

Original languageEnglish (US)
JournalActa Pharmaceutica Sinica B
DOIs
StatePublished - Aug 1 2021

Bibliographical note

Funding Information:
This research was supported by the National Institute of Allergy and Infectious Diseases , the National Institutes of Health , United States grant number R01AI136982 (to Robert J. Geraghty and Zhengqiang Wang, USA). We thank the Minnesota Supercomputing Institute for molecular modeling resource and Christine Dreis for technical assistance.

Funding Information:
This research was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, United States grant number R01AI136982 (to Robert J. Geraghty and Zhengqiang Wang, USA). We thank the Minnesota Supercomputing Institute for molecular modeling resource and Christine Dreis for technical assistance.

Publisher Copyright:
© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences

Keywords

  • Human cytomegalovirus
  • Mechanism of action
  • N-Benzyl hydroxypyridone carboxamides
  • Structure–activity relationship

Fingerprint

Dive into the research topics of 'Discovery of N-benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HCMV)'. Together they form a unique fingerprint.

Cite this