SAR studies of 4-acyl-1,6-dialkylpiperazin-2-one arenavirus cell entry inhibitors

Michael B. Plewe, Landon R. Whitby, Shibani Naik, Eric R. Brown, Nadezda V. Sokolova, Vidyasagar Reddy Gantla, Joanne York, Jack H. Nunberg, Lihong Zhang, Birte Kalveram, Alexander N. Freiberg, Dale L. Boger, Greg Henkel, Ken McCormack

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Old World (Africa) and New World (South America) arenaviruses are associated with human hemorrhagic fevers. Efforts to develop small molecule therapeutics have yielded several chemical series including the 4-acyl-1,6-dialkylpiperazin-2-ones. Herein, we describe an extensive exploration of this chemotype. In initial Phase I studies, R1 and R4 scanning libraries were assayed to identify potent substituents against Old World (Lassa) virus. In subsequent Phase II studies, R6 substituents and iterative R1, R4 and R6 substituent combinations were evaluated to obtain compounds with improved Lassa and New World (Machupo, Junin, and Tacaribe) arenavirus inhibitory activity, in vitro human liver microsome metabolic stability and aqueous solubility.

Original languageEnglish
Article number126620
JournalBioorganic and Medicinal Chemistry Letters
Issue number22
StatePublished - Nov 15 2019


  • Arenavirus
  • Entry inhibitor
  • Junin
  • Lassa
  • Machupo
  • Piperazinone


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