Heterocyclic rimantadine analogues with antiviral activity

Bioorg Med Chem. 2003 Dec 1;11(24):5485-92. doi: 10.1016/j.bmc.2003.09.024.

Abstract

2-(1-Adamantyl)pyrrolidines 6, 7, 2-(1-adamantyl)piperidines 10, 12a-c, 15a,b and 2-(1-adamantyl)hexahydroazepines 19, 21, 22 were synthesized and tested for their antiviral activity against influenza A, B viruses and the human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The synthetic procedure followed for the preparation of the parent piperidine 10 represents a general method for the synthesis of 2-alkyl- or cycloalkyl-substituted piperidine alkaloids. Parent aminoadamantanes 6, 10 and 19 contain the 1-aminoethyl pharmacophore group of rimantadine drug 2, extended into a saturated nitrogen heterocycle: pyrrolidine, piperidine and hexahydroazepine, respectively. The ring size effect in anti-influenza A activity was investigated. Rimantadine analogues 6 and 10 were, respectively, 6- and 4-fold more active than the drug Rimantadine 2, whereas the hexahydroazepine derivative 19 was inactive. Thus, enlargement from a 5-(pyrrolidine)- or 6-(piperidine)- to a 7-(hexahydroazepine)- membered heterocyclic ring dramatically reduced the anti-influenza virus A activity. Substitution of piperidine 10 with a dialkyaminoethyl group led to the active compounds 15a and 15b: compound 15a was active against influenza A virus whereas both 15a and 15b were active against HIV-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / toxicity
  • Cell Line
  • HIV-1 / drug effects
  • HIV-2 / drug effects
  • Humans
  • Influenza A virus / drug effects
  • Influenza B virus / drug effects
  • Molecular Structure
  • Rimantadine / analogs & derivatives*
  • Rimantadine / chemical synthesis
  • Rimantadine / pharmacology
  • Rimantadine / toxicity
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Rimantadine