Squaric acid/4-aminoquinoline conjugates: novel potent antiplasmodial agents

Eur J Med Chem. 2013 Nov:69:365-72. doi: 10.1016/j.ejmech.2013.08.037. Epub 2013 Sep 13.

Abstract

We report the synthesis and structure-activity relationship (SAR) analysis of a series of hybrid compounds containing a squaric moiety conjugated with heterocyclic moieties from well-known antimalarials. This novel series of compounds presents improved antiplasmodial activity compared with the squaric derivatives described in our previous work. Three compounds, 8b (IC₅₀ = 99 nM), 8c (IC₅₀ = 95 nM), and 8d (IC₅₀ = 105 nM) had greater in vitro potency than chloroquine 1 (IC₅₀ = 140 nM) against chloroquine resistant Plasmodium falciparum. In addition, they were noncytotoxic against NIH 3T3 and Hek 293T cells.

Keywords: 4-Aminoquinoline; Antiplasmodial activity; Hybrid; Malaria; Squaramide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / chemistry
  • Aminoquinolines / pharmacology*
  • Animals
  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Cyclobutanes / chemistry
  • Cyclobutanes / pharmacology*
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Mice
  • Molecular Structure
  • NIH 3T3 Cells
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects*
  • Structure-Activity Relationship

Substances

  • Aminoquinolines
  • Antimalarials
  • Cyclobutanes
  • 4-aminoquinoline
  • squaric acid