Structure-activity relationships and mechanistic studies of novel mitochondria-targeted, leishmanicidal derivatives of the 4-aminostyrylquinoline scaffold

Eur J Med Chem. 2019 Jun 1:171:38-53. doi: 10.1016/j.ejmech.2019.03.007. Epub 2019 Mar 14.

Abstract

A new class of quinoline derivatives, bearing amino chains at C-4 and a styryl group at C-2, were tested on Leishmania donovani promastigotes and axenic and intracellular Leishmania pifanoi amastigotes. The introduction of the C-4 substituent improves the activity, which is due to interference with the mitochondrial activity of the parasite and its concomitant bioenergetic collapse by ATP exhaustion. Some compounds show a promising antileishmanial profile, with low micromolar or submicromolar activity on promastigote and amastigote forms and a good selectivity index.

Keywords: 2-Styrylquinolines; 4-Aminoquinolines; Leishmanicidal compounds; Mitochondrial metabolism.

MeSH terms

  • Antiprotozoal Agents / chemical synthesis
  • Antiprotozoal Agents / chemistry
  • Antiprotozoal Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Leishmania / drug effects*
  • Microscopy, Confocal
  • Mitochondria / drug effects*
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Quinolines / chemical synthesis
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antiprotozoal Agents
  • Quinolines
  • styrylquinoline