Pharmacological effects of primaquine ureas and semicarbazides on the central nervous system in mice and antimalarial activity in vitro

Fundam Clin Pharmacol. 2016 Feb;30(1):58-69. doi: 10.1111/fcp.12161. Epub 2015 Nov 16.

Abstract

New primaquine (PQ) urea and semicarbazide derivatives 1-4 were screened for the first time for central nervous system (CNS) and antimalarial activity. Behavioural tests were performed on mice. In vitro cytotoxicity on L-6 cells and activity against erythrocytic stages of Plasmodium falciparum was determined. Compound 4 inhibited 'head-twitch' responses and decreased body temperature of mice, which suggests some involvement of the serotonergic system. Compound 4 protected mice against clonic seizures and was superior in the antimalarial test. A hybrid of two PQ urea 2 showed a strong antimalarial activity, confirming the previous findings of the high activity of bis(8-aminoquinolines) and other bisantimalarial drugs. All the compounds decreased the locomotor activity of mice, what suggests their weak depressive effects on the CNS, while PQ derivatives 1 and 2 increased amphetamine-induced hyperactivity. None of the compounds impaired coordination, what suggests a lack of their neurotoxicity. All the tested compounds presented an antinociceptive activity in the 'writhing' test. Compounds 3 and 4 were active in nociceptive tests, and those effects were reversed by naloxone. Compound 4 could be a useful lead compound in the development of CNS active agents and antimalarials, whereas compound 3 may be considered as the most promising lead for new antinociceptive agents.

Keywords: antimalarial screening; behavioural tests; central nervous system activity; primaquine; semicarbazide; urea.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Behavior, Animal / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Central Nervous System / drug effects*
  • Erythrocytes / drug effects
  • Erythrocytes / parasitology
  • Humans
  • Male
  • Mice
  • Molecular Structure
  • Myoblasts / drug effects
  • Plasmodium falciparum / drug effects*
  • Primaquine / analogs & derivatives
  • Primaquine / chemistry
  • Primaquine / pharmacology*
  • Semicarbazides / chemistry
  • Semicarbazides / pharmacology*
  • Toxicity Tests, Acute
  • Urea / analogs & derivatives
  • Urea / chemistry
  • Urea / pharmacology*

Substances

  • Antimalarials
  • Semicarbazides
  • Urea
  • Primaquine