New hydrazine and hydrazide quinoxaline 1,4-di-N-oxide derivatives: In silico ADMET, antiplasmodial and antileishmanial activity

Bioorg Med Chem Lett. 2017 Apr 15;27(8):1820-1825. doi: 10.1016/j.bmcl.2017.02.049. Epub 2017 Feb 21.

Abstract

We report the design (in silico ADMET criteria), synthesis, cytotoxicity studies (HepG-2 cells), and biological evaluation of 15 hydrazine/hydrazide quinoxaline 1,4-di-N-oxide derivatives against the 3D7 chloroquine sensitive strain and FCR-3 multidrug resistant strain of Plasmodium falciparum and Leishmania infantum (axenic amastigotes). Fourteen of derivatives are novel quinoxaline 1,4-di-N-oxide derivatives. Compounds 18 (3D7 IC50=1.40μM, FCR-3 IC50=2.56μM) and 19 (3D7 IC50=0.24μM, FCR-3 IC50=2.8μM) were identified as the most active against P. falciparum, and they were the least cytotoxic (CC50-values>241μM) and most selective (SI>86). None of the compounds tested against L. infantum were considered to be active. Additionally, the functional role of the hydrazine and hydrazide structures were studied in the quinoxaline 1,4-di-N-oxide system.

Keywords: Hydrazide; Hydrazine; Leishmaniasis; Malaria; Quinoxaline 1,4-di-N-oxide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiprotozoal Agents / chemistry*
  • Antiprotozoal Agents / pharmacology*
  • Humans
  • Hydrazines / chemistry*
  • Hydrazines / pharmacology*
  • Leishmania infantum / drug effects
  • Leishmaniasis, Visceral / drug therapy
  • Malaria, Falciparum / drug therapy
  • Plasmodium falciparum / drug effects
  • Quinoxalines / chemistry*
  • Quinoxalines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antiprotozoal Agents
  • Hydrazines
  • Quinoxalines
  • quindoxin