Antileishmanial Activities of (Z)-2-(Nitroimidazolylmethylene)-3(2H)-Benzofuranones: Synthesis, In Vitro Assessment, and Bioactivation by NTR 1 and 2

Latifeh Navidpour (Lead / Corresponding author), Marta Lopes Lima, Rachel Milne, Susan Wyllie, Narges Hadj-Esfandiari, Muhammad Iqbal Choudhary, Samreen Khan, Sammer Yousuf

Research output: Contribution to journalArticlepeer-review

Abstract

The antileishmanial activity of a series of (Z)-2-(heteroarylmethylene)-3(2H)- benzofuranone derivatives, possessing 5-nitroimidazole or 4-nitroimidazole moieties, was investigated against Leishmania major promastigotes and some analogues exhibited prominent activities. Compounds with IC50 values lower than 20 mM were further examined against L. donovani axenic amastigotes. Evaluated analogues in 5-nitroimidazole subgroup demonstrated significantly superior activity (∼17-88-folds) against L. donovani in comparison to L. major. (Z)-7-Methoxy-2-(1-methyl-5-nitroimidazole-2-ylmethylene)-3 (2H)-benzofuranone (5n) showed the highest L. donovani anti-axenic amastigote activity with IC50 of 0.016 mM. The cytotoxicity of these analogues was determined using PMM peritoneal mouse macrophage and THP-1 human leukemia monocytic cell lines and high selectivity indices of 26 to 431 were obtained for their anti-axenic amastigote effect over the cytotoxicity on PMM cells. Further studies on their mode of action showed that 5-nitroimidazole compounds were bioactivated predominantly by nitroreductase 1 (NTR1) and 4-nitroimidazole analogues by both NTR1 and 2. It is likely that this bioactivation results in the production of nitroso and hydroxylamine metabolites that are cytotoxic for the Leishmania parasite.

Original languageEnglish
Article numbere00583-22
Number of pages13
JournalAntimicrobial Agents and Chemotherapy
Volume66
Issue number11
Early online date26 Oct 2022
DOIs
Publication statusPublished - 15 Nov 2022

Keywords

  • Leishmania major
  • Leishmania donovani
  • 2-(nitroimidazolylmethylene)-3(2H)-benzofuranone
  • ntr1
  • NTR2
  • NTR1

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