The anti-parasite action of imidazole derivatives likely involves oxidative stress but not HIF-1α signaling

Oluyomi Stephen Adeyemi, Abiodun Omokehinde Eseola, Winfried Plass, Kentaro Kato, Chiagoziem A. Otuechere, Oluwakemi Josephine Awakan, Olubunmi Atolani, David Adeiza Otohinoyi, Tobiloba Christiana Elebiyo, Ikponmwosa Owen Evbuomwan

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Therapeutic options for toxoplasmosis are limited. This fact underscores ongoing research efforts to identify and develop better therapy. Previously, we reported the anti-parasitic potential of a new series of derivatives of imidazole. Objective: In the current investigation, we attempted the investigation of the possible action mechanism of few promising anti-parasite imidazole derivatives namely C1 (bis-imidazole), C2 (phenyl-substituted 1H-imidazole) and C3 (thiophene-imidazole) Methods: We evaluated if oxidative stress, hypoxia as well as metabolic reprogramming of host L-tryptophan pathway form part of the parasite growth inhibition by imidazoles. Anti-parasite assay was performed for imidazoles at concentrations ranging from 0 to 10 μM, while pyrimethamine was used as reference drug to validate assay. Results: Imidazole compounds restricted parasite growth dose-dependently. However, in the presence of an antioxidant (Trolox), L-tryptophan and/or CoCl2 (chemical inducer of hypoxia), the growth inhibitory efficacy of imidazoles was appreciably abolished. Further, imidazole treatment led to elevated level of reactive oxygen species, while reducing parasite mitochondrial membrane potential compared with control. In contrast, imidazole had no effect on host HIF-1α level suggesting its exclusion in the anti-parasite action. Conclusion: Taken together, imidazole-based compounds might restrict parasite growth by causing oxidative stress. The findings provide new insight on the likely biochemical mechanisms of imidazoles as prospective anti-parasite therapy. Data gives new perspective that not only underscores the anti-parasite prospects of imidazoles, but implicates the host L-tryptophan pathway as a feasible treatment option for T. gondii infections.

Original languageEnglish
Article number109676
JournalChemico-Biological Interactions
Volume349
DOIs
Publication statusPublished - 2021 Nov 1

Keywords

  • Drug discovery
  • Hypoxia
  • Infection
  • Mechanism of action
  • Medicinal biochemistry
  • Toxoplasmosis

ASJC Scopus subject areas

  • Toxicology

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