TY - JOUR
T1 - The anti-parasite action of imidazole derivatives likely involves oxidative stress but not HIF-1α signaling
AU - Adeyemi, Oluyomi Stephen
AU - Eseola, Abiodun Omokehinde
AU - Plass, Winfried
AU - Kato, Kentaro
AU - Otuechere, Chiagoziem A.
AU - Awakan, Oluwakemi Josephine
AU - Atolani, Olubunmi
AU - Otohinoyi, David Adeiza
AU - Elebiyo, Tobiloba Christiana
AU - Evbuomwan, Ikponmwosa Owen
N1 - Funding Information:
Authors appreciate Landmark University Nigeria while, OS Adeyemi acknowledges the JSPS for a Postdoctoral Fellowship. Furthermore, AO Eseola recognizes support of the Alexander von Humboldt Foundation (postdoctoral fellowship) as well as the Redeemer's University Nigeria. In addition, the Deutsche Forschungsgemeinschaft (DFG) (PL 155/11, PL 155/12 and PL155/13) is acknowledged for financial support. Authors also acknowledge the International Foundation for Science (IFS) Grant (F/5672–2).
Publisher Copyright:
© 2021 Elsevier B.V.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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.
AB - 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.
KW - Drug discovery
KW - Hypoxia
KW - Infection
KW - Mechanism of action
KW - Medicinal biochemistry
KW - Toxoplasmosis
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U2 - 10.1016/j.cbi.2021.109676
DO - 10.1016/j.cbi.2021.109676
M3 - Article
C2 - 34592218
AN - SCOPUS:85115940405
VL - 349
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
SN - 0009-2797
M1 - 109676
ER -