Abstract
The mechanism of antimalarial activity of clotrimazole was studied placing emphasis on its role in inhibiting hemoperoxidase for inducing oxidative stress in Plasmodium falciparum. Clotrimazole, in the presence of H2O2, causes irreversible inactivation of the enzyme, and the inactivation follows pseudo-first order kinetics, consistent with a mechanism-based (suicide) mode. The pseudo-first order kinetic constants are ki = 2.85 microM, k(inact) = 0.9 min(-1), and t(1/2) = 0.77 min. The one-electron oxidation product of clotrimazole has been identified by EPR spectroscopy as the 5,5'-dimethyl-1-pyrroline N-oxide (DMPO) adduct of the nitrogen-centered radical (aN = 15 G), and as DMPO protects against inactivation, this radical is involved in the inactivation process. Binding studies indicate that the clotrimazole oxidation product interacts at the heme moiety, and the heme-clotrimazole adduct has been dissociated from the inactivated enzyme and identified (m/z 1363) by mass analysis. We found that the inhibition of hemoperoxidase increases the accumulation of H2O2 in P. falciparum and causes oxidative stress. Furthermore, the inhibition of hemoperoxidase correlates well with the inhibition of parasite growth. The results described herein indicate that the antimalarial activity of clotrimazole might be due to the inhibition of hemoperoxidase and subsequent development of oxidative stress in P. falciparum.
Highlights
The mechanism of antimalarial activity of clotrimazole was studied placing emphasis on its role in inhibiting hemoperoxidase for inducing oxidative stress in Plasmodium falciparum
The one-electron oxidation product of clotrimazole has been identified by EPR spectroscopy as the 5,5-dimethyl-1pyrroline N-oxide (DMPO) adduct of the nitrogen-centered radical, and as DMPO protects against inactivation, this radical is involved in the inactivation process
The results described indicate that the antimalarial activity of clotrimazole might be due to the inhibition of hemoperoxidase and subsequent development of oxidative stress in P. falciparum
Summary
The mechanism of antimalarial activity of clotrimazole was studied placing emphasis on its role in inhibiting hemoperoxidase for inducing oxidative stress in Plasmodium falciparum. The results described indicate that the antimalarial activity of clotrimazole might be due to the inhibition of hemoperoxidase and subsequent development of oxidative stress in P. falciparum. It shows antiproliferative effect by acting as a translation initiation inhibitor [4], inhibits angiogenesis by blocking vascular endothelial growth factor expression [5], decreases glycolysis of lung carcinoma and colon adenocarcinoma cells [6], and induces apoptosis by altering calcium homeostasis of leukemic lymphoblasts [7]. Inhibition of oxidized glutathione (GSSH) export from the infected human red cells or from the parasite itself is considered to be one possible mechanism of anti-malarial effect of CLT. The studies, provide new insights on the mechanism of antimalarial activity of clotrimazole
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