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J. Biol. Chem., Vol. 280, Issue 50, 41129-41136, December 16, 2005

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Clotrimazole Inhibits Hemoperoxidase of Plasmodium falciparum and Induces Oxidative Stress

PROPOSED ANTIMALARIAL MECHANISM OF CLOTRIMAZOLE^*

Vishal Trivedi1, Prem Chand, Kumkum Srivastava¶, Sunil K. Puri¶, Prakas R. Maulik, and Uday Bandyopadhyay||2

From the Molecular and Structural Biology Division, ^¶Parasitology Division, ^||Drug Target Discovery and Development Division, Central Drug Research Institute, Chatter Manzil Palace, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India and Department of Physics, Indian Institute of Technology, Kanpur 208016, Uttar Pradesh, India

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 k_i= 2.85 µM, k_inact = 0.9 min^-1, and t = 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 (a^N = 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.

Received for publication, February 10, 2005 , and in revised form, March 22, 2005.

^* This work was supported in part by the Council of Scientific and Industrial Research (CSIR), New Delhi, for providing grants through the CSIR Networked Project (SMM03 (P22)). This is CDR1 Communication No. 6771. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a Council of Scientific and Industrial Research fellowship.

² To whom correspondence should be addressed. Tel.: 91-522-2612411; Fax: 91-522-2613405; E-mail: ubandyo_1964{at}yahoo.com.

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