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Antimicrobial Agents and Chemotherapy, August 2002, p. 2627-2632, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2627-2632.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Efficacy of Proton Pump Inhibitor Drugs against Plasmodium falciparum In Vitro and Their Probable Pharmacophores

Michael A. Riel,1 Dennis E. Kyle,2 Apurba K. Bhattacharjee,1 and Wilbur K. Milhous1*

Parasitology Department,2 Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 209101

Received 11 October 2001/ Returned for modification 29 November 2001/ Accepted 12 April 2002

The substituted benzimidazoles omeprazole, lansoprazole, rabeprazole, and pantoprazole were found to have in vitro activity against three different isolates of Plasmodium falciparum: D6 (which is chloroquine and pyrimethamine sensitive), W2 (chloroquine and pyrimethamine resistant), and TM91C235 (multidrug resistant). Lansoprazole and rabeprazole were the most effective against all three isolates, with a 50% inhibitory concentration (IC50) range of 7 to 11 µM. Omeprazole showed intermediate activity against D6 and W2 isolates, with IC50s of 27 to 28 µM, but had poor activity against TM91C235, with an IC50 of 76 µM. Pantoprazole was the least effective, with IC50s of 73 µM against D6, 53 µM against W2, and 39 µM against TM91C235. A pharmacophore model describing the important features responsible for potent activity of the drugs was developed using computational techniques of semiempirical quantum chemical methods and the three-dimensional QSAR procedure of the CATALYST software. The important features of the pharmacophore, according to the findings based on the CATALYST procedures, are the hydrogen bond acceptor and donor sites at the benzimidine nitrogen atoms and the two aromatic hydrophobic sites in the molecules. AM1 quantum chemical calculations identified the electrostatic potential surface surrounding the sulfoxide atom as crucial for potent activity.

* Corresponding author. Mailing address: Walter Reed Army Institute of Research, Division of Experimental Therapeutics, 503 Robert Grant Ave., Silver Spring, MD 20910-7500. Phone: (301) 319-9172. Fax: (301) 319-9449. E-mail: Wilbur.milhous{at}na.amedd.army.mil.

Antimicrobial Agents and Chemotherapy, August 2002, p. 2627-2632, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2627-2632.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.





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