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Antimicrobial Agents and Chemotherapy, January 2003, p. 154-160, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.154-160.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Structure-Activity Relationships for Inhibition of Cysteine Protease Activity and Development of Plasmodium falciparum by Peptidyl Vinyl Sulfones

Bhaskar R. Shenai,1* Belinda J. Lee,1 Alejandro Alvarez-Hernandez,2 Pek Y. Chong,2 Cory D. Emal,2 R. Jeffrey Neitz,2 William R. Roush,2 and Philip J. Rosenthal1

Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California,1 Department of Chemistry, University of Michigan, Ann Arbor, Michigan2

Received 3 June 2002/ Returned for modification 28 August 2002/ Accepted 24 September 2002

The Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3 appear to be required for hemoglobin hydrolysis by intraerythrocytic malaria parasites. Previous studies showed that peptidyl vinyl sulfone inhibitors of falcipain-2 blocked the development of P. falciparum in culture and exerted antimalarial effects in vivo. We now report the structure-activity relationships for inhibition of falcipain-2, falcipain-3, and parasite development by 39 new vinyl sulfone, vinyl sulfonate ester, and vinyl sulfonamide cysteine protease inhibitors. Levels of inhibition of falcipain-2 and falcipain-3 were generally similar, and many potent compounds were identified. Optimal antimalarial compounds, which inhibited P. falciparum development at low nanomolar concentrations, were phenyl vinyl sulfones, vinyl sulfonate esters, and vinyl sulfonamides with P2 leucine moieties. Our results identify independent structural correlates of falcipain inhibition and antiparasitic activity and suggest that peptidyl vinyl sulfones have promise as antimalarial agents.

* Corresponding author. Mailing address: Box 0811, University of California, San Francisco, San Francisco, CA 94143-0811. Phone: (415) 206-3352. Fax: (415) 648-8425. E-mail: bshenai{at}itsa.ucsf.edu.

Antimicrobial Agents and Chemotherapy, January 2003, p. 154-160, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.154-160.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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