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In vitro and In vivo Antimalarial Activity of Amphiphilic Naphthothiazolium Salts with Amine-Bearing Side Chains

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  • The Kenneth S. Warren Institute, Ossining, New York; University of North Carolina, Chapel Hill, North Carolina; Johns Hopkins Malaria Institute, Baltimore, Maryland

Because of emerging resistance to existing drugs, new chemical classes of antimalarial drugs are urgently needed. We have rationally designed a library of compounds that were predicted to accumulate in the digestive vacuole and then decrystallize hemozoin by breaking the iron carboxylate bond in hemozoin. We report the synthesis of 16 naphthothiazolium salts with amine-bearing side chains and their activities against the erythrocytic stage of Plasmodium falciparum in vitro. KSWI-855, the compound with the highest efficacy against the asexual stages of P. falciparum in vitro, also had in vitro activity against P. falciparum gametocytes and in vivo activity against P. berghei in a murine malaria model.

Author Notes

* Address correspondence to Carla Cerami, Department of Epidemiology, School of Global Public Health, University of North Carolina, CB# 7435, Chapel Hill, NC 27599. E-mail: ccerami@.unc.edu

Financial support: This study was supported by internal funding from The Kenneth W. Warren Institute and Award No. UL1RR025747 from the National Center for Research Resources.

Disclosure: None of the authors have any financial conflicts of interest.

Authors' addresses: Peter Ulrich, Department of Chemistry, The Kenneth S. Warren Institute, Ossining, NY, E-mail: pculrich@earthlink.net. Gregory R. Gipson, Martha A. Clark, and Carla Cerami, Department of Epidemiology, University of North Carolina, Chapel Hill, NC, E-mails: gregory_gipson@med.unc.edu, martha_clark@med.unc.edy, and ccerami@.unc.edu. Abhai Tripathi and David J. Sullivan Jr., Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Institute, Baltimore, MD, E-mails: atripathi@jhsph.edu and dsulliva@jhsph.edu.

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