KAI407, a Potent Non-8-Aminoquinoline Compound That Kills Plasmodium cynomolgi Early Dormant Liver Stage ParasitesIn Vitro

• DOI: 10.1128/aac.01927-13
• Publication Date: 2013-12-24T04:23:33Z
• Authors: Anne-Marie Zeeman; Sandra M. van Ams...; Case W. McNamara; Annemarie Voorber...; Els J. Klooster; Alexander van den...; Edmond J. Remarque; David M. Plouffe; Geert-Jan van Gemert; Adrian Luty; Robert Sauerwein; Kerstin Gagaring; Rachel Borboa; Zhong Chen; Kelli Kuhen; Richard J. Glynne; Arnab K. Chatterjee; Advait Nagle; Jason Roland; Elizabeth A. Winz...; Didier Leroy; Brice Campo; Thierry T. Diagana; Bryan K. S. Yeung; Alan W. Thomas; Clemens H. M. Kocken
• Keywords: Primaquine; Atovaquone; Plasmodium (life cycle); Serial dilution

Preventing relapses of Plasmodium vivax malaria through a radical cure depends on use the 8-aminoquinoline primaquine, which is associated with safety and compliance issues. For future eradication strategies, new, safer curative compounds that efficiently kill dormant liver stages (hypnozoites) will be essential. A new compound potential activity was identified using low-throughput assay in vitro-cultured hypnozoite forms cynomolgi (an excellent accessible model for vivax). In this assay, primary rhesus hepatocytes are infected P. sporozoites, exoerythrocytic development monitored presence compounds. Liver stage cultures fixed after 6 days stained anti-Hsp70 antibodies, relative proportions small (hypnozoite) large (schizont) to untreated controls determined. This used screen series 18 known antimalarials 14 non-8-aminoquinolines (preselected blood and/or activity) three-point 10-fold dilutions (0.1, 1, 10 μM final concentrations). novel compound, designated KAI407 showed an profile similar primaquine (PQ), killing earliest parasites become either hepatic schizonts or hypnozoites (50% inhibitory concentration [IC50] hypnozoites, KAI407, 0.69 μM, PQ, 0.84 μM; developing stages, 0.64 0.37 μM). When given as causal prophylaxis, single oral dose 100 mg/kg body weight prevented parasitemia mice. From these results, we conclude may represent class prophylaxis potentially cure.