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KAI407, a potent non 8-aminoquinoline compound that kills Plasmodium cynomolgi dormant liver stage parasites in vitro.

Diagana, Thierry Tidiane and Mcnamara, Case and Roland, Jason and Nagle, Advait and Yeung, Bryan King Sing and Zeeman, Anne-Marie and Winzeler, Elizabeth and Plouffe, David and Kocken, Clemens (2014) KAI407, a potent non 8-aminoquinoline compound that kills Plasmodium cynomolgi dormant liver stage parasites in vitro. Antimicrobial Agents and Chemotherapy.

Official URL: http://www.pnas.org

Abstract

Abstract
A new compound with potential radical cure antimalarial activity was identified using a low throughput assay with in vitro cultured Plasmodium cynomolgi hypnozoite-forms. In this assay primary rhesus hepatocytes are infected with P. cynomolgi sporozoites, and exooerythrocytic development is monitored in the presence of compounds. After 6 days of culturing, the liver stage cultures are fixed and stained with anti-Hsp70 antibodies and the relative proportion of small (hypnozoite) and large (schizont) forms relative to the untreated control are counted. This assay was used to screen a series of 18 known antimalarials and 14 new non 8-aminoquinolines (preselected for blood and/or liver stage activity) in three-point tenfold dilutions (0.1, 1 and 10 µM final concentrations). A novel compound, designated KAI407 showed a profile similar to primaquine, efficiently killing both in vitro cultured developing liver stages and hypnozoite-forms (IC50 for small stages: were 0.69 µM (KAI407) and 0.84 µM (PQ); for developing liver stages: 0.64 µM (KAI407) and 0.37 µM (PQ)). When given as causal prophylaxis, a single oral dose of 100 mg/kg prevented blood stage parasitemia in mice. From these results we conclude that KAI407 may represent a new compound class for radical cure of P. vivax malaria.

Item Type: Article
Date Deposited: 27 Apr 2016 23:45
Last Modified: 27 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/10017

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