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. 2011 Aug 29;2(11):840-4.
doi: 10.1021/ml2001517. eCollection 2011 Nov 10.

Cyclopropyl Carboxamides: A New Oral Antimalarial Series Derived from the Tres Cantos Anti-Malarial Set (TCAMS)

Lourdes Rueda  1 , Isabel Castellote  1 , Julia Castro-Pichel  1 , Maria J Chaparro  1 , Juan Carlos de la Rosa  1 , Adolfo Garcia-Perez  1 , Mariola Gordo  1 , Maria Belen Jimenez-Diaz  1 , Albane Kessler  1 , Simon J F Macdonald  2 , Maria Santos Martinez  1 , Laura M Sanz  1 , Francisco Javier Gamo  1 , Esther Fernandez  1
Affiliations

Cyclopropyl Carboxamides: A New Oral Antimalarial Series Derived from the Tres Cantos Anti-Malarial Set (TCAMS)

Lourdes Rueda et al. ACS Med Chem Lett. .

Abstract

Rapid triaging of three series of related hits selected from the Tres Cantos Anti-Malarial Set (TCAMS) are described. A triazolopyrimidine series was deprioritized due to delayed inhibition of parasite growth. A lactic acid series has derivatives with IC50 < 500 nM in a standard Plasmodium falciparum in vitro whole cell assay (Pf assay) but shows half-lives of < 30 min in both human and murine microsomes. Compound 19, from a series of cyclopropyl carboxamides, is a highly potent in vitro inhibitor of P. falciparum (IC50 = 3 nM) and has an oral bioavailability of 55% in CD-1 mice and an ED90 of 20 mg/kg after oral dosing in a nonmyelo-depleted P. falciparum murine model.

Keywords: Medicines for Malaria Venture; Plasmodium falciparum; TCAMS; Tres Cantos Anti-Malarial Set; carboxamide; cyclopropyl; in vivo activity; malaria; murine; oral bioavailability; triazole.

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Figures

Figure 1
Figure 1
Plot of compound dose (chloroquine 2, 13, and 19) vs log10 (% parasitemia) after oral administration. See the text for assay details and estimated ED50 and ED90 values.
See this image and copyright information in PMC

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