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IDENTIFICATION OF A NEW CHEMICAL CLASS OF ANTIMALARIALS

Saturday, 28th of July 2012

IDENTIFICATION OF A NEW CHEMICAL CLASS OF ANTIMALARIALS

Abstract below; full text available to J Infect Dis subscribers

J Infect Dis. (2012)

First published online: June 25, 2012

Identification of a New Chemical Class of Antimalarials

Ralf Brunnera,b, Hamed Aissaouic, Christoph Bossc, Zbynek Bozdechd, Reto Bruna,b,

Olivier Corminboeufc, Stephane Delahayec, Christoph Fischlia,b, Bibia Heidmannc, Marcel Kaisera,b,

Jolanda Kambera,b, Solange Meyerc, Petros Papastogiannidisa,b, Romain Siegristc, Till Vossa,b,

Richard Welfordc, Sergio Wittlina,b and Christoph Binkertc

- Author Affiliations

1. ^aMolecular Parasitology & Infection Biology, Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland

2. ^bUniversity of Basel, CH-4003 Basel, Switzerland

3. ^cDrug Discovery Chemistry & Biology, Actelion Pharmaceuticals Ltd, CH-4123 Allschwil, Switzerland

4. ^dSchool of Biological Sciences, Nanyang Technological University, 637551 Singapore

1. Correspondence: Christoph Binkert, E-mail: christoph.binkert@ext.actelion.com, Telephone: +41 61 565 6541, Fax: +41 61 565 8902

Abstract below, also at http://jid.oxfordjournals.org/content/early/2012/06/23/infdis.jis418.abstract?etoc

The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with IC₅₀ values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all three asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials.

ACT-213615 is orally bioavailable in mice, exhibits activity in the murine P. berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model.

ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potential.