Identification of a new chemical class of antimalarials.
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 half-maximal inhibitory concentration (IC(50)) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all 3 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 Plasmodium 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.
Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel CH-4002, Switzerland.
Ralf
R
Brunner
Hamed
H
Aissaoui
Christoph
C
Boss
Zbynek
Z
Bozdech
Reto
R
Brun
Olivier
O
Corminboeuf
Stephane
S
Delahaye
Christoph
C
Fischli
Bibia
B
Heidmann
Marcel
M
Kaiser
Jolanda
J
Kamber
Solange
S
Meyer
Petros
P
Papastogiannidis
Romain
R
Siegrist
Till
T
Voss
Richard
R
Welford
Sergio
S
Wittlin
Christoph
C
Binkert
D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002460:Cell Line; D004912:Erythrocytes / Q000469:parasitology; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy* / Q000469:parasitology; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D010962:Plasmodium berghei / Q000187:drug effects*; D051381:Rats
D000962:Antimalarials; D010879:Piperazines