Abstract
The goal for developing new antimalarial drugs is to find a molecule that can target multiple stages of the parasite's life cycle, thus impacting prevention, treatment, and transmission of the disease. The 4(1H)-quinolone-3- diarylethers are selective potent inhibitors of the parasite's mitochondrial cytochrome bc1 complex. These compounds are highly active against the human malaria parasites Plasmodium falciparum and Plasmodium vivax. They target both the liver and blood stages of the parasite as well as the forms that are crucial for disease transmission, that is, the gametocytes, the zygote, the ookinete, and the oocyst. Selected as a preclinical candidate, ELQ-300 has good oral bioavailability at efficacious doses in mice, is metabolically stable, and is highly active in blocking transmission in rodent models of malaria. Given its predicted low dose in patients and its predicted long half-life, ELQ-300 has potential as a new drug for the treatment, prevention, and, ultimately, eradication of human malaria.
| Original language | English |
|---|---|
| Article number | 177ra37 |
| Pages (from-to) | 1-13 |
| Number of pages | 13 |
| Journal | Science Translational Medicine |
| Volume | 5 |
| Issue number | 177 |
| DOIs | |
| Publication status | Published - 20 Mar 2013 |
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Quinolone-3-diarylethers : A new class of antimalarial drug. / Nilsen, Aaron; LaCrue, Alexis N.; White, Karen L.; Forquer, Isaac P.; Cross, R. Matthew; Marfurt, Jutta; Mather, Michael W.; Delves, Michael J.; Shackleford, David M.; Saenz, Fabian E.; Morrisey, Joanne M.; Steuten, Jessica; Mutka, Tina; Li, Yuexin; Wirjanata, Grennady; Ryan, Eileen; Duffy, Sandra; Kelly, Jane Xu; Sebayang, Boni F.; Zeeman, Anne-Marie; Noviyanti, Rintis; Sinden, Robert E.; Kocken, Clemens H M; Price, Ric N.; Avery, Vicky M.; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Ferrer, Santiago; Herreros, Esperanza; Sanz, Laura María; Gamo–Benito, Francisco Javier; bathurst, Ian; Burrows, Jeremy N.; Siegl, Peter; Guy, R. Kiplin; Winter, Rolf W.; Vaidya, Akhil B.; Charman, Susan A.; Kyle, Dennis E.; Manetsch, Roman; Riscoe, Michael K.
In: Science Translational Medicine, Vol. 5, No. 177, 177ra37, 20.03.2013, p. 1-13.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Quinolone-3-diarylethers
T2 - A new class of antimalarial drug
AU - Nilsen, Aaron
AU - LaCrue, Alexis N.
AU - White, Karen L.
AU - Forquer, Isaac P.
AU - Cross, R. Matthew
AU - Marfurt, Jutta
AU - Mather, Michael W.
AU - Delves, Michael J.
AU - Shackleford, David M.
AU - Saenz, Fabian E.
AU - Morrisey, Joanne M.
AU - Steuten, Jessica
AU - Mutka, Tina
AU - Li, Yuexin
AU - Wirjanata, Grennady
AU - Ryan, Eileen
AU - Duffy, Sandra
AU - Kelly, Jane Xu
AU - Sebayang, Boni F.
AU - Zeeman, Anne-Marie
AU - Noviyanti, Rintis
AU - Sinden, Robert E.
AU - Kocken, Clemens H M
AU - Price, Ric N.
AU - Avery, Vicky M.
AU - Angulo-Barturen, Iñigo
AU - Jiménez-Díaz, María Belén
AU - Ferrer, Santiago
AU - Herreros, Esperanza
AU - Sanz, Laura María
AU - Gamo–Benito, Francisco Javier
AU - bathurst, Ian
AU - Burrows, Jeremy N.
AU - Siegl, Peter
AU - Guy, R. Kiplin
AU - Winter, Rolf W.
AU - Vaidya, Akhil B.
AU - Charman, Susan A.
AU - Kyle, Dennis E.
AU - Manetsch, Roman
AU - Riscoe, Michael K.
PY - 2013/3/20
Y1 - 2013/3/20
N2 - The goal for developing new antimalarial drugs is to find a molecule that can target multiple stages of the parasite's life cycle, thus impacting prevention, treatment, and transmission of the disease. The 4(1H)-quinolone-3- diarylethers are selective potent inhibitors of the parasite's mitochondrial cytochrome bc1 complex. These compounds are highly active against the human malaria parasites Plasmodium falciparum and Plasmodium vivax. They target both the liver and blood stages of the parasite as well as the forms that are crucial for disease transmission, that is, the gametocytes, the zygote, the ookinete, and the oocyst. Selected as a preclinical candidate, ELQ-300 has good oral bioavailability at efficacious doses in mice, is metabolically stable, and is highly active in blocking transmission in rodent models of malaria. Given its predicted low dose in patients and its predicted long half-life, ELQ-300 has potential as a new drug for the treatment, prevention, and, ultimately, eradication of human malaria.
AB - The goal for developing new antimalarial drugs is to find a molecule that can target multiple stages of the parasite's life cycle, thus impacting prevention, treatment, and transmission of the disease. The 4(1H)-quinolone-3- diarylethers are selective potent inhibitors of the parasite's mitochondrial cytochrome bc1 complex. These compounds are highly active against the human malaria parasites Plasmodium falciparum and Plasmodium vivax. They target both the liver and blood stages of the parasite as well as the forms that are crucial for disease transmission, that is, the gametocytes, the zygote, the ookinete, and the oocyst. Selected as a preclinical candidate, ELQ-300 has good oral bioavailability at efficacious doses in mice, is metabolically stable, and is highly active in blocking transmission in rodent models of malaria. Given its predicted low dose in patients and its predicted long half-life, ELQ-300 has potential as a new drug for the treatment, prevention, and, ultimately, eradication of human malaria.
KW - 4(1h) quinolone 3 diarylether derivative
KW - amodiaquine
KW - antimalarial agent
KW - artesunate
KW - atovaquone
KW - chloroquine
KW - elq 271
KW - elq 300
KW - gsk 932121a
KW - mefloquine
KW - p 4q 391
KW - piperaquine
KW - proguanil
KW - ubiquinol cytochrome c reductase
KW - unclassified drug
KW - animal cell
KW - animal experiment
KW - animal model
KW - antimalarial activity
KW - apicomplexan life cycle stage
KW - area under the curve
KW - article
KW - controlled study
KW - drug bioavailability
KW - drug clearance
KW - drug cytotoxicity
KW - drug distribution
KW - drug efficacy
KW - drug half life
KW - drug mechanism
KW - drug potency
KW - drug potentiation
KW - drug safety
KW - drug selectivity
KW - drug sensitivity
KW - drug structure
KW - enzyme inhibition
KW - ex vivo study
KW - female
KW - gametocyte
KW - human
KW - human cell
KW - IC 50
KW - in vitro study
KW - in vivo study
KW - low drug dose
KW - malaria
KW - malaria control
KW - malaria falciparum
KW - mouse
KW - nonhuman
KW - parasite transmission
KW - parasite vector
KW - Plasmodium berghei
KW - Plasmodium falciparum
KW - Plasmodium vivax
KW - Plasmodium yoelii
KW - priority journal
KW - single drug dose
KW - Animals
KW - Antimalarials
KW - Atovaquone
KW - Drug Resistance
KW - Drug Synergism
KW - Life Cycle Stages
KW - Malaria
KW - Malaria, Falciparum
KW - Mice
KW - Proguanil
KW - Pyridones
KW - Quinolones
UR - http://www.scopus.com/inward/record.url?scp=84876002292&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.3005029
DO - 10.1126/scitranslmed.3005029
M3 - Article
VL - 5
SP - 1
EP - 13
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 177
M1 - 177ra37
ER -