Quinolone-3-diarylethers

A new class of antimalarial drug

Aaron Nilsen, Alexis N. LaCrue, Karen L. White, Isaac P. Forquer, R. Matthew Cross, Jutta Marfurt, Michael W. Mather, Michael J. Delves, David M. Shackleford, Fabian E. Saenz, Joanne M. Morrisey, Jessica Steuten, Tina Mutka, Yuexin Li, Grennady Wirjanata, Eileen Ryan, Sandra Duffy, Jane Xu Kelly, Boni F. Sebayang, Anne-Marie Zeeman & 21 others Rintis Noviyanti, Robert E. Sinden, Clemens H M Kocken, Ric N. Price, Vicky M. Avery, Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Santiago Ferrer, Esperanza Herreros, Laura María Sanz, Francisco Javier Gamo–Benito, Ian bathurst, Jeremy N. Burrows, Peter Siegl, R. Kiplin Guy, Rolf W. Winter, Akhil B. Vaidya, Susan A. Charman, Dennis E. Kyle, Roman Manetsch, Michael K. Riscoe

Research output: Contribution to journalArticleResearchpeer-review

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 languageEnglish
Article number177ra37
Pages (from-to)1-13
Number of pages13
JournalScience Translational Medicine
Volume5
Issue number177
DOIs
Publication statusPublished - 20 Mar 2013

Fingerprint

Quinolones
Antimalarials
Parasites
Malaria
4-Quinolones
Plasmodium vivax
Oocysts
Falciparum Malaria
Zygote
Electron Transport Complex III
Life Cycle Stages
Biological Availability
Half-Life
Rodentia
Liver
Therapeutics
Pharmaceutical Preparations
6-Chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one

Cite this

Nilsen, A., LaCrue, A. N., White, K. L., Forquer, I. P., Cross, R. M., Marfurt, J., ... Riscoe, M. K. (2013). Quinolone-3-diarylethers: A new class of antimalarial drug. Science Translational Medicine, 5(177), 1-13. [177ra37]. https://doi.org/10.1126/scitranslmed.3005029
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. / Quinolone-3-diarylethers : A new class of antimalarial drug. In: Science Translational Medicine. 2013 ; Vol. 5, No. 177. pp. 1-13.
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Nilsen, A, LaCrue, AN, White, KL, Forquer, IP, Cross, RM, Marfurt, J, Mather, MW, Delves, MJ, Shackleford, DM, Saenz, FE, Morrisey, JM, Steuten, J, Mutka, T, Li, Y, Wirjanata, G, Ryan, E, Duffy, S, Kelly, JX, Sebayang, BF, Zeeman, A-M, Noviyanti, R, Sinden, RE, Kocken, CHM, Price, RN, Avery, VM, Angulo-Barturen, I, Jiménez-Díaz, MB, Ferrer, S, Herreros, E, Sanz, LM, Gamo–Benito, FJ, bathurst, I, Burrows, JN, Siegl, P, Guy, RK, Winter, RW, Vaidya, AB, Charman, SA, Kyle, DE, Manetsch, R & Riscoe, MK 2013, 'Quinolone-3-diarylethers: A new class of antimalarial drug', Science Translational Medicine, vol. 5, no. 177, 177ra37, pp. 1-13. https://doi.org/10.1126/scitranslmed.3005029

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 journalArticleResearchpeer-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 -

Nilsen A, LaCrue AN, White KL, Forquer IP, Cross RM, Marfurt J et al. Quinolone-3-diarylethers: A new class of antimalarial drug. Science Translational Medicine. 2013 Mar 20;5(177):1-13. 177ra37. https://doi.org/10.1126/scitranslmed.3005029