Discovery, synthesis, and optimization of antimalarial 4(1H)-quinolone-3-diarylethers

Aaron Nilsen, Galen P Miley, Isaac P Forquer, Michael W Mather, Kasiram Katneni, Yuexin Li, Sovitj Pou, April M Pershing, Allison M Stickles, Eileen Ryan, Jane Xu Kelly, J Stone Doggett, Karen Louise White, David J Hinrichs, Rolf W Winter, Susan Ann Charman, Lev N Zakharov, Ian C Bathurst, Jeremy Burrows, Akhil B Vaidya & 1 others Michael K Riscoe

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.
Original languageEnglish
Pages (from-to)3818 - 3834
Number of pages17
JournalJournal of Medicinal Chemistry
Volume57
Issue number9
DOIs
Publication statusPublished - 2014

Cite this

Nilsen, A., Miley, G. P., Forquer, I. P., Mather, M. W., Katneni, K., Li, Y., ... Riscoe, M. K. (2014). Discovery, synthesis, and optimization of antimalarial 4(1H)-quinolone-3-diarylethers. Journal of Medicinal Chemistry, 57(9), 3818 - 3834. https://doi.org/10.1021/jm500147k
Nilsen, Aaron ; Miley, Galen P ; Forquer, Isaac P ; Mather, Michael W ; Katneni, Kasiram ; Li, Yuexin ; Pou, Sovitj ; Pershing, April M ; Stickles, Allison M ; Ryan, Eileen ; Kelly, Jane Xu ; Doggett, J Stone ; White, Karen Louise ; Hinrichs, David J ; Winter, Rolf W ; Charman, Susan Ann ; Zakharov, Lev N ; Bathurst, Ian C ; Burrows, Jeremy ; Vaidya, Akhil B ; Riscoe, Michael K. / Discovery, synthesis, and optimization of antimalarial 4(1H)-quinolone-3-diarylethers. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 9. pp. 3818 - 3834.
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abstract = "The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.",
author = "Aaron Nilsen and Miley, {Galen P} and Forquer, {Isaac P} and Mather, {Michael W} and Kasiram Katneni and Yuexin Li and Sovitj Pou and Pershing, {April M} and Stickles, {Allison M} and Eileen Ryan and Kelly, {Jane Xu} and Doggett, {J Stone} and White, {Karen Louise} and Hinrichs, {David J} and Winter, {Rolf W} and Charman, {Susan Ann} and Zakharov, {Lev N} and Bathurst, {Ian C} and Jeremy Burrows and Vaidya, {Akhil B} and Riscoe, {Michael K}",
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language = "English",
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pages = "3818 -- 3834",
journal = "Journal of Medicinal Chemistry",
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Nilsen, A, Miley, GP, Forquer, IP, Mather, MW, Katneni, K, Li, Y, Pou, S, Pershing, AM, Stickles, AM, Ryan, E, Kelly, JX, Doggett, JS, White, KL, Hinrichs, DJ, Winter, RW, Charman, SA, Zakharov, LN, Bathurst, IC, Burrows, J, Vaidya, AB & Riscoe, MK 2014, 'Discovery, synthesis, and optimization of antimalarial 4(1H)-quinolone-3-diarylethers' Journal of Medicinal Chemistry, vol. 57, no. 9, pp. 3818 - 3834. https://doi.org/10.1021/jm500147k

Discovery, synthesis, and optimization of antimalarial 4(1H)-quinolone-3-diarylethers. / Nilsen, Aaron; Miley, Galen P; Forquer, Isaac P; Mather, Michael W; Katneni, Kasiram; Li, Yuexin; Pou, Sovitj; Pershing, April M; Stickles, Allison M; Ryan, Eileen; Kelly, Jane Xu; Doggett, J Stone; White, Karen Louise; Hinrichs, David J; Winter, Rolf W; Charman, Susan Ann; Zakharov, Lev N; Bathurst, Ian C; Burrows, Jeremy; Vaidya, Akhil B; Riscoe, Michael K.

In: Journal of Medicinal Chemistry, Vol. 57, No. 9, 2014, p. 3818 - 3834.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Discovery, synthesis, and optimization of antimalarial 4(1H)-quinolone-3-diarylethers

AU - Nilsen, Aaron

AU - Miley, Galen P

AU - Forquer, Isaac P

AU - Mather, Michael W

AU - Katneni, Kasiram

AU - Li, Yuexin

AU - Pou, Sovitj

AU - Pershing, April M

AU - Stickles, Allison M

AU - Ryan, Eileen

AU - Kelly, Jane Xu

AU - Doggett, J Stone

AU - White, Karen Louise

AU - Hinrichs, David J

AU - Winter, Rolf W

AU - Charman, Susan Ann

AU - Zakharov, Lev N

AU - Bathurst, Ian C

AU - Burrows, Jeremy

AU - Vaidya, Akhil B

AU - Riscoe, Michael K

PY - 2014

Y1 - 2014

N2 - The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.

AB - The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.

UR - http://pubs.acs.org/doi/pdf/10.1021/jm500147k

U2 - 10.1021/jm500147k

DO - 10.1021/jm500147k

M3 - Article

VL - 57

SP - 3818

EP - 3834

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 9

ER -