Discovery, synthesis, and optimization of antimalarial 4(1 H)-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 L. White; David J. Hinrichs; Rolf W. Winter; Susan A. Charman; Lev N. Zakharov; Ian Bathurst; Jeremy N. Burrows; Akhil B. Vaidya; Michael K. Riscoe

doi:10.1021/jm500147k

Discovery, synthesis, and optimization of antimalarial 4(1 H)-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 L. White, David J. Hinrichs, Rolf W. Winter, Susan A. Charman, Lev N. Zakharov, Ian Bathurst, Jeremy N. Burrows, Akhil B. VaidyaMichael K. Riscoe

Research output: Contribution to journal › Article › peer-review

95 Scopus citations

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 language	English (US)
Pages (from-to)	3818-3834
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	57
Issue number	9
DOIs	https://doi.org/10.1021/jm500147k
State	Published - May 8 2014

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Nilsen, A., Miley, G. P., Forquer, I. P., Mather, M. W., Katneni, K., Li, Y., Pou, S., Pershing, A. M., Stickles, A. M., Ryan, E., Kelly, J. X., Doggett, J. S., White, K. L., Hinrichs, D. J., Winter, R. W., Charman, S. A., Zakharov, L. N., Bathurst, I., Burrows, J. N., ... Riscoe, M. K. (2014). Discovery, synthesis, and optimization of antimalarial 4(1 H)-quinolone-3-diarylethers. Journal of Medicinal Chemistry, 57(9), 3818-3834. https://doi.org/10.1021/jm500147k

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, I, Burrows, JN, Vaidya, AB & Riscoe, MK 2014, 'Discovery, synthesis, and optimization of antimalarial 4(1 H)-quinolone-3-diarylethers', Journal of Medicinal Chemistry, vol. 57, no. 9, pp. 3818-3834. https://doi.org/10.1021/jm500147k

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

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 L.} and Hinrichs, {David J.} and Winter, {Rolf W.} and Charman, {Susan A.} and Zakharov, {Lev N.} and Ian Bathurst and Burrows, {Jeremy N.} and Vaidya, {Akhil B.} and Riscoe, {Michael K.}",

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doi = "10.1021/jm500147k",

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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 L.

AU - Hinrichs, David J.

AU - Winter, Rolf W.

AU - Charman, Susan A.

AU - Zakharov, Lev N.

AU - Bathurst, Ian

AU - Burrows, Jeremy N.

AU - Vaidya, Akhil B.

AU - Riscoe, Michael K.

PY - 2014/5/8

Y1 - 2014/5/8

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.

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

Abstract

ASJC Scopus subject areas

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