Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium

Matthew Cross, David L Flanigan, Andrii Monastyrskyi, Alexis N LaCrue, Fabian E Saenz, Jordany R Maignan, Tina S Mutka, Karen Louise White, David Shackleford, Ian C Bathurst, Frank R Fronczek, Lukasz Wojtas, Wayne C Guida, Susan Ann Charman, Jeremy Burrows, Dennis E Kyle, Roman Manetsch

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure-activity and structure-property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99 after 6 days.
Original languageEnglish
Pages (from-to)8860 - 8879
Number of pages20
JournalJournal of Medicinal Chemistry
Volume57
Issue number21
DOIs
Publication statusPublished - 2014

Cite this

Cross, M., Flanigan, D. L., Monastyrskyi, A., LaCrue, A. N., Saenz, F. E., Maignan, J. R., ... Manetsch, R. (2014). Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium. Journal of Medicinal Chemistry, 57(21), 8860 - 8879. https://doi.org/10.1021/jm500942v
Cross, Matthew ; Flanigan, David L ; Monastyrskyi, Andrii ; LaCrue, Alexis N ; Saenz, Fabian E ; Maignan, Jordany R ; Mutka, Tina S ; White, Karen Louise ; Shackleford, David ; Bathurst, Ian C ; Fronczek, Frank R ; Wojtas, Lukasz ; Guida, Wayne C ; Charman, Susan Ann ; Burrows, Jeremy ; Kyle, Dennis E ; Manetsch, Roman. / Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 21. pp. 8860 - 8879.
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title = "Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium",
abstract = "The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure-activity and structure-property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99 after 6 days.",
author = "Matthew Cross and Flanigan, {David L} and Andrii Monastyrskyi and LaCrue, {Alexis N} and Saenz, {Fabian E} and Maignan, {Jordany R} and Mutka, {Tina S} and White, {Karen Louise} and David Shackleford and Bathurst, {Ian C} and Fronczek, {Frank R} and Lukasz Wojtas and Guida, {Wayne C} and Charman, {Susan Ann} and Jeremy Burrows and Kyle, {Dennis E} and Roman Manetsch",
year = "2014",
doi = "10.1021/jm500942v",
language = "English",
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journal = "Journal of Medicinal Chemistry",
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Cross, M, Flanigan, DL, Monastyrskyi, A, LaCrue, AN, Saenz, FE, Maignan, JR, Mutka, TS, White, KL, Shackleford, D, Bathurst, IC, Fronczek, FR, Wojtas, L, Guida, WC, Charman, SA, Burrows, J, Kyle, DE & Manetsch, R 2014, 'Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium' Journal of Medicinal Chemistry, vol. 57, no. 21, pp. 8860 - 8879. https://doi.org/10.1021/jm500942v

Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium. / Cross, Matthew; Flanigan, David L; Monastyrskyi, Andrii; LaCrue, Alexis N; Saenz, Fabian E; Maignan, Jordany R; Mutka, Tina S; White, Karen Louise; Shackleford, David; Bathurst, Ian C; Fronczek, Frank R; Wojtas, Lukasz; Guida, Wayne C; Charman, Susan Ann; Burrows, Jeremy; Kyle, Dennis E; Manetsch, Roman.

In: Journal of Medicinal Chemistry, Vol. 57, No. 21, 2014, p. 8860 - 8879.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium

AU - Cross, Matthew

AU - Flanigan, David L

AU - Monastyrskyi, Andrii

AU - LaCrue, Alexis N

AU - Saenz, Fabian E

AU - Maignan, Jordany R

AU - Mutka, Tina S

AU - White, Karen Louise

AU - Shackleford, David

AU - Bathurst, Ian C

AU - Fronczek, Frank R

AU - Wojtas, Lukasz

AU - Guida, Wayne C

AU - Charman, Susan Ann

AU - Burrows, Jeremy

AU - Kyle, Dennis E

AU - Manetsch, Roman

PY - 2014

Y1 - 2014

N2 - The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure-activity and structure-property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99 after 6 days.

AB - The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure-activity and structure-property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99 after 6 days.

UR - http://pubs.acs.org/doi/pdf/10.1021/jm500942v

U2 - 10.1021/jm500942v

DO - 10.1021/jm500942v

M3 - Article

VL - 57

SP - 8860

EP - 8879

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 21

ER -