Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold

Brett D Schwartz, Tina S Skinner-Adams, Katherine T Andrews, Mark J Coster, Michael D Edstein, Donna MacKenzie, Susan A Charman, Maria Koltun, Scott Blundell, Anna Campbell, Rebecca H Pouwer, Ronald J Quinn, Karren D Beattie, Peter C Healy, Rohan A Davis

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A series of amide (8-32, 40-45) and urea (33, 34, 36-39) analogues based on the thiaplakortone A natural product scaffold were synthesised and screened for in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine- and mefloquine-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogues displayed potent inhibition of P. falciparum growth (IC50 <500 nM) and good selectivity for P. falciparum versus human neonatal foreskin fibroblast cells (selectivity index >100). Two of these compounds, 8 and 33, exhibited good aqueous solubility and metabolic stability, and when administered subcutaneously to mice (32 mg kg-1), plasma concentrations remained above 0.2 μM for at least 8 h. Both 8 and 33 were well tolerated in mice after subcutaneous administration of 32 mg kg-1 twice daily for 4 days. Using this regimen blood stage P. berghei was suppressed by 52% for 8 and 26% for 33, relative to the vehicle control.
Original languageEnglish
Pages (from-to)1558-1570
Number of pages13
JournalOrganic and Biomolecular Chemistry
Volume13
Issue number5
DOIs
Publication statusPublished - 2015

Cite this

Schwartz, B. D., Skinner-Adams, T. S., Andrews, K. T., Coster, M. J., Edstein, M. D., MacKenzie, D., ... Davis, R. A. (2015). Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold. Organic and Biomolecular Chemistry, 13(5), 1558-1570. https://doi.org/10.1039/c4ob01849d
Schwartz, Brett D ; Skinner-Adams, Tina S ; Andrews, Katherine T ; Coster, Mark J ; Edstein, Michael D ; MacKenzie, Donna ; Charman, Susan A ; Koltun, Maria ; Blundell, Scott ; Campbell, Anna ; Pouwer, Rebecca H ; Quinn, Ronald J ; Beattie, Karren D ; Healy, Peter C ; Davis, Rohan A. / Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold. In: Organic and Biomolecular Chemistry. 2015 ; Vol. 13, No. 5. pp. 1558-1570.
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abstract = "A series of amide (8-32, 40-45) and urea (33, 34, 36-39) analogues based on the thiaplakortone A natural product scaffold were synthesised and screened for in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine- and mefloquine-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogues displayed potent inhibition of P. falciparum growth (IC50 <500 nM) and good selectivity for P. falciparum versus human neonatal foreskin fibroblast cells (selectivity index >100). Two of these compounds, 8 and 33, exhibited good aqueous solubility and metabolic stability, and when administered subcutaneously to mice (32 mg kg-1), plasma concentrations remained above 0.2 μM for at least 8 h. Both 8 and 33 were well tolerated in mice after subcutaneous administration of 32 mg kg-1 twice daily for 4 days. Using this regimen blood stage P. berghei was suppressed by 52{\%} for 8 and 26{\%} for 33, relative to the vehicle control.",
author = "Schwartz, {Brett D} and Skinner-Adams, {Tina S} and Andrews, {Katherine T} and Coster, {Mark J} and Edstein, {Michael D} and Donna MacKenzie and Charman, {Susan A} and Maria Koltun and Scott Blundell and Anna Campbell and Pouwer, {Rebecca H} and Quinn, {Ronald J} and Beattie, {Karren D} and Healy, {Peter C} and Davis, {Rohan A}",
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Schwartz, BD, Skinner-Adams, TS, Andrews, KT, Coster, MJ, Edstein, MD, MacKenzie, D, Charman, SA, Koltun, M, Blundell, S, Campbell, A, Pouwer, RH, Quinn, RJ, Beattie, KD, Healy, PC & Davis, RA 2015, 'Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold' Organic and Biomolecular Chemistry, vol. 13, no. 5, pp. 1558-1570. https://doi.org/10.1039/c4ob01849d

Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold. / Schwartz, Brett D; Skinner-Adams, Tina S; Andrews, Katherine T; Coster, Mark J; Edstein, Michael D; MacKenzie, Donna; Charman, Susan A; Koltun, Maria; Blundell, Scott; Campbell, Anna; Pouwer, Rebecca H; Quinn, Ronald J; Beattie, Karren D; Healy, Peter C; Davis, Rohan A.

In: Organic and Biomolecular Chemistry, Vol. 13, No. 5, 2015, p. 1558-1570.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold

AU - Schwartz, Brett D

AU - Skinner-Adams, Tina S

AU - Andrews, Katherine T

AU - Coster, Mark J

AU - Edstein, Michael D

AU - MacKenzie, Donna

AU - Charman, Susan A

AU - Koltun, Maria

AU - Blundell, Scott

AU - Campbell, Anna

AU - Pouwer, Rebecca H

AU - Quinn, Ronald J

AU - Beattie, Karren D

AU - Healy, Peter C

AU - Davis, Rohan A

PY - 2015

Y1 - 2015

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AB - A series of amide (8-32, 40-45) and urea (33, 34, 36-39) analogues based on the thiaplakortone A natural product scaffold were synthesised and screened for in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine- and mefloquine-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogues displayed potent inhibition of P. falciparum growth (IC50 <500 nM) and good selectivity for P. falciparum versus human neonatal foreskin fibroblast cells (selectivity index >100). Two of these compounds, 8 and 33, exhibited good aqueous solubility and metabolic stability, and when administered subcutaneously to mice (32 mg kg-1), plasma concentrations remained above 0.2 μM for at least 8 h. Both 8 and 33 were well tolerated in mice after subcutaneous administration of 32 mg kg-1 twice daily for 4 days. Using this regimen blood stage P. berghei was suppressed by 52% for 8 and 26% for 33, relative to the vehicle control.

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U2 - 10.1039/c4ob01849d

DO - 10.1039/c4ob01849d

M3 - Article

VL - 13

SP - 1558

EP - 1570

JO - Organic and Biomolecular Chemistry

JF - Organic and Biomolecular Chemistry

SN - 1477-0520

IS - 5

ER -