Falcipain Inhibitors Based on the Natural Product Gallinamide A Are Potent in Vitro and in Vivo Antimalarials

Alexander Stoye, Annette Juillard, Arthur H. Tang, Jennifer Legac, Jiri Gut, Karen L. White, Susan A. Charman, Philip J. Rosenthal, Georges E.R. Grau, Nicholas H. Hunt, Richard J. Payne

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A library of analogues of the cyanobacterium-derived depsipeptide natural product gallinamide A were designed and prepared using a highly efficient and convergent synthetic route. Analogues were shown to exhibit potent inhibitory activity against the Plasmodium falciparum cysteine proteases falcipain 2 and falcipain 3 and against cultured chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. Three lead compounds were selected for evaluation of in vivo efficacy against Plasmodium berghei infection in mice on the basis of their improved blood, plasma, and microsomal stability profiles compared with the parent natural product. One of the lead analogues cured P. berghei-infected mice in the Peters 4 day-suppressive test when administered 25 mg kg-1 intraperitoneally daily for 4 days. The compound was also capable of clearing parasites in established infections at 50 mg kg-1 intraperitoneally daily for 4 days and exhibited moderate activity when administered as four oral doses of 100 mg kg-1.

Original languageEnglish
Pages (from-to)5562-5578
Number of pages17
JournalJournal of Medicinal Chemistry
Volume62
Issue number11
DOIs
Publication statusPublished - 13 Jun 2019

Cite this

Stoye, Alexander ; Juillard, Annette ; Tang, Arthur H. ; Legac, Jennifer ; Gut, Jiri ; White, Karen L. ; Charman, Susan A. ; Rosenthal, Philip J. ; Grau, Georges E.R. ; Hunt, Nicholas H. ; Payne, Richard J. / Falcipain Inhibitors Based on the Natural Product Gallinamide A Are Potent in Vitro and in Vivo Antimalarials. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 11. pp. 5562-5578.
@article{f00fbe5665374f0fba3172744981b142,
title = "Falcipain Inhibitors Based on the Natural Product Gallinamide A Are Potent in Vitro and in Vivo Antimalarials",
abstract = "A library of analogues of the cyanobacterium-derived depsipeptide natural product gallinamide A were designed and prepared using a highly efficient and convergent synthetic route. Analogues were shown to exhibit potent inhibitory activity against the Plasmodium falciparum cysteine proteases falcipain 2 and falcipain 3 and against cultured chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. Three lead compounds were selected for evaluation of in vivo efficacy against Plasmodium berghei infection in mice on the basis of their improved blood, plasma, and microsomal stability profiles compared with the parent natural product. One of the lead analogues cured P. berghei-infected mice in the Peters 4 day-suppressive test when administered 25 mg kg-1 intraperitoneally daily for 4 days. The compound was also capable of clearing parasites in established infections at 50 mg kg-1 intraperitoneally daily for 4 days and exhibited moderate activity when administered as four oral doses of 100 mg kg-1.",
author = "Alexander Stoye and Annette Juillard and Tang, {Arthur H.} and Jennifer Legac and Jiri Gut and White, {Karen L.} and Charman, {Susan A.} and Rosenthal, {Philip J.} and Grau, {Georges E.R.} and Hunt, {Nicholas H.} and Payne, {Richard J.}",
year = "2019",
month = "6",
day = "13",
doi = "10.1021/acs.jmedchem.9b00504",
language = "English",
volume = "62",
pages = "5562--5578",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
number = "11",

}

Stoye, A, Juillard, A, Tang, AH, Legac, J, Gut, J, White, KL, Charman, SA, Rosenthal, PJ, Grau, GER, Hunt, NH & Payne, RJ 2019, 'Falcipain Inhibitors Based on the Natural Product Gallinamide A Are Potent in Vitro and in Vivo Antimalarials' Journal of Medicinal Chemistry, vol. 62, no. 11, pp. 5562-5578. https://doi.org/10.1021/acs.jmedchem.9b00504

Falcipain Inhibitors Based on the Natural Product Gallinamide A Are Potent in Vitro and in Vivo Antimalarials. / Stoye, Alexander; Juillard, Annette; Tang, Arthur H.; Legac, Jennifer; Gut, Jiri; White, Karen L.; Charman, Susan A.; Rosenthal, Philip J.; Grau, Georges E.R.; Hunt, Nicholas H.; Payne, Richard J.

In: Journal of Medicinal Chemistry, Vol. 62, No. 11, 13.06.2019, p. 5562-5578.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Falcipain Inhibitors Based on the Natural Product Gallinamide A Are Potent in Vitro and in Vivo Antimalarials

AU - Stoye, Alexander

AU - Juillard, Annette

AU - Tang, Arthur H.

AU - Legac, Jennifer

AU - Gut, Jiri

AU - White, Karen L.

AU - Charman, Susan A.

AU - Rosenthal, Philip J.

AU - Grau, Georges E.R.

AU - Hunt, Nicholas H.

AU - Payne, Richard J.

PY - 2019/6/13

Y1 - 2019/6/13

N2 - A library of analogues of the cyanobacterium-derived depsipeptide natural product gallinamide A were designed and prepared using a highly efficient and convergent synthetic route. Analogues were shown to exhibit potent inhibitory activity against the Plasmodium falciparum cysteine proteases falcipain 2 and falcipain 3 and against cultured chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. Three lead compounds were selected for evaluation of in vivo efficacy against Plasmodium berghei infection in mice on the basis of their improved blood, plasma, and microsomal stability profiles compared with the parent natural product. One of the lead analogues cured P. berghei-infected mice in the Peters 4 day-suppressive test when administered 25 mg kg-1 intraperitoneally daily for 4 days. The compound was also capable of clearing parasites in established infections at 50 mg kg-1 intraperitoneally daily for 4 days and exhibited moderate activity when administered as four oral doses of 100 mg kg-1.

AB - A library of analogues of the cyanobacterium-derived depsipeptide natural product gallinamide A were designed and prepared using a highly efficient and convergent synthetic route. Analogues were shown to exhibit potent inhibitory activity against the Plasmodium falciparum cysteine proteases falcipain 2 and falcipain 3 and against cultured chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. Three lead compounds were selected for evaluation of in vivo efficacy against Plasmodium berghei infection in mice on the basis of their improved blood, plasma, and microsomal stability profiles compared with the parent natural product. One of the lead analogues cured P. berghei-infected mice in the Peters 4 day-suppressive test when administered 25 mg kg-1 intraperitoneally daily for 4 days. The compound was also capable of clearing parasites in established infections at 50 mg kg-1 intraperitoneally daily for 4 days and exhibited moderate activity when administered as four oral doses of 100 mg kg-1.

UR - http://www.scopus.com/inward/record.url?scp=85067339818&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.9b00504

DO - 10.1021/acs.jmedchem.9b00504

M3 - Article

VL - 62

SP - 5562

EP - 5578

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 11

ER -