Identification of a potential antimalarial drug candidate from a series of 2-aminopyrazines by optimization of aqueous solubility and potency across the parasite life cycle

Claire Le Manach, Aloysius T. Nchinda, Tanya Paquet, Diego Gonzàlez Cabrera, Yassir Younis, Ze Han, Sridevi Bashyam, Mohammed Zabiulla, Dale Taylor, Nina Lawrence, Karen L. White, Susan A. Charman, David Waterson, Michael J. Witty, Sergio Wittlin, Mariëtte E. Botha, Sindisiswe H. Nondaba, Janette Reader, Lyn Marie Birkholtz, María Belén Jiménez-Díaz

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Introduction of water-solubilizing groups on the 5-phenyl ring of a 2-aminopyrazine series led to the identification of highly potent compounds against the blood life-cycle stage of the human malaria parasite Plasmodium falciparum. Several compounds displayed high in vivo efficacy in two different mouse models for malaria, P. berghei-infected mice and P. falciparum-infected NOD-scid IL-2Rnull mice. One of the frontrunners, compound 3, was identified to also have good pharmacokinetics and additionally very potent activity against the liver and gametocyte parasite life-cycle stages.
Original languageEnglish
Pages (from-to)9890-9905
Number of pages16
JournalJournal of Medicinal Chemistry
Volume59
Issue number21
DOIs
Publication statusPublished - 10 Nov 2016

Cite this

Le Manach, Claire ; Nchinda, Aloysius T. ; Paquet, Tanya ; Gonzàlez Cabrera, Diego ; Younis, Yassir ; Han, Ze ; Bashyam, Sridevi ; Zabiulla, Mohammed ; Taylor, Dale ; Lawrence, Nina ; White, Karen L. ; Charman, Susan A. ; Waterson, David ; Witty, Michael J. ; Wittlin, Sergio ; Botha, Mariëtte E. ; Nondaba, Sindisiswe H. ; Reader, Janette ; Birkholtz, Lyn Marie ; Jiménez-Díaz, María Belén. / Identification of a potential antimalarial drug candidate from a series of 2-aminopyrazines by optimization of aqueous solubility and potency across the parasite life cycle. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 21. pp. 9890-9905.
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title = "Identification of a potential antimalarial drug candidate from a series of 2-aminopyrazines by optimization of aqueous solubility and potency across the parasite life cycle",
abstract = "Introduction of water-solubilizing groups on the 5-phenyl ring of a 2-aminopyrazine series led to the identification of highly potent compounds against the blood life-cycle stage of the human malaria parasite Plasmodium falciparum. Several compounds displayed high in vivo efficacy in two different mouse models for malaria, P. berghei-infected mice and P. falciparum-infected NOD-scid IL-2Rnull mice. One of the frontrunners, compound 3, was identified to also have good pharmacokinetics and additionally very potent activity against the liver and gametocyte parasite life-cycle stages.",
author = "{Le Manach}, Claire and Nchinda, {Aloysius T.} and Tanya Paquet and {Gonz{\`a}lez Cabrera}, Diego and Yassir Younis and Ze Han and Sridevi Bashyam and Mohammed Zabiulla and Dale Taylor and Nina Lawrence and White, {Karen L.} and Charman, {Susan A.} and David Waterson and Witty, {Michael J.} and Sergio Wittlin and Botha, {Mari{\"e}tte E.} and Nondaba, {Sindisiswe H.} and Janette Reader and Birkholtz, {Lyn Marie} and Jim{\'e}nez-D{\'i}az, {Mar{\'i}a Bel{\'e}n}",
year = "2016",
month = "11",
day = "10",
doi = "10.1021/acs.jmedchem.6b01265",
language = "English",
volume = "59",
pages = "9890--9905",
journal = "Journal of Medicinal Chemistry",
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Le Manach, C, Nchinda, AT, Paquet, T, Gonzàlez Cabrera, D, Younis, Y, Han, Z, Bashyam, S, Zabiulla, M, Taylor, D, Lawrence, N, White, KL, Charman, SA, Waterson, D, Witty, MJ, Wittlin, S, Botha, ME, Nondaba, SH, Reader, J, Birkholtz, LM & Jiménez-Díaz, MB 2016, 'Identification of a potential antimalarial drug candidate from a series of 2-aminopyrazines by optimization of aqueous solubility and potency across the parasite life cycle' Journal of Medicinal Chemistry, vol. 59, no. 21, pp. 9890-9905. https://doi.org/10.1021/acs.jmedchem.6b01265

Identification of a potential antimalarial drug candidate from a series of 2-aminopyrazines by optimization of aqueous solubility and potency across the parasite life cycle. / Le Manach, Claire; Nchinda, Aloysius T.; Paquet, Tanya; Gonzàlez Cabrera, Diego; Younis, Yassir; Han, Ze; Bashyam, Sridevi; Zabiulla, Mohammed; Taylor, Dale; Lawrence, Nina; White, Karen L.; Charman, Susan A.; Waterson, David; Witty, Michael J.; Wittlin, Sergio; Botha, Mariëtte E.; Nondaba, Sindisiswe H.; Reader, Janette; Birkholtz, Lyn Marie; Jiménez-Díaz, María Belén.

In: Journal of Medicinal Chemistry, Vol. 59, No. 21, 10.11.2016, p. 9890-9905.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Identification of a potential antimalarial drug candidate from a series of 2-aminopyrazines by optimization of aqueous solubility and potency across the parasite life cycle

AU - Le Manach, Claire

AU - Nchinda, Aloysius T.

AU - Paquet, Tanya

AU - Gonzàlez Cabrera, Diego

AU - Younis, Yassir

AU - Han, Ze

AU - Bashyam, Sridevi

AU - Zabiulla, Mohammed

AU - Taylor, Dale

AU - Lawrence, Nina

AU - White, Karen L.

AU - Charman, Susan A.

AU - Waterson, David

AU - Witty, Michael J.

AU - Wittlin, Sergio

AU - Botha, Mariëtte E.

AU - Nondaba, Sindisiswe H.

AU - Reader, Janette

AU - Birkholtz, Lyn Marie

AU - Jiménez-Díaz, María Belén

PY - 2016/11/10

Y1 - 2016/11/10

N2 - Introduction of water-solubilizing groups on the 5-phenyl ring of a 2-aminopyrazine series led to the identification of highly potent compounds against the blood life-cycle stage of the human malaria parasite Plasmodium falciparum. Several compounds displayed high in vivo efficacy in two different mouse models for malaria, P. berghei-infected mice and P. falciparum-infected NOD-scid IL-2Rnull mice. One of the frontrunners, compound 3, was identified to also have good pharmacokinetics and additionally very potent activity against the liver and gametocyte parasite life-cycle stages.

AB - Introduction of water-solubilizing groups on the 5-phenyl ring of a 2-aminopyrazine series led to the identification of highly potent compounds against the blood life-cycle stage of the human malaria parasite Plasmodium falciparum. Several compounds displayed high in vivo efficacy in two different mouse models for malaria, P. berghei-infected mice and P. falciparum-infected NOD-scid IL-2Rnull mice. One of the frontrunners, compound 3, was identified to also have good pharmacokinetics and additionally very potent activity against the liver and gametocyte parasite life-cycle stages.

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U2 - 10.1021/acs.jmedchem.6b01265

DO - 10.1021/acs.jmedchem.6b01265

M3 - Article

VL - 59

SP - 9890

EP - 9905

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 21

ER -