2,4-Diaminothienopyrimidines as orally active antimalarial agents

Diego Gonzalez Cabrera, Claire Le Manach, Frederic Douelle, Yassir Younis, Tzu-Shean Feng, Tanya Paquet, Aloysius T Nchinda, Leslie J Street, Dale Taylor, Carmen de Kock, Lubbe Wiesner, Sandra Duffy, Karen Louise White, Mohammed K Zabiulla, Yuvaraj Sambandan, Sridevi Bashyam, David Waterson, Michael J Witty, Susan Ann Charman, Vicky M Avery & 2 others Sergio Wittlin, Kelly Chibale

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A novel series of 2,4-diaminothienopyrimidines with potential as antimalarials was identified from whole-cell high-throughput screening of a SoftFocus ion channel library. Synthesis and structure-activity relationship studies identified compounds with potent antiplasmodial activity and low in vitro cytotoxicity. Several of these analogues exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the hERG potassium channel was identified as a liability for this series.
Original languageEnglish
Pages (from-to)1014 - 1022
Number of pages9
JournalJournal of Medicinal Chemistry
Volume57
Issue number3
DOIs
Publication statusPublished - 2014

Cite this

Cabrera, D. G., Le Manach, C., Douelle, F., Younis, Y., Feng, T-S., Paquet, T., ... Chibale, K. (2014). 2,4-Diaminothienopyrimidines as orally active antimalarial agents. Journal of Medicinal Chemistry, 57(3), 1014 - 1022. https://doi.org/10.1021/jm401760c
Cabrera, Diego Gonzalez ; Le Manach, Claire ; Douelle, Frederic ; Younis, Yassir ; Feng, Tzu-Shean ; Paquet, Tanya ; Nchinda, Aloysius T ; Street, Leslie J ; Taylor, Dale ; de Kock, Carmen ; Wiesner, Lubbe ; Duffy, Sandra ; White, Karen Louise ; Zabiulla, Mohammed K ; Sambandan, Yuvaraj ; Bashyam, Sridevi ; Waterson, David ; Witty, Michael J ; Charman, Susan Ann ; Avery, Vicky M ; Wittlin, Sergio ; Chibale, Kelly. / 2,4-Diaminothienopyrimidines as orally active antimalarial agents. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 3. pp. 1014 - 1022.
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title = "2,4-Diaminothienopyrimidines as orally active antimalarial agents",
abstract = "A novel series of 2,4-diaminothienopyrimidines with potential as antimalarials was identified from whole-cell high-throughput screening of a SoftFocus ion channel library. Synthesis and structure-activity relationship studies identified compounds with potent antiplasmodial activity and low in vitro cytotoxicity. Several of these analogues exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the hERG potassium channel was identified as a liability for this series.",
author = "Cabrera, {Diego Gonzalez} and {Le Manach}, Claire and Frederic Douelle and Yassir Younis and Tzu-Shean Feng and Tanya Paquet and Nchinda, {Aloysius T} and Street, {Leslie J} and Dale Taylor and {de Kock}, Carmen and Lubbe Wiesner and Sandra Duffy and White, {Karen Louise} and Zabiulla, {Mohammed K} and Yuvaraj Sambandan and Sridevi Bashyam and David Waterson and Witty, {Michael J} and Charman, {Susan Ann} and Avery, {Vicky M} and Sergio Wittlin and Kelly Chibale",
year = "2014",
doi = "10.1021/jm401760c",
language = "English",
volume = "57",
pages = "1014 -- 1022",
journal = "Journal of Medicinal Chemistry",
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Cabrera, DG, Le Manach, C, Douelle, F, Younis, Y, Feng, T-S, Paquet, T, Nchinda, AT, Street, LJ, Taylor, D, de Kock, C, Wiesner, L, Duffy, S, White, KL, Zabiulla, MK, Sambandan, Y, Bashyam, S, Waterson, D, Witty, MJ, Charman, SA, Avery, VM, Wittlin, S & Chibale, K 2014, '2,4-Diaminothienopyrimidines as orally active antimalarial agents' Journal of Medicinal Chemistry, vol. 57, no. 3, pp. 1014 - 1022. https://doi.org/10.1021/jm401760c

2,4-Diaminothienopyrimidines as orally active antimalarial agents. / Cabrera, Diego Gonzalez; Le Manach, Claire; Douelle, Frederic; Younis, Yassir; Feng, Tzu-Shean; Paquet, Tanya; Nchinda, Aloysius T; Street, Leslie J; Taylor, Dale; de Kock, Carmen; Wiesner, Lubbe; Duffy, Sandra; White, Karen Louise; Zabiulla, Mohammed K; Sambandan, Yuvaraj; Bashyam, Sridevi; Waterson, David; Witty, Michael J; Charman, Susan Ann; Avery, Vicky M; Wittlin, Sergio; Chibale, Kelly.

In: Journal of Medicinal Chemistry, Vol. 57, No. 3, 2014, p. 1014 - 1022.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - 2,4-Diaminothienopyrimidines as orally active antimalarial agents

AU - Cabrera, Diego Gonzalez

AU - Le Manach, Claire

AU - Douelle, Frederic

AU - Younis, Yassir

AU - Feng, Tzu-Shean

AU - Paquet, Tanya

AU - Nchinda, Aloysius T

AU - Street, Leslie J

AU - Taylor, Dale

AU - de Kock, Carmen

AU - Wiesner, Lubbe

AU - Duffy, Sandra

AU - White, Karen Louise

AU - Zabiulla, Mohammed K

AU - Sambandan, Yuvaraj

AU - Bashyam, Sridevi

AU - Waterson, David

AU - Witty, Michael J

AU - Charman, Susan Ann

AU - Avery, Vicky M

AU - Wittlin, Sergio

AU - Chibale, Kelly

PY - 2014

Y1 - 2014

N2 - A novel series of 2,4-diaminothienopyrimidines with potential as antimalarials was identified from whole-cell high-throughput screening of a SoftFocus ion channel library. Synthesis and structure-activity relationship studies identified compounds with potent antiplasmodial activity and low in vitro cytotoxicity. Several of these analogues exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the hERG potassium channel was identified as a liability for this series.

AB - A novel series of 2,4-diaminothienopyrimidines with potential as antimalarials was identified from whole-cell high-throughput screening of a SoftFocus ion channel library. Synthesis and structure-activity relationship studies identified compounds with potent antiplasmodial activity and low in vitro cytotoxicity. Several of these analogues exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the hERG potassium channel was identified as a liability for this series.

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U2 - 10.1021/jm401760c

DO - 10.1021/jm401760c

M3 - Article

VL - 57

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EP - 1022

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -

Cabrera DG, Le Manach C, Douelle F, Younis Y, Feng T-S, Paquet T et al. 2,4-Diaminothienopyrimidines as orally active antimalarial agents. Journal of Medicinal Chemistry. 2014;57(3):1014 - 1022. https://doi.org/10.1021/jm401760c