Evaluation of 4-amino 2-anilinoquinazolines against Plasmodium and other apicomplexan parasites in vitro and in a P. Falciparum Humanized NOD-scid IL2R null Mouse Model of Malaria

Paul R. Gilson, William Nguyen, William A. Poole, Jose E. Teixeira, Jennifer K. Thompson, Kaiyuan Guo, Rebecca J. Stewart, Trent D. Ashton, Karen L. White, Laura M. Sanz, Francisco Javier Gamo, Susan A. Charman, Sergio Wittlin, James Duffy, Christopher J. Tonkin, Wai Hong Tham, Brendan S. Crabb, Brian M. Cooke, Christopher D. Huston, Alan F. Cowman & 1 others Brad E. Sleebs

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A series of 4-amino 2-anilinoquinazolines optimized for activity against the most lethal malaria parasite of humans, Plasmodium falciparum, was evaluated for activity against other human Plasmodium parasites and related apicomplexans that infect humans and animals. Four of the most promising compounds from the 4-amino 2-anilinoquinazoline series were equally as effective against the asexual blood stages of the zoonotic P. knowlesi, suggesting that they could also be effective against the closely related P. vivax, another important human pathogen. The 2-anilinoquinazoline compounds were also potent against an array of P. falciparum parasites resistant to clinically available antimalarial compounds, although slightly less so than against the drug-sensitive 3D7 parasite line. The apicomplexan parasites Toxoplasma gondii, Babesia bovis, and Cryptosporidium parvum were less sensitive to the 2-anilinoquinazoline series with a 50% effective concentration generally in the low micromolar range, suggesting that the yet to be discovered target of these compounds is absent or highly divergent in non-Plasmodium parasites. The 2-anilinoquinazoline compounds act as rapidly as chloroquine in vitro and when tested in rodents displayed a half-life that contributed to the compound’s capacity to clear P. falciparum blood stages in a humanized mouse model. At a dose of 50 mg/kg of body weight, adverse effects to the humanized mice were noted, and evaluation against a panel of experimental high-risk off targets indicated some potential off-target activity. Further optimization of the 2-anilinoquinazoline antimalarial class will concentrate on improving in vivo efficacy and addressing adverse risk.

Original languageEnglish
Article numbere01804-18
Number of pages15
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number3
DOIs
Publication statusPublished - 1 Mar 2019

Keywords

  • Antimalarial agents
  • Apicomplexan parasites
  • Drug metabolism
  • Pharmacokinetics
  • Plasmodium
  • Plasmodium falciparum
  • Quinazoline

Cite this

Gilson, Paul R. ; Nguyen, William ; Poole, William A. ; Teixeira, Jose E. ; Thompson, Jennifer K. ; Guo, Kaiyuan ; Stewart, Rebecca J. ; Ashton, Trent D. ; White, Karen L. ; Sanz, Laura M. ; Gamo, Francisco Javier ; Charman, Susan A. ; Wittlin, Sergio ; Duffy, James ; Tonkin, Christopher J. ; Tham, Wai Hong ; Crabb, Brendan S. ; Cooke, Brian M. ; Huston, Christopher D. ; Cowman, Alan F. ; Sleebs, Brad E. / Evaluation of 4-amino 2-anilinoquinazolines against Plasmodium and other apicomplexan parasites in vitro and in a P. Falciparum Humanized NOD-scid IL2R null Mouse Model of Malaria. In: Antimicrobial Agents and Chemotherapy. 2019 ; Vol. 63, No. 3.
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title = "Evaluation of 4-amino 2-anilinoquinazolines against Plasmodium and other apicomplexan parasites in vitro and in a P. Falciparum Humanized NOD-scid IL2R null Mouse Model of Malaria",
abstract = "A series of 4-amino 2-anilinoquinazolines optimized for activity against the most lethal malaria parasite of humans, Plasmodium falciparum, was evaluated for activity against other human Plasmodium parasites and related apicomplexans that infect humans and animals. Four of the most promising compounds from the 4-amino 2-anilinoquinazoline series were equally as effective against the asexual blood stages of the zoonotic P. knowlesi, suggesting that they could also be effective against the closely related P. vivax, another important human pathogen. The 2-anilinoquinazoline compounds were also potent against an array of P. falciparum parasites resistant to clinically available antimalarial compounds, although slightly less so than against the drug-sensitive 3D7 parasite line. The apicomplexan parasites Toxoplasma gondii, Babesia bovis, and Cryptosporidium parvum were less sensitive to the 2-anilinoquinazoline series with a 50{\%} effective concentration generally in the low micromolar range, suggesting that the yet to be discovered target of these compounds is absent or highly divergent in non-Plasmodium parasites. The 2-anilinoquinazoline compounds act as rapidly as chloroquine in vitro and when tested in rodents displayed a half-life that contributed to the compound’s capacity to clear P. falciparum blood stages in a humanized mouse model. At a dose of 50 mg/kg of body weight, adverse effects to the humanized mice were noted, and evaluation against a panel of experimental high-risk off targets indicated some potential off-target activity. Further optimization of the 2-anilinoquinazoline antimalarial class will concentrate on improving in vivo efficacy and addressing adverse risk.",
keywords = "Antimalarial agents, Apicomplexan parasites, Drug metabolism, Pharmacokinetics, Plasmodium, Plasmodium falciparum, Quinazoline",
author = "Gilson, {Paul R.} and William Nguyen and Poole, {William A.} and Teixeira, {Jose E.} and Thompson, {Jennifer K.} and Kaiyuan Guo and Stewart, {Rebecca J.} and Ashton, {Trent D.} and White, {Karen L.} and Sanz, {Laura M.} and Gamo, {Francisco Javier} and Charman, {Susan A.} and Sergio Wittlin and James Duffy and Tonkin, {Christopher J.} and Tham, {Wai Hong} and Crabb, {Brendan S.} and Cooke, {Brian M.} and Huston, {Christopher D.} and Cowman, {Alan F.} and Sleebs, {Brad E.}",
year = "2019",
month = "3",
day = "1",
doi = "10.1128/AAC.01804-18",
language = "English",
volume = "63",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "1098-6596",
publisher = "American Society for Microbiology",
number = "3",

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Gilson, PR, Nguyen, W, Poole, WA, Teixeira, JE, Thompson, JK, Guo, K, Stewart, RJ, Ashton, TD, White, KL, Sanz, LM, Gamo, FJ, Charman, SA, Wittlin, S, Duffy, J, Tonkin, CJ, Tham, WH, Crabb, BS, Cooke, BM, Huston, CD, Cowman, AF & Sleebs, BE 2019, 'Evaluation of 4-amino 2-anilinoquinazolines against Plasmodium and other apicomplexan parasites in vitro and in a P. Falciparum Humanized NOD-scid IL2R null Mouse Model of Malaria' Antimicrobial Agents and Chemotherapy, vol. 63, no. 3, e01804-18. https://doi.org/10.1128/AAC.01804-18

Evaluation of 4-amino 2-anilinoquinazolines against Plasmodium and other apicomplexan parasites in vitro and in a P. Falciparum Humanized NOD-scid IL2R null Mouse Model of Malaria. / Gilson, Paul R.; Nguyen, William; Poole, William A.; Teixeira, Jose E.; Thompson, Jennifer K.; Guo, Kaiyuan; Stewart, Rebecca J.; Ashton, Trent D.; White, Karen L.; Sanz, Laura M.; Gamo, Francisco Javier; Charman, Susan A.; Wittlin, Sergio; Duffy, James; Tonkin, Christopher J.; Tham, Wai Hong; Crabb, Brendan S.; Cooke, Brian M.; Huston, Christopher D.; Cowman, Alan F.; Sleebs, Brad E.

In: Antimicrobial Agents and Chemotherapy, Vol. 63, No. 3, e01804-18, 01.03.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Evaluation of 4-amino 2-anilinoquinazolines against Plasmodium and other apicomplexan parasites in vitro and in a P. Falciparum Humanized NOD-scid IL2R null Mouse Model of Malaria

AU - Gilson, Paul R.

AU - Nguyen, William

AU - Poole, William A.

AU - Teixeira, Jose E.

AU - Thompson, Jennifer K.

AU - Guo, Kaiyuan

AU - Stewart, Rebecca J.

AU - Ashton, Trent D.

AU - White, Karen L.

AU - Sanz, Laura M.

AU - Gamo, Francisco Javier

AU - Charman, Susan A.

AU - Wittlin, Sergio

AU - Duffy, James

AU - Tonkin, Christopher J.

AU - Tham, Wai Hong

AU - Crabb, Brendan S.

AU - Cooke, Brian M.

AU - Huston, Christopher D.

AU - Cowman, Alan F.

AU - Sleebs, Brad E.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - A series of 4-amino 2-anilinoquinazolines optimized for activity against the most lethal malaria parasite of humans, Plasmodium falciparum, was evaluated for activity against other human Plasmodium parasites and related apicomplexans that infect humans and animals. Four of the most promising compounds from the 4-amino 2-anilinoquinazoline series were equally as effective against the asexual blood stages of the zoonotic P. knowlesi, suggesting that they could also be effective against the closely related P. vivax, another important human pathogen. The 2-anilinoquinazoline compounds were also potent against an array of P. falciparum parasites resistant to clinically available antimalarial compounds, although slightly less so than against the drug-sensitive 3D7 parasite line. The apicomplexan parasites Toxoplasma gondii, Babesia bovis, and Cryptosporidium parvum were less sensitive to the 2-anilinoquinazoline series with a 50% effective concentration generally in the low micromolar range, suggesting that the yet to be discovered target of these compounds is absent or highly divergent in non-Plasmodium parasites. The 2-anilinoquinazoline compounds act as rapidly as chloroquine in vitro and when tested in rodents displayed a half-life that contributed to the compound’s capacity to clear P. falciparum blood stages in a humanized mouse model. At a dose of 50 mg/kg of body weight, adverse effects to the humanized mice were noted, and evaluation against a panel of experimental high-risk off targets indicated some potential off-target activity. Further optimization of the 2-anilinoquinazoline antimalarial class will concentrate on improving in vivo efficacy and addressing adverse risk.

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KW - Antimalarial agents

KW - Apicomplexan parasites

KW - Drug metabolism

KW - Pharmacokinetics

KW - Plasmodium

KW - Plasmodium falciparum

KW - Quinazoline

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DO - 10.1128/AAC.01804-18

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JO - Antimicrobial Agents and Chemotherapy

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