Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria

Paul M. O’ Neill, Paul A. Stocks, Sunil Sabbani, Natalie L. Roberts, Richard K. Amewu, Emma R. Shore, Ghaith Aljayyoussi, Iñigo Angulo-Barturén, María Belén, Jiménez-Díaz, Santiago Ferrer Bazaga, María Santos Martínez, Brice Campo, Raman Sharma, Susan A. Charman, Eileen Ryan, Gong Chen, David M. Shackleford, Jill Davies, Gemma L. Nixon & 2 others Giancarlo A. Biagini, Stephen A. Ward

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.

Original languageEnglish
Pages (from-to)2996-3005
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number11
DOIs
Publication statusPublished - 15 Jul 2018

Cite this

O’ Neill, Paul M. ; Stocks, Paul A. ; Sabbani, Sunil ; Roberts, Natalie L. ; Amewu, Richard K. ; Shore, Emma R. ; Aljayyoussi, Ghaith ; Angulo-Barturén, Iñigo ; Belén, María ; Jiménez-Díaz ; Bazaga, Santiago Ferrer ; Martínez, María Santos ; Campo, Brice ; Sharma, Raman ; Charman, Susan A. ; Ryan, Eileen ; Chen, Gong ; Shackleford, David M. ; Davies, Jill ; Nixon, Gemma L. ; Biagini, Giancarlo A. ; Ward, Stephen A. / Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205 : Towards tetraoxane scaffolds with potential for single dose cure of malaria. In: Bioorganic and Medicinal Chemistry. 2018 ; Vol. 26, No. 11. pp. 2996-3005.
@article{0efca31f899d4274953419d8d3877741,
title = "Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria",
abstract = "A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.",
author = "{O’ Neill}, {Paul M.} and Stocks, {Paul A.} and Sunil Sabbani and Roberts, {Natalie L.} and Amewu, {Richard K.} and Shore, {Emma R.} and Ghaith Aljayyoussi and I{\~n}igo Angulo-Bartur{\'e}n and Mar{\'i}a Bel{\'e}n and Jim{\'e}nez-D{\'i}az and Bazaga, {Santiago Ferrer} and Mart{\'i}nez, {Mar{\'i}a Santos} and Brice Campo and Raman Sharma and Charman, {Susan A.} and Eileen Ryan and Gong Chen and Shackleford, {David M.} and Jill Davies and Nixon, {Gemma L.} and Biagini, {Giancarlo A.} and Ward, {Stephen A.}",
year = "2018",
month = "7",
day = "15",
doi = "10.1016/j.bmc.2018.05.006",
language = "English",
volume = "26",
pages = "2996--3005",
journal = "Bioorganic & Medicinal Chemistry",
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O’ Neill, PM, Stocks, PA, Sabbani, S, Roberts, NL, Amewu, RK, Shore, ER, Aljayyoussi, G, Angulo-Barturén, I, Belén, M, Jiménez-Díaz, Bazaga, SF, Martínez, MS, Campo, B, Sharma, R, Charman, SA, Ryan, E, Chen, G, Shackleford, DM, Davies, J, Nixon, GL, Biagini, GA & Ward, SA 2018, 'Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria' Bioorganic and Medicinal Chemistry, vol. 26, no. 11, pp. 2996-3005. https://doi.org/10.1016/j.bmc.2018.05.006

Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205 : Towards tetraoxane scaffolds with potential for single dose cure of malaria. / O’ Neill, Paul M.; Stocks, Paul A.; Sabbani, Sunil; Roberts, Natalie L.; Amewu, Richard K.; Shore, Emma R.; Aljayyoussi, Ghaith; Angulo-Barturén, Iñigo; Belén, María; Jiménez-Díaz; Bazaga, Santiago Ferrer; Martínez, María Santos; Campo, Brice; Sharma, Raman; Charman, Susan A.; Ryan, Eileen; Chen, Gong; Shackleford, David M.; Davies, Jill; Nixon, Gemma L.; Biagini, Giancarlo A.; Ward, Stephen A.

In: Bioorganic and Medicinal Chemistry, Vol. 26, No. 11, 15.07.2018, p. 2996-3005.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205

T2 - Towards tetraoxane scaffolds with potential for single dose cure of malaria

AU - O’ Neill, Paul M.

AU - Stocks, Paul A.

AU - Sabbani, Sunil

AU - Roberts, Natalie L.

AU - Amewu, Richard K.

AU - Shore, Emma R.

AU - Aljayyoussi, Ghaith

AU - Angulo-Barturén, Iñigo

AU - Belén, María

AU - Jiménez-Díaz, null

AU - Bazaga, Santiago Ferrer

AU - Martínez, María Santos

AU - Campo, Brice

AU - Sharma, Raman

AU - Charman, Susan A.

AU - Ryan, Eileen

AU - Chen, Gong

AU - Shackleford, David M.

AU - Davies, Jill

AU - Nixon, Gemma L.

AU - Biagini, Giancarlo A.

AU - Ward, Stephen A.

PY - 2018/7/15

Y1 - 2018/7/15

N2 - A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.

AB - A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.

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U2 - 10.1016/j.bmc.2018.05.006

DO - 10.1016/j.bmc.2018.05.006

M3 - Article

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SP - 2996

EP - 3005

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

SN - 0968-0896

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