Diels-Alder/thiol-olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore

Paul M. O'Neill; Edite Verissimo; Stephen A. Ward; Jill Davies; Edward E. Korshin; Nuna Araujo; Matthew D. Pugh; M. Lurdes S. Cristiano; Paul A. Stocks; Mario D. Bachi

doi:10.1016/j.bmcl.2006.02.059

Diels-Alder/thiol-olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore

Paul M. O'Neill, Edite Verissimo, Stephen A. Ward, Jill Davies, Edward E. Korshin, Nuna Araujo, Matthew D. Pugh, M. Lurdes S. Cristiano, Paul A. Stocks, Mario D. Bachi

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

A Diels-Alder/thiol-olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a-22b is reported. Some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of the synthetic antimalarial agent arteflene. Iron(II)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with TEMPO provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. Reactive C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides.

Original language	English
Pages (from-to)	2991-2995
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	16
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2006.02.059
State	Published - 1 Jun 2006
Externally published	Yes

Bibliographical note

Funding Information:
The authors thank the EPSRC (M.P.), the BBSRC (S.A.W., P.O.N., P.A.S., Grants BB/C006321/1 and 26/B13581) and the FCT (Fundação para a Ciência e a Tecnologia) Portugal, for funding this work. We also thank Dr. J. L. Maggs (Department of Pharmacology, University of Liverpool) for carrying out the LCMS study on analogue 19b .

Funding

The authors thank the EPSRC (M.P.), the BBSRC (S.A.W., P.O.N., P.A.S., Grants BB/C006321/1 and 26/B13581) and the FCT (Fundação para a Ciência e a Tecnologia) Portugal, for funding this work. We also thank Dr. J. L. Maggs (Department of Pharmacology, University of Liverpool) for carrying out the LCMS study on analogue 19b .

Funders	Funder number
Engineering and Physical Sciences Research Council
Biotechnology and Biological Sciences Research Council	BB/C006321/1, 26/B13581
Fundação para a Ciência e a Tecnologia
Fundació Catalana de Trasplantament

Keywords

Arteflene
Artemisinin
Endoperoxide
Malaria
Mechanism of action

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bmcl.2006.02.059

Cite this

O'Neill, P. M., Verissimo, E., Ward, S. A., Davies, J., Korshin, E. E., Araujo, N., Pugh, M. D., Cristiano, M. L. S., Stocks, P. A., & Bachi, M. D. (2006). Diels-Alder/thiol-olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore. Bioorganic and Medicinal Chemistry Letters, 16(11), 2991-2995. https://doi.org/10.1016/j.bmcl.2006.02.059

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title = "Diels-Alder/thiol-olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore",

abstract = "A Diels-Alder/thiol-olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a-22b is reported. Some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of the synthetic antimalarial agent arteflene. Iron(II)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with TEMPO provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. Reactive C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides.",

keywords = "Arteflene, Artemisinin, Endoperoxide, Malaria, Mechanism of action",

author = "O'Neill, {Paul M.} and Edite Verissimo and Ward, {Stephen A.} and Jill Davies and Korshin, {Edward E.} and Nuna Araujo and Pugh, {Matthew D.} and Cristiano, {M. Lurdes S.} and Stocks, {Paul A.} and Bachi, {Mario D.}",

note = "Funding Information: The authors thank the EPSRC (M.P.), the BBSRC (S.A.W., P.O.N., P.A.S., Grants BB/C006321/1 and 26/B13581) and the FCT (Funda{\c c}{\~a}o para a Ci{\^e}ncia e a Tecnologia) Portugal, for funding this work. We also thank Dr. J. L. Maggs (Department of Pharmacology, University of Liverpool) for carrying out the LCMS study on analogue 19b .",

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O'Neill, PM, Verissimo, E, Ward, SA, Davies, J, Korshin, EE, Araujo, N, Pugh, MD, Cristiano, MLS, Stocks, PA & Bachi, MD 2006, 'Diels-Alder/thiol-olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore', Bioorganic and Medicinal Chemistry Letters, vol. 16, no. 11, pp. 2991-2995. https://doi.org/10.1016/j.bmcl.2006.02.059

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AU - Verissimo, Edite

AU - Ward, Stephen A.

AU - Davies, Jill

AU - Korshin, Edward E.

AU - Araujo, Nuna

AU - Pugh, Matthew D.

AU - Cristiano, M. Lurdes S.

AU - Stocks, Paul A.

AU - Bachi, Mario D.

N1 - Funding Information: The authors thank the EPSRC (M.P.), the BBSRC (S.A.W., P.O.N., P.A.S., Grants BB/C006321/1 and 26/B13581) and the FCT (Fundação para a Ciência e a Tecnologia) Portugal, for funding this work. We also thank Dr. J. L. Maggs (Department of Pharmacology, University of Liverpool) for carrying out the LCMS study on analogue 19b .

PY - 2006/6/1

Y1 - 2006/6/1

N2 - A Diels-Alder/thiol-olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a-22b is reported. Some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of the synthetic antimalarial agent arteflene. Iron(II)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with TEMPO provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. Reactive C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides.

AB - A Diels-Alder/thiol-olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a-22b is reported. Some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of the synthetic antimalarial agent arteflene. Iron(II)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with TEMPO provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. Reactive C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides.

KW - Arteflene

KW - Artemisinin

KW - Endoperoxide

KW - Malaria

KW - Mechanism of action

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SN - 0960-894X

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ER -

Diels-Alder/thiol-olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

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