Synthesis of spiro-1,2-dioxolanes and their activity against Plasmodium falciparum

Derek C. Martyn; Armando P. Ramirez; Meaghan J. Beattie; Joseph F. Cortese; Vishal Patel; Margaret A. Rush; K. A. Woerpel; Jon Clardy

doi:10.1016/j.bmcl.2008.10.083

Synthesis of spiro-1,2-dioxolanes and their activity against Plasmodium falciparum

Derek C. Martyn, Armando P. Ramirez, Meaghan J. Beattie, Joseph F. Cortese, Vishal Patel, Margaret A. Rush, K. A. Woerpel, Jon Clardy

Chemistry

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

Abstract

Artemisinin-derived compounds play an integral role in current malaria chemotherapy. Given the virtual certainty of emerging resistance, we have investigated spiro-1,2-dioxolanes as an alternative scaffold. The endoperoxide functionality was generated by the SnCl₄-mediated annulation of a bis-silylperoxide and an alkene. The first set of eight analogs gave EC₅₀ values of 50-150 nM against Plasmodium falciparum 3D7 and Dd2 strains, except for the carboxylic acid analog. A second series, synthesized by coupling a spiro-1,2-dioxolane carboxylic acid to four separate amines, afforded the most potent compound (EC₅₀ ∼5 nM).

Original language	English (US)
Pages (from-to)	6521-6524
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	24
DOIs	https://doi.org/10.1016/j.bmcl.2008.10.083
State	Published - Dec 15 2008

Keywords

Dioxolane
Endoperoxide
Malaria
Plasmodium

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2008.10.083

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title = "Synthesis of spiro-1,2-dioxolanes and their activity against Plasmodium falciparum",

abstract = "Artemisinin-derived compounds play an integral role in current malaria chemotherapy. Given the virtual certainty of emerging resistance, we have investigated spiro-1,2-dioxolanes as an alternative scaffold. The endoperoxide functionality was generated by the SnCl4-mediated annulation of a bis-silylperoxide and an alkene. The first set of eight analogs gave EC50 values of 50-150 nM against Plasmodium falciparum 3D7 and Dd2 strains, except for the carboxylic acid analog. A second series, synthesized by coupling a spiro-1,2-dioxolane carboxylic acid to four separate amines, afforded the most potent compound (EC50 ∼5 nM).",

keywords = "Dioxolane, Endoperoxide, Malaria, Plasmodium",

author = "Martyn, {Derek C.} and Ramirez, {Armando P.} and Beattie, {Meaghan J.} and Cortese, {Joseph F.} and Vishal Patel and Rush, {Margaret A.} and Woerpel, {K. A.} and Jon Clardy",

note = "Funding Information: The authors thank the Medicines for Malaria Venture (MMV) for financial support, and SPARC funding from the Broad Institute of MIT and Harvard. A.R. and K.A.W. thank the National Science Foundation (CHE-0315572) for support. ",

year = "2008",

month = dec,

day = "15",

doi = "10.1016/j.bmcl.2008.10.083",

language = "English (US)",

volume = "18",

pages = "6521--6524",

journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Synthesis of spiro-1,2-dioxolanes and their activity against Plasmodium falciparum

AU - Martyn, Derek C.

AU - Ramirez, Armando P.

AU - Beattie, Meaghan J.

AU - Cortese, Joseph F.

AU - Patel, Vishal

AU - Rush, Margaret A.

AU - Woerpel, K. A.

AU - Clardy, Jon

N1 - Funding Information: The authors thank the Medicines for Malaria Venture (MMV) for financial support, and SPARC funding from the Broad Institute of MIT and Harvard. A.R. and K.A.W. thank the National Science Foundation (CHE-0315572) for support.

PY - 2008/12/15

Y1 - 2008/12/15

N2 - Artemisinin-derived compounds play an integral role in current malaria chemotherapy. Given the virtual certainty of emerging resistance, we have investigated spiro-1,2-dioxolanes as an alternative scaffold. The endoperoxide functionality was generated by the SnCl4-mediated annulation of a bis-silylperoxide and an alkene. The first set of eight analogs gave EC50 values of 50-150 nM against Plasmodium falciparum 3D7 and Dd2 strains, except for the carboxylic acid analog. A second series, synthesized by coupling a spiro-1,2-dioxolane carboxylic acid to four separate amines, afforded the most potent compound (EC50 ∼5 nM).

AB - Artemisinin-derived compounds play an integral role in current malaria chemotherapy. Given the virtual certainty of emerging resistance, we have investigated spiro-1,2-dioxolanes as an alternative scaffold. The endoperoxide functionality was generated by the SnCl4-mediated annulation of a bis-silylperoxide and an alkene. The first set of eight analogs gave EC50 values of 50-150 nM against Plasmodium falciparum 3D7 and Dd2 strains, except for the carboxylic acid analog. A second series, synthesized by coupling a spiro-1,2-dioxolane carboxylic acid to four separate amines, afforded the most potent compound (EC50 ∼5 nM).

KW - Dioxolane

KW - Endoperoxide

KW - Malaria

KW - Plasmodium

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 24

ER -

Synthesis of spiro-1,2-dioxolanes and their activity against Plasmodium falciparum

Abstract

Keywords

ASJC Scopus subject areas

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