Stereochemical modification of geminal dialkyl substituents on pantothenamides alters antimicrobial activity

Annabelle Hoegl; Hamed Darabi; Elisa Tran; Emelia Awuah; Eleanor S.C. Kerdo; Eric Habib; Kevin J. Saliba; Karine Auclair

doi:10.1016/j.bmcl.2014.06.013

Stereochemical modification of geminal dialkyl substituents on pantothenamides alters antimicrobial activity

Annabelle Hoegl, Hamed Darabi, Elisa Tran, Emelia Awuah, Eleanor S.C. Kerdo, Eric Habib, Kevin J. Saliba, Karine Auclair^*

^*Corresponding author for this work

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

18 Citations (Scopus)

Abstract

Pantothenamides are N-substituted pantothenate derivatives which are known to exert antimicrobial activity through interference with coenzyme A (CoA) biosynthesis or downstream CoA-utilizing proteins. A previous report has shown that replacement of the ProR methyl group of the benchmark N- pentylpantothenamide with an allyl group (R-anti configuration) yielded one of the most potent antibacterial pantothenamides reported so far (MIC of 3.2 μM for both sensitive and resistant Staphylococcus aureus). We describe herein a synthetic route for accessing the corresponding R-syn diastereomer using a key diastereoselective reduction with Baker's yeast, and report on the scope of this reaction for modified systems. Interestingly, whilst the R-anti diastereomer is the only one to show antibacterial activity, the R-syn isomer proved to be significantly more potent against the malaria parasite (IC₅₀ of 2.4 ± 0.2 μM). Our research underlines the striking influence that stereochemistry has on the biological activity of pantothenamides, and may find utility in the study of various CoA-utilizing systems.

Original language	English
Pages (from-to)	3274-3277
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	15
DOIs	https://doi.org/10.1016/j.bmcl.2014.06.013
Publication status	Published - 1 Aug 2014

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title = "Stereochemical modification of geminal dialkyl substituents on pantothenamides alters antimicrobial activity",

abstract = "Pantothenamides are N-substituted pantothenate derivatives which are known to exert antimicrobial activity through interference with coenzyme A (CoA) biosynthesis or downstream CoA-utilizing proteins. A previous report has shown that replacement of the ProR methyl group of the benchmark N- pentylpantothenamide with an allyl group (R-anti configuration) yielded one of the most potent antibacterial pantothenamides reported so far (MIC of 3.2 μM for both sensitive and resistant Staphylococcus aureus). We describe herein a synthetic route for accessing the corresponding R-syn diastereomer using a key diastereoselective reduction with Baker's yeast, and report on the scope of this reaction for modified systems. Interestingly, whilst the R-anti diastereomer is the only one to show antibacterial activity, the R-syn isomer proved to be significantly more potent against the malaria parasite (IC50 of 2.4 ± 0.2 μM). Our research underlines the striking influence that stereochemistry has on the biological activity of pantothenamides, and may find utility in the study of various CoA-utilizing systems.",

keywords = "Antibacterial, Antiplasmodial, Baker's yeast, Coenzyme A, Pantothenamides",

author = "Annabelle Hoegl and Hamed Darabi and Elisa Tran and Emelia Awuah and Kerdo, {Eleanor S.C.} and Eric Habib and Saliba, {Kevin J.} and Karine Auclair",

year = "2014",

month = aug,

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doi = "10.1016/j.bmcl.2014.06.013",

language = "English",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Stereochemical modification of geminal dialkyl substituents on pantothenamides alters antimicrobial activity

AU - Hoegl, Annabelle

AU - Darabi, Hamed

AU - Tran, Elisa

AU - Awuah, Emelia

AU - Kerdo, Eleanor S.C.

AU - Habib, Eric

AU - Saliba, Kevin J.

AU - Auclair, Karine

PY - 2014/8/1

Y1 - 2014/8/1

N2 - Pantothenamides are N-substituted pantothenate derivatives which are known to exert antimicrobial activity through interference with coenzyme A (CoA) biosynthesis or downstream CoA-utilizing proteins. A previous report has shown that replacement of the ProR methyl group of the benchmark N- pentylpantothenamide with an allyl group (R-anti configuration) yielded one of the most potent antibacterial pantothenamides reported so far (MIC of 3.2 μM for both sensitive and resistant Staphylococcus aureus). We describe herein a synthetic route for accessing the corresponding R-syn diastereomer using a key diastereoselective reduction with Baker's yeast, and report on the scope of this reaction for modified systems. Interestingly, whilst the R-anti diastereomer is the only one to show antibacterial activity, the R-syn isomer proved to be significantly more potent against the malaria parasite (IC50 of 2.4 ± 0.2 μM). Our research underlines the striking influence that stereochemistry has on the biological activity of pantothenamides, and may find utility in the study of various CoA-utilizing systems.

AB - Pantothenamides are N-substituted pantothenate derivatives which are known to exert antimicrobial activity through interference with coenzyme A (CoA) biosynthesis or downstream CoA-utilizing proteins. A previous report has shown that replacement of the ProR methyl group of the benchmark N- pentylpantothenamide with an allyl group (R-anti configuration) yielded one of the most potent antibacterial pantothenamides reported so far (MIC of 3.2 μM for both sensitive and resistant Staphylococcus aureus). We describe herein a synthetic route for accessing the corresponding R-syn diastereomer using a key diastereoselective reduction with Baker's yeast, and report on the scope of this reaction for modified systems. Interestingly, whilst the R-anti diastereomer is the only one to show antibacterial activity, the R-syn isomer proved to be significantly more potent against the malaria parasite (IC50 of 2.4 ± 0.2 μM). Our research underlines the striking influence that stereochemistry has on the biological activity of pantothenamides, and may find utility in the study of various CoA-utilizing systems.

KW - Antibacterial

KW - Antiplasmodial

KW - Baker's yeast

KW - Coenzyme A

KW - Pantothenamides

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U2 - 10.1016/j.bmcl.2014.06.013

DO - 10.1016/j.bmcl.2014.06.013

M3 - Article

SN - 0960-894X

VL - 24

SP - 3274

EP - 3277

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 15

ER -

Stereochemical modification of geminal dialkyl substituents on pantothenamides alters antimicrobial activity

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