Discovery of pyridyl-based inhibitors of Plasmodium falciparum N-myristoyltransferase

Zhiyong Yu; James A. Brannigan; Kaveri Rangachari; William P. Heal; Anthony J. Wilkinson; Anthony A. Holder; Robin J. Leatherbarrow; Edward W. Tate

doi:10.1039/c5md00242g

Discovery of pyridyl-based inhibitors of Plasmodium falciparum N-myristoyltransferase

Zhiyong Yu, James A. Brannigan, Kaveri Rangachari, William P. Heal, Anthony J. Wilkinson, Anthony A. Holder, Robin J. Leatherbarrow, Edward W. Tate^*

^*Corresponding author for this work

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

Abstract

N-Myristoyltransferase (NMT) represents an attractive drug target in parasitic infections such as malaria due to its genetic essentiality and amenability to inhibition by drug-like small molecules. Scaffold simplification from previously reported inhibitors containing bicyclic cores identified phenyl derivative 3, providing a versatile platform to study the effects of substitution on the scaffold, which yielded pyridyl 19. This molecule exhibited improved enzyme and cellular potency, and reduced lipophilicity compared to inhibitor 3. Further structure-based inhibitor design led to the discovery of 30, the most potent inhibitor in this series, which showed single-digit nM enzyme affinity and sub-μM anti-plasmodial activity.

Original language	English
Pages (from-to)	1767-1772
Number of pages	6
Journal	MedChemComm
Volume	6
Issue number	10
DOIs	https://doi.org/10.1039/c5md00242g
Publication status	Published - 17 Aug 2015

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title = "Discovery of pyridyl-based inhibitors of Plasmodium falciparum N-myristoyltransferase",

abstract = "N-Myristoyltransferase (NMT) represents an attractive drug target in parasitic infections such as malaria due to its genetic essentiality and amenability to inhibition by drug-like small molecules. Scaffold simplification from previously reported inhibitors containing bicyclic cores identified phenyl derivative 3, providing a versatile platform to study the effects of substitution on the scaffold, which yielded pyridyl 19. This molecule exhibited improved enzyme and cellular potency, and reduced lipophilicity compared to inhibitor 3. Further structure-based inhibitor design led to the discovery of 30, the most potent inhibitor in this series, which showed single-digit nM enzyme affinity and sub-μM anti-plasmodial activity.",

author = "Zhiyong Yu and Brannigan, {James A.} and Kaveri Rangachari and Heal, {William P.} and Wilkinson, {Anthony J.} and Holder, {Anthony A.} and Leatherbarrow, {Robin J.} and Tate, {Edward W.}",

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AU - Yu, Zhiyong

AU - Brannigan, James A.

AU - Rangachari, Kaveri

AU - Heal, William P.

AU - Wilkinson, Anthony J.

AU - Holder, Anthony A.

AU - Leatherbarrow, Robin J.

AU - Tate, Edward W.

PY - 2015/8/17

Y1 - 2015/8/17

N2 - N-Myristoyltransferase (NMT) represents an attractive drug target in parasitic infections such as malaria due to its genetic essentiality and amenability to inhibition by drug-like small molecules. Scaffold simplification from previously reported inhibitors containing bicyclic cores identified phenyl derivative 3, providing a versatile platform to study the effects of substitution on the scaffold, which yielded pyridyl 19. This molecule exhibited improved enzyme and cellular potency, and reduced lipophilicity compared to inhibitor 3. Further structure-based inhibitor design led to the discovery of 30, the most potent inhibitor in this series, which showed single-digit nM enzyme affinity and sub-μM anti-plasmodial activity.

AB - N-Myristoyltransferase (NMT) represents an attractive drug target in parasitic infections such as malaria due to its genetic essentiality and amenability to inhibition by drug-like small molecules. Scaffold simplification from previously reported inhibitors containing bicyclic cores identified phenyl derivative 3, providing a versatile platform to study the effects of substitution on the scaffold, which yielded pyridyl 19. This molecule exhibited improved enzyme and cellular potency, and reduced lipophilicity compared to inhibitor 3. Further structure-based inhibitor design led to the discovery of 30, the most potent inhibitor in this series, which showed single-digit nM enzyme affinity and sub-μM anti-plasmodial activity.

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DO - 10.1039/c5md00242g

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VL - 6

SP - 1767

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JO - MedChemComm

JF - MedChemComm

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Discovery of pyridyl-based inhibitors of Plasmodium falciparum N-myristoyltransferase

Abstract

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