Structure-based bioisosteric design, synthesis and biological evaluation of novel pyrimidines as antiplasmodial antifolate agents

Moaz M. Abdou; Paul M. O'Neill; Eric Amigues; Magdalini Matziari

doi:10.1016/j.jscs.2022.101539

Structure-based bioisosteric design, synthesis and biological evaluation of novel pyrimidines as antiplasmodial antifolate agents

Moaz M. Abdou^*, Paul M. O'Neill, Eric Amigues, Magdalini Matziari

^*Corresponding author for this work

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

5 Citations (Scopus)

Abstract

The efficacy of most marketed antimalarial drugs has been compromised by the development of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. This article describes the synthesis and the in vitro antimalarial profiling of antifolate P218 analogues, by exploring a bioisosteric replacement of the carboxylic group by a phosphinic moiety as well as structural isomerization of P218. The detailed synthetic route employed to access the title compounds is described. The listed compounds exhibited low antimalarial activity against drug-resistant strains of P. falciparum including chloroquine-resistant W2.

Original language	English
Article number	101539
Journal	Journal of Saudi Chemical Society
Volume	26
Issue number	6
DOIs	https://doi.org/10.1016/j.jscs.2022.101539
Publication status	Published - Nov 2022

Keywords

2,4-Diaminopyrimidines
Antimalarial
Bioisosterism
Malarial dihydrofolate reductase
P218
Phosphinic acid

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10.1016/j.jscs.2022.101539

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title = "Structure-based bioisosteric design, synthesis and biological evaluation of novel pyrimidines as antiplasmodial antifolate agents",

abstract = "The efficacy of most marketed antimalarial drugs has been compromised by the development of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. This article describes the synthesis and the in vitro antimalarial profiling of antifolate P218 analogues, by exploring a bioisosteric replacement of the carboxylic group by a phosphinic moiety as well as structural isomerization of P218. The detailed synthetic route employed to access the title compounds is described. The listed compounds exhibited low antimalarial activity against drug-resistant strains of P. falciparum including chloroquine-resistant W2.",

keywords = "2,4-Diaminopyrimidines, Antimalarial, Bioisosterism, Malarial dihydrofolate reductase, P218, Phosphinic acid",

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note = "Funding Information: This work was financially supported by the Key Program Special Fund in XJTLU (KSF E-52). The authors express their appreciation and gratitude to Dr. Jenny Legac, University of California, for doing biological evaluation. Publisher Copyright: {\textcopyright} 2022 The Authors",

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doi = "10.1016/j.jscs.2022.101539",

language = "English",

volume = "26",

journal = "Journal of Saudi Chemical Society",

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AU - Abdou, Moaz M.

AU - O'Neill, Paul M.

AU - Amigues, Eric

AU - Matziari, Magdalini

N1 - Funding Information: This work was financially supported by the Key Program Special Fund in XJTLU (KSF E-52). The authors express their appreciation and gratitude to Dr. Jenny Legac, University of California, for doing biological evaluation. Publisher Copyright: © 2022 The Authors

PY - 2022/11

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N2 - The efficacy of most marketed antimalarial drugs has been compromised by the development of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. This article describes the synthesis and the in vitro antimalarial profiling of antifolate P218 analogues, by exploring a bioisosteric replacement of the carboxylic group by a phosphinic moiety as well as structural isomerization of P218. The detailed synthetic route employed to access the title compounds is described. The listed compounds exhibited low antimalarial activity against drug-resistant strains of P. falciparum including chloroquine-resistant W2.

AB - The efficacy of most marketed antimalarial drugs has been compromised by the development of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. This article describes the synthesis and the in vitro antimalarial profiling of antifolate P218 analogues, by exploring a bioisosteric replacement of the carboxylic group by a phosphinic moiety as well as structural isomerization of P218. The detailed synthetic route employed to access the title compounds is described. The listed compounds exhibited low antimalarial activity against drug-resistant strains of P. falciparum including chloroquine-resistant W2.

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KW - Bioisosterism

KW - Malarial dihydrofolate reductase

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KW - Phosphinic acid

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DO - 10.1016/j.jscs.2022.101539

M3 - Article

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SN - 1319-6103

VL - 26

JO - Journal of Saudi Chemical Society

JF - Journal of Saudi Chemical Society

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M1 - 101539

ER -

Structure-based bioisosteric design, synthesis and biological evaluation of novel pyrimidines as antiplasmodial antifolate agents

Abstract

Keywords

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