Synthesis of acyclic nucleoside phosphonates targeting flavin-dependent thymidylate synthase in Mycobacterium tuberculosis

Nicolas G. Biteau; Vincent Roy; Jean Christophe Lambry; Hubert F. Becker; Hannu Myllykallio; Luigi A. Agrofoglio

doi:10.1016/j.bmc.2021.116351

Synthesis of acyclic nucleoside phosphonates targeting flavin-dependent thymidylate synthase in Mycobacterium tuberculosis

Nicolas G. Biteau
, Vincent Roy
, Jean Christophe Lambry
, Hubert F. Becker
, Hannu Myllykallio
, Luigi A. Agrofoglio

conventionnée avec l'Université d'Orléans

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

Abstract

Flavin-Dependent Thymidylate Synthase (FDTS) encoded by ThyX gene was discovered as a new class of thymidylate synthase involved in the de novo synthesis of dTMP named only in 30 % of human pathogenic bacteria. This target was pursed for the development of new antibacterial agents against multiresistant pathogens. We have developed a new class of ANPs based on the mimic of two natural's cofactors (dUMP and FAD) as inhibitors against Mycobacterium tuberculosis ThyX. Several synthetic efforts were performed to optimize regioselective N1-alkylation, cross-coupling metathesis and Sonogashira cross-coupling. Compound 19c showed a poor 31.8% inhibitory effect on ThyX at 200 μM.

Original language	English
Article number	116351
Journal	Bioorganic and Medicinal Chemistry
Volume	46
DOIs	https://doi.org/10.1016/j.bmc.2021.116351
Publication status	Published - 15 Sept 2021

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Acyclic nucleoside phosphonate
Flavin-dependent thymidylate synthase
Ruthenium-catalyzed cross-metathesis
Sonogashira cross-coupling

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10.1016/j.bmc.2021.116351

Cite this

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title = "Synthesis of acyclic nucleoside phosphonates targeting flavin-dependent thymidylate synthase in Mycobacterium tuberculosis",

abstract = "Flavin-Dependent Thymidylate Synthase (FDTS) encoded by ThyX gene was discovered as a new class of thymidylate synthase involved in the de novo synthesis of dTMP named only in 30 \% of human pathogenic bacteria. This target was pursed for the development of new antibacterial agents against multiresistant pathogens. We have developed a new class of ANPs based on the mimic of two natural's cofactors (dUMP and FAD) as inhibitors against Mycobacterium tuberculosis ThyX. Several synthetic efforts were performed to optimize regioselective N1-alkylation, cross-coupling metathesis and Sonogashira cross-coupling. Compound 19c showed a poor 31.8\% inhibitory effect on ThyX at 200 μM.",

keywords = "Acyclic nucleoside phosphonate, Flavin-dependent thymidylate synthase, Ruthenium-catalyzed cross-metathesis, Sonogashira cross-coupling",

author = "Biteau, \{Nicolas G.\} and Vincent Roy and Lambry, \{Jean Christophe\} and Becker, \{Hubert F.\} and Hannu Myllykallio and Agrofoglio, \{Luigi A.\}",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",

year = "2021",

month = sep,

day = "15",

doi = "10.1016/j.bmc.2021.116351",

language = "English",

volume = "46",

journal = "Bioorganic and Medicinal Chemistry",

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}

TY - JOUR

T1 - Synthesis of acyclic nucleoside phosphonates targeting flavin-dependent thymidylate synthase in Mycobacterium tuberculosis

AU - Biteau, Nicolas G.

AU - Roy, Vincent

AU - Lambry, Jean Christophe

AU - Becker, Hubert F.

AU - Myllykallio, Hannu

AU - Agrofoglio, Luigi A.

PY - 2021/9/15

Y1 - 2021/9/15

N2 - Flavin-Dependent Thymidylate Synthase (FDTS) encoded by ThyX gene was discovered as a new class of thymidylate synthase involved in the de novo synthesis of dTMP named only in 30 % of human pathogenic bacteria. This target was pursed for the development of new antibacterial agents against multiresistant pathogens. We have developed a new class of ANPs based on the mimic of two natural's cofactors (dUMP and FAD) as inhibitors against Mycobacterium tuberculosis ThyX. Several synthetic efforts were performed to optimize regioselective N1-alkylation, cross-coupling metathesis and Sonogashira cross-coupling. Compound 19c showed a poor 31.8% inhibitory effect on ThyX at 200 μM.

AB - Flavin-Dependent Thymidylate Synthase (FDTS) encoded by ThyX gene was discovered as a new class of thymidylate synthase involved in the de novo synthesis of dTMP named only in 30 % of human pathogenic bacteria. This target was pursed for the development of new antibacterial agents against multiresistant pathogens. We have developed a new class of ANPs based on the mimic of two natural's cofactors (dUMP and FAD) as inhibitors against Mycobacterium tuberculosis ThyX. Several synthetic efforts were performed to optimize regioselective N1-alkylation, cross-coupling metathesis and Sonogashira cross-coupling. Compound 19c showed a poor 31.8% inhibitory effect on ThyX at 200 μM.

KW - Acyclic nucleoside phosphonate

KW - Flavin-dependent thymidylate synthase

KW - Ruthenium-catalyzed cross-metathesis

KW - Sonogashira cross-coupling

U2 - 10.1016/j.bmc.2021.116351

DO - 10.1016/j.bmc.2021.116351

M3 - Article

C2 - 34391120

AN - SCOPUS:85112388917

SN - 0968-0896

VL - 46

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

M1 - 116351

ER -

Synthesis of acyclic nucleoside phosphonates targeting flavin-dependent thymidylate synthase in Mycobacterium tuberculosis

Abstract

UN SDGs

Keywords

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