Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido based inhibitors of Trypanosoma brucei FolD and testing for antiparasitic activity

Thomas C. Eadsforth; Andrea Pinto; Rosaria Luciani; Lucia Tamborini; Gregorio Cullia; Carlo De Micheli; Luciana Marinelli; Sandro Cosconati; Ettore Novellino; Leonardo Lo Presti; Anabela Cordeiro Da Silva; Paola Conti; William N. Hunter; Maria P. Costi

doi:10.1021/acs.jmedchem.5b00687

Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido based inhibitors of Trypanosoma brucei FolD and testing for antiparasitic activity

Thomas C. Eadsforth, Andrea Pinto, Rosaria Luciani, Lucia Tamborini, Gregorio Cullia, Carlo De Micheli, Luciana Marinelli, Sandro Cosconati, Ettore Novellino, Leonardo Lo Presti, Anabela Cordeiro Da Silva, Paola Conti (Lead / Corresponding author), William N. Hunter (Lead / Corresponding author), Maria P. Costi (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

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

9 Citations (Scopus)

Abstract

The bifunctional enzyme N⁵,N¹⁰-methylenetetrahydrofolate dehydrogenase/cyclo hydrolase (FolD) is essential for growth in Trypanosomatidae. We sought to develop inhibitors of Trypanosoma brucei FolD (TbFolD) as potential antiparasitic agents. Compound 2 was synthesized, and the molecular structure was unequivocally assigned through X-ray crystallography of the intermediate compound 3. Compound 2 showed an IC₅₀ of 2.2 μM, against TbFolD and displayed antiparasitic activity against T. brucei (IC₅₀ 49 μM). Using compound 2, we were able to obtain the first X-ray structure of TbFolD in the presence of NADP⁺ and the inhibitor, which then guided the rational design of a new series of potent TbFolD inhibitors.

Original language	English
Pages (from-to)	7938-7948
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	20
Early online date	31 Aug 2015
DOIs	https://doi.org/10.1021/acs.jmedchem.5b00687
Publication status	Published - 22 Oct 2015

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10.1021/acs.jmedchem.5b00687

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Eadsforth, T. C., Pinto, A., Luciani, R., Tamborini, L., Cullia, G., De Micheli, C., Marinelli, L., Cosconati, S., Novellino, E., Lo Presti, L., Cordeiro Da Silva, A., Conti, P., Hunter, W. N., & Costi, M. P. (2015). Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido based inhibitors of Trypanosoma brucei FolD and testing for antiparasitic activity. Journal of Medicinal Chemistry, 58(20), 7938-7948. https://doi.org/10.1021/acs.jmedchem.5b00687

Eadsforth, Thomas C. ; Pinto, Andrea ; Luciani, Rosaria ; Tamborini, Lucia ; Cullia, Gregorio ; De Micheli, Carlo ; Marinelli, Luciana ; Cosconati, Sandro ; Novellino, Ettore ; Lo Presti, Leonardo ; Cordeiro Da Silva, Anabela ; Conti, Paola ; Hunter, William N. ; Costi, Maria P. / Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido based inhibitors of Trypanosoma brucei FolD and testing for antiparasitic activity. In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 20. pp. 7938-7948.

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title = "Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido based inhibitors of Trypanosoma brucei FolD and testing for antiparasitic activity",

abstract = "The bifunctional enzyme N5,N10-methylenetetrahydrofolate dehydrogenase/cyclo hydrolase (FolD) is essential for growth in Trypanosomatidae. We sought to develop inhibitors of Trypanosoma brucei FolD (TbFolD) as potential antiparasitic agents. Compound 2 was synthesized, and the molecular structure was unequivocally assigned through X-ray crystallography of the intermediate compound 3. Compound 2 showed an IC50 of 2.2 μM, against TbFolD and displayed antiparasitic activity against T. brucei (IC50 49 μM). Using compound 2, we were able to obtain the first X-ray structure of TbFolD in the presence of NADP+ and the inhibitor, which then guided the rational design of a new series of potent TbFolD inhibitors.",

author = "Eadsforth, {Thomas C.} and Andrea Pinto and Rosaria Luciani and Lucia Tamborini and Gregorio Cullia and {De Micheli}, Carlo and Luciana Marinelli and Sandro Cosconati and Ettore Novellino and {Lo Presti}, Leonardo and {Cordeiro Da Silva}, Anabela and Paola Conti and Hunter, {William N.} and Costi, {Maria P.}",

year = "2015",

month = oct,

day = "22",

doi = "10.1021/acs.jmedchem.5b00687",

language = "English",

volume = "58",

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Eadsforth, TC, Pinto, A, Luciani, R, Tamborini, L, Cullia, G, De Micheli, C, Marinelli, L, Cosconati, S, Novellino, E, Lo Presti, L, Cordeiro Da Silva, A, Conti, P, Hunter, WN & Costi, MP 2015, 'Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido based inhibitors of Trypanosoma brucei FolD and testing for antiparasitic activity', Journal of Medicinal Chemistry, vol. 58, no. 20, pp. 7938-7948. https://doi.org/10.1021/acs.jmedchem.5b00687

Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido based inhibitors of Trypanosoma brucei FolD and testing for antiparasitic activity. / Eadsforth, Thomas C.; Pinto, Andrea; Luciani, Rosaria; Tamborini, Lucia; Cullia, Gregorio; De Micheli, Carlo; Marinelli, Luciana; Cosconati, Sandro; Novellino, Ettore; Lo Presti, Leonardo; Cordeiro Da Silva, Anabela; Conti, Paola (Lead / Corresponding author); Hunter, William N. (Lead / Corresponding author); Costi, Maria P. (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 58, No. 20, 22.10.2015, p. 7938-7948.

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

TY - JOUR

T1 - Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido based inhibitors of Trypanosoma brucei FolD and testing for antiparasitic activity

AU - Eadsforth, Thomas C.

AU - Pinto, Andrea

AU - Luciani, Rosaria

AU - Tamborini, Lucia

AU - Cullia, Gregorio

AU - De Micheli, Carlo

AU - Marinelli, Luciana

AU - Cosconati, Sandro

AU - Novellino, Ettore

AU - Lo Presti, Leonardo

AU - Cordeiro Da Silva, Anabela

AU - Conti, Paola

AU - Hunter, William N.

AU - Costi, Maria P.

PY - 2015/10/22

Y1 - 2015/10/22

N2 - The bifunctional enzyme N5,N10-methylenetetrahydrofolate dehydrogenase/cyclo hydrolase (FolD) is essential for growth in Trypanosomatidae. We sought to develop inhibitors of Trypanosoma brucei FolD (TbFolD) as potential antiparasitic agents. Compound 2 was synthesized, and the molecular structure was unequivocally assigned through X-ray crystallography of the intermediate compound 3. Compound 2 showed an IC50 of 2.2 μM, against TbFolD and displayed antiparasitic activity against T. brucei (IC50 49 μM). Using compound 2, we were able to obtain the first X-ray structure of TbFolD in the presence of NADP+ and the inhibitor, which then guided the rational design of a new series of potent TbFolD inhibitors.

AB - The bifunctional enzyme N5,N10-methylenetetrahydrofolate dehydrogenase/cyclo hydrolase (FolD) is essential for growth in Trypanosomatidae. We sought to develop inhibitors of Trypanosoma brucei FolD (TbFolD) as potential antiparasitic agents. Compound 2 was synthesized, and the molecular structure was unequivocally assigned through X-ray crystallography of the intermediate compound 3. Compound 2 showed an IC50 of 2.2 μM, against TbFolD and displayed antiparasitic activity against T. brucei (IC50 49 μM). Using compound 2, we were able to obtain the first X-ray structure of TbFolD in the presence of NADP+ and the inhibitor, which then guided the rational design of a new series of potent TbFolD inhibitors.

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U2 - 10.1021/acs.jmedchem.5b00687

DO - 10.1021/acs.jmedchem.5b00687

M3 - Article

C2 - 26322631

AN - SCOPUS:84945433856

VL - 58

SP - 7938

EP - 7948

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 20

ER -

Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido based inhibitors of Trypanosoma brucei FolD and testing for antiparasitic activity

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State-of-the-Art Facilities for Structural Biology at the University of Dundee

Aref#d: 19401. Structure, specificity and mechanism of biosynthetic enzymes in trypanosomatids and inhibitor discovery of essential microbial functions (Programme Grant)

Hunter, Bill

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Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido based inhibitors of Trypanosoma brucei FolD and testing for antiparasitic activity

Abstract

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State-of-the-Art Facilities for Structural Biology at the University of Dundee

Aref#d: 19401. Structure, specificity and mechanism of biosynthetic enzymes in trypanosomatids and inhibitor discovery of essential microbial functions (Programme Grant)

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Hunter, Bill

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