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

11 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

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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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

@article{3a21ca2721214171aa81e8a35524225d,

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,

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

language = "English",

volume = "58",

pages = "7938--7948",

journal = "Journal of Medicinal Chemistry",

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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

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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DO - 10.1021/acs.jmedchem.5b00687

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C2 - 26322631

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SN - 0022-2623

VL - 58

SP - 7938

EP - 7948

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

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

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)

Hunter, Bill

Cite this

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

ASJC Scopus subject areas

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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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