2,4-diaminopyrimidines as inhibitors of Leishmanial and Trypanosomal dihydrofolate reductase

Didier Pez; Isabel Leal; Fabio Zuccotto; Cyrille Boussard; Reto Brun; Simon L. Croft; Vanessa Yardley; Luis M. Ruiz Perez; Dolores Gonzalez  Pacanowska; Ian H.  Gilbert

doi:10.1016/j.bmc.2003.08.012

2,4-diaminopyrimidines as inhibitors of Leishmanial and Trypanosomal dihydrofolate reductase

Didier Pez, Isabel Leal, Fabio Zuccotto, Cyrille Boussard, Reto Brun, Simon L. Croft, Vanessa Yardley, Luis M. Ruiz Perez, Dolores Gonzalez Pacanowska, Ian H. Gilbert (Lead / Corresponding author)

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56 Citations (Scopus)

Abstract

This paper describes the synthesis of 4'-substituted and 3,4'-disubstituted 5-benzyl-2,4-diaminopyrimidines as selective inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Compounds were then assayed against the recombinant parasite and human enzymes. Some of the compounds showed good activity. They were also tested against the intact parasites using in vitro assays. Good activity was found against Trypanosoma cruzi, moderate activity against Trypanosoma brucei and Leishmania donovani. Molecular modeling was undertaken to explain the results. The leishmanial enzyme was found to have a more extensive lipophilic binding region in the active site than the human enzyme. Compounds which bound within the pocket showed the highest selectivity. (C) 2003 Elsevier Ltd. All rights reserved.

Original language	English
Pages (from-to)	4693-4711
Number of pages	19
Journal	Bioorganic & Medicinal Chemistry
Volume	11
Issue number	22
Early online date	22 Sept 2003
DOIs	https://doi.org/10.1016/j.bmc.2003.08.012
Publication status	Published - 3 Nov 2003

Keywords

Animals
Binding sites
Cells, Cultured
Folic acid antagonists
Humans
Leishmania donovani
Leishmania major
Macrophages, Peritoneal
Mice
Mice, Inbred BALB C
Models, Molecular
Muscle, Skeletal
Pyrimidines
Rats
Recombinant proteins
Structure-activity relationship
Tetrahydrofolate dehydrogenase
Trypanocidal agents
Trypanosoma brucei rhodesiense
Trypanosoma cruzi
Journal article

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10.1016/j.bmc.2003.08.012

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title = "2,4-diaminopyrimidines as inhibitors of Leishmanial and Trypanosomal dihydrofolate reductase",

abstract = "This paper describes the synthesis of 4'-substituted and 3,4'-disubstituted 5-benzyl-2,4-diaminopyrimidines as selective inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Compounds were then assayed against the recombinant parasite and human enzymes. Some of the compounds showed good activity. They were also tested against the intact parasites using in vitro assays. Good activity was found against Trypanosoma cruzi, moderate activity against Trypanosoma brucei and Leishmania donovani. Molecular modeling was undertaken to explain the results. The leishmanial enzyme was found to have a more extensive lipophilic binding region in the active site than the human enzyme. Compounds which bound within the pocket showed the highest selectivity. (C) 2003 Elsevier Ltd. All rights reserved.",

keywords = "Animals, Binding sites, Cells, Cultured, Folic acid antagonists, Humans, Leishmania donovani, Leishmania major, Macrophages, Peritoneal, Mice, Mice, Inbred BALB C, Models, Molecular, Muscle, Skeletal, Pyrimidines, Rats, Recombinant proteins, Structure-activity relationship, Tetrahydrofolate dehydrogenase, Trypanocidal agents, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Journal article",

author = "Didier Pez and Isabel Leal and Fabio Zuccotto and Cyrille Boussard and Reto Brun and Croft, {Simon L.} and Vanessa Yardley and Perez, {Luis M. Ruiz} and Pacanowska, {Dolores Gonzalez} and Gilbert, {Ian H.}",

year = "2003",

month = nov,

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doi = "10.1016/j.bmc.2003.08.012",

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AU - Pez, Didier

AU - Leal, Isabel

AU - Zuccotto, Fabio

AU - Boussard, Cyrille

AU - Brun, Reto

AU - Croft, Simon L.

AU - Yardley, Vanessa

AU - Perez, Luis M. Ruiz

AU - Pacanowska, Dolores Gonzalez

AU - Gilbert, Ian H.

PY - 2003/11/3

Y1 - 2003/11/3

N2 - This paper describes the synthesis of 4'-substituted and 3,4'-disubstituted 5-benzyl-2,4-diaminopyrimidines as selective inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Compounds were then assayed against the recombinant parasite and human enzymes. Some of the compounds showed good activity. They were also tested against the intact parasites using in vitro assays. Good activity was found against Trypanosoma cruzi, moderate activity against Trypanosoma brucei and Leishmania donovani. Molecular modeling was undertaken to explain the results. The leishmanial enzyme was found to have a more extensive lipophilic binding region in the active site than the human enzyme. Compounds which bound within the pocket showed the highest selectivity. (C) 2003 Elsevier Ltd. All rights reserved.

AB - This paper describes the synthesis of 4'-substituted and 3,4'-disubstituted 5-benzyl-2,4-diaminopyrimidines as selective inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Compounds were then assayed against the recombinant parasite and human enzymes. Some of the compounds showed good activity. They were also tested against the intact parasites using in vitro assays. Good activity was found against Trypanosoma cruzi, moderate activity against Trypanosoma brucei and Leishmania donovani. Molecular modeling was undertaken to explain the results. The leishmanial enzyme was found to have a more extensive lipophilic binding region in the active site than the human enzyme. Compounds which bound within the pocket showed the highest selectivity. (C) 2003 Elsevier Ltd. All rights reserved.

KW - Animals

KW - Binding sites

KW - Cells, Cultured

KW - Folic acid antagonists

KW - Humans

KW - Leishmania donovani

KW - Leishmania major

KW - Macrophages, Peritoneal

KW - Mice

KW - Mice, Inbred BALB C

KW - Models, Molecular

KW - Muscle, Skeletal

KW - Pyrimidines

KW - Rats

KW - Recombinant proteins

KW - Structure-activity relationship

KW - Tetrahydrofolate dehydrogenase

KW - Trypanocidal agents

KW - Trypanosoma brucei rhodesiense

KW - Trypanosoma cruzi

KW - Journal article

U2 - 10.1016/j.bmc.2003.08.012

DO - 10.1016/j.bmc.2003.08.012

M3 - Article

C2 - 14556785

SN - 0968-0896

VL - 11

SP - 4693

EP - 4711

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 22

ER -

2,4-diaminopyrimidines as inhibitors of Leishmanial and Trypanosomal dihydrofolate reductase

Abstract

Keywords

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