The structure-based design and synthesis of selective inhibitors of Trypanosoma cruzi dihydrofolate reductase

Fabio Zuccotto; Reto Brun; Dolores  Gonzalez Pacanowska; Luis M. Ruiz Perez; Ian H. Gilbert

doi:10.1016/S0960-894X(99)00213-9

The structure-based design and synthesis of selective inhibitors of Trypanosoma cruzi dihydrofolate reductase

Fabio Zuccotto, Reto Brun, Dolores Gonzalez Pacanowska, Luis M. Ruiz Perez, Ian H. Gilbert (Lead / Corresponding author)

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

30 Citations (Scopus)

Abstract

This paper describes the design and synthesis of potential inhibitors of Trypanosoma cruzi dihydrofolate reductase using a structure-based approach. A model of the structure of the T cruzi enzyme was compared with the structure of the human enzyme. The differences were used to design modifications of methotrexate to produce compounds which should be selective for the parasite enzyme. The derivatives of methotrexate were synthesised and tested against the enzyme and intact parasites. (C) 1999 Elsevier Science Ltd. All rights reserved.

Original language	English
Pages (from-to)	1463-1468
Number of pages	6
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	9
Issue number	10
DOIs	https://doi.org/10.1016/S0960-894X(99)00213-9
Publication status	Published - 17 May 1999

Keywords

Animals
Binding Sites
Cell Line
Drug Design
Enzyme Inhibitors
Folic Acid Antagonists
Humans
Mice
Molecular Structure
Recombinant Proteins
Tetrahydrofolate Dehydrogenase
Trypanosoma cruzi
Journal Article
Research Support, Non-U.S. Gov't

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10.1016/S0960-894X(99)00213-9

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title = "The structure-based design and synthesis of selective inhibitors of Trypanosoma cruzi dihydrofolate reductase",

abstract = "This paper describes the design and synthesis of potential inhibitors of Trypanosoma cruzi dihydrofolate reductase using a structure-based approach. A model of the structure of the T cruzi enzyme was compared with the structure of the human enzyme. The differences were used to design modifications of methotrexate to produce compounds which should be selective for the parasite enzyme. The derivatives of methotrexate were synthesised and tested against the enzyme and intact parasites. (C) 1999 Elsevier Science Ltd. All rights reserved.",

keywords = "Animals, Binding Sites, Cell Line, Drug Design, Enzyme Inhibitors, Folic Acid Antagonists, Humans, Mice, Molecular Structure, Recombinant Proteins, Tetrahydrofolate Dehydrogenase, Trypanosoma cruzi, Journal Article, Research Support, Non-U.S. Gov't",

author = "Fabio Zuccotto and Reto Brun and {Gonzalez Pacanowska}, Dolores and {Ruiz Perez}, {Luis M.} and Gilbert, {Ian H.}",

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AU - Zuccotto, Fabio

AU - Brun, Reto

AU - Gonzalez Pacanowska, Dolores

AU - Ruiz Perez, Luis M.

AU - Gilbert, Ian H.

PY - 1999/5/17

Y1 - 1999/5/17

N2 - This paper describes the design and synthesis of potential inhibitors of Trypanosoma cruzi dihydrofolate reductase using a structure-based approach. A model of the structure of the T cruzi enzyme was compared with the structure of the human enzyme. The differences were used to design modifications of methotrexate to produce compounds which should be selective for the parasite enzyme. The derivatives of methotrexate were synthesised and tested against the enzyme and intact parasites. (C) 1999 Elsevier Science Ltd. All rights reserved.

AB - This paper describes the design and synthesis of potential inhibitors of Trypanosoma cruzi dihydrofolate reductase using a structure-based approach. A model of the structure of the T cruzi enzyme was compared with the structure of the human enzyme. The differences were used to design modifications of methotrexate to produce compounds which should be selective for the parasite enzyme. The derivatives of methotrexate were synthesised and tested against the enzyme and intact parasites. (C) 1999 Elsevier Science Ltd. All rights reserved.

KW - Animals

KW - Binding Sites

KW - Cell Line

KW - Drug Design

KW - Enzyme Inhibitors

KW - Folic Acid Antagonists

KW - Humans

KW - Mice

KW - Molecular Structure

KW - Recombinant Proteins

KW - Tetrahydrofolate Dehydrogenase

KW - Trypanosoma cruzi

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/S0960-894X(99)00213-9

DO - 10.1016/S0960-894X(99)00213-9

M3 - Article

C2 - 10360757

SN - 0960-894X

VL - 9

SP - 1463

EP - 1468

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 10

ER -

The structure-based design and synthesis of selective inhibitors of Trypanosoma cruzi dihydrofolate reductase

Abstract

Keywords

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