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Type: Artigo
Title: Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors: Synthesis, biological evaluation and X-ray structural studies
Author: Pippione, Agnese C.
Sainas, Stefano
Goyal, Parveen
Fritzson, Ingela
Cassiano, Gustavo C.
Giraudo, Alessandro
Giorgis, Marta
Tavella, Tatyana A.
Bagnati, Renzo
Rolando, Barbara
Caing-Carlsson, Rhawnie
Costa, Fabio T. M.
Andrade, Carolina Horta
Al-Karadaghi, Salam
Boschi, Donatella
Friemann, Rosmarie
Lolli, Marco L.
Abstract: Plasmodium falciparum dihydroorotate dehydrogenase (PJDHODH) has been clinically validated as a target for antimalarial drug discovery, as a triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. Here, we have identified new hydroxyazole scaffold-based PJDHODH inhibitors belonging to two different chemical series. The first series was designed by a scaffold hopping strategy that exploits the use of hydroxylated azoles. Within this series, the hydroxythiadiazole 3 was identified as the best selective PJDHODH inhibitor (IC50 12.0 mu M). The second series was designed by modulating four different positions of the hydroxypyrazole scaffold. In particular, hydroxypyrazoles 7e and 7f were shown to be active in the low mu M range (IC50 2.8 and 5.3 mu M, respectively). All three compounds, 3, 7e and 7f showed clear selectivity over human DHODH (IC50> 200 mu M), low cytotoxicity, and retained micromolar activity in P. falciparum-infected erythrocytes. The crystallographic structures of PJDHODH in complex with compounds 3 and 7e proved their binding mode, supplying essential data for future optimization of these scaffolds. (C) 2018 Elsevier Masson SAS. All rights reserved
Subject: Malária
Plasmodium falciparum
Country: França
Editor: Elsevier
Rights: Fechado
Identifier DOI: 10.1016/j.ejmech.2018.11.044
Date Issue: 2019
Appears in Collections:IB - Artigos e Outros Documentos

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