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Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors: Synthesis, biological evaluation and X-ray structural studies.

Journal article
Authors Agnese C Pippione
Stefano Sainas
Parveen Goyal
Ingela Fritzson
Gustavo C Cassiano
Alessandro Giraudo
Marta Giorgis
Tatyana A Tavella
Renzo Bagnati
Barbara Rolando
Rhawnie Caing Carlsson
Fabio T M Costa
Carolina Horta Andrade
Salam Al-Karadaghi
Donatella Boschi
Rosmarie Friemann
Marco L Lolli
Published in European journal of medicinal chemistry
Volume 163
Issue 1
Pages 266-280
ISSN 1768-3254
Publication year 2019
Published at Department of Chemistry and Molecular Biology
Centre for antibiotic resistance research, CARe
Pages 266-280
Language en
Subject categories Structural Biology, Organic synthesis


Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) 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 PfDHODH 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 PfDHODH inhibitor (IC50 12.0 μM). 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 μM range (IC50 2.8 and 5.3 μM, respectively). All three compounds, 3, 7e and 7f showed clear selectivity over human DHODH (IC50 > 200 μM), low cytotoxicity, and retained micromolar activity in P. falciparum-infected erythrocytes. The crystallographic structures of PfDHODH in complex with compounds 3 and 7e proved their binding mode, supplying essential data for future optimization of these scaffolds.

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