1. Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors: Synthesis, biological evaluation and X-ray structural studies
- Author
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Fabio T. M. Costa, Carolina Horta Andrade, Renzo Bagnati, Donatella Boschi, Stefano Sainas, Ingela Fritzson, Barbara Rolando, Agnese Chiara Pippione, Gustavo Capatti Cassiano, Parveen Goyal, Tatyana Almeida Tavella, Marta Giorgis, Rhawnie Caing-Carlsson, Marco Lucio Lolli, Alessandro Giraudo, Rosmarie Friemann, and Salam Al-Karadaghi
- Subjects
Azoles ,Oxidoreductases Acting on CH-CH Group Donors ,Erythrocytes ,Stereochemistry ,Plasmodium falciparum ,Dihydroorotate Dehydrogenase ,Pyrazole ,Crystallography, X-Ray ,01 natural sciences ,Antimalarials ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Oxidoreductase ,Drug Discovery ,Humans ,X-ray-crystallography ,Enzyme Inhibitors ,Dihydroorotate dehydrogenase (DHODH) inhibitors ,Cytotoxicity ,IC50 ,030304 developmental biology ,Dihydroorotate Dehydrogenase Inhibitor ,Bioisosterism ,Pharmacology ,chemistry.chemical_classification ,0303 health sciences ,Scaffold hopping ,Binding Sites ,Malaria ,biology ,010405 organic chemistry ,Chemistry ,Drug discovery ,Organic Chemistry ,General Medicine ,biology.organism_classification ,0104 chemical sciences ,Dihydroorotate dehydrogenase ,Pyrazoles ,Protein Binding - Abstract
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.
- Published
- 2019