6i55

Publication Abstract from PubMed

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 12.0muM). 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 muM range (IC50 2.8 and 5.3muM, respectively). All three compounds, 3, 7e and 7f showed clear selectivity over human DHODH (IC50>200muM), 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.

Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors: Synthesis, biological evaluation and X-ray structural studies.,Pippione AC, Sainas S, Goyal P, Fritzson I, Cassiano GC, Giraudo A, Giorgis M, Tavella TA, Bagnati R, Rolando B, Caing-Carlsson R, Costa FTM, Andrade CH, Al-Karadaghi S, Boschi D, Friemann R, Lolli ML Eur J Med Chem. 2018 Nov 22;163:266-280. doi: 10.1016/j.ejmech.2018.11.044. PMID:30529545^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.