Isoxazolopyrimidine-Based Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity

Abstract

Malaria kills nearly 0.5 million people yearly and impacts the lives of those living in over 90 countries where it is endemic. The current treatment programs are threatened by increasing drug resistance. Dihydroorotate dehydrogenase (DHODH) is now clinically validated as a target for antimalarial drug discovery as a triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. We discovered a related isoxazolopyrimidine series in a phenotypic screen, later determining that it targeted DHODH. To determine if the isoxazolopyrimidines could yield a drug candidate, we initiated hit-to-lead medicinal chemistry. Several potent analogues were identified, including a compound that showed in vivo antimalarial activity. The isoxazolopyrimidines were more rapidly metabolized than their triazolopyrimidine counterparts, and the pharmacokinetic data were not consistent with the goal of a single-dose treatment for malaria.

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…Similarly, Philips and co‐workers explored the isoxazolopyrimidine scaffold as a possible bioisosteric replacement, in which they identified compound 526 as the most promising in the class, with in vivo activity. However, this compound suffered from rapid metabolism and poor pharmacokinetic properties . In a study designed to exploit collateral sensitivity toward P. falciparum DHODH emerging from mutational resistance, Ross et al.…”

Driving antimalarial design through understanding of target mechanism

“…DSM265 is currently being developed by MMV in partnership with Takeda and has shown promise in Phase Ia/b studies as a single-dose treatment and as a once-weekly chemoprophylaxis as well as Phase IIa efficacy studies in patients with Pf and Pv malaria infections [65][66][67][68]. DSM265 has completed Phase IIa clinical trials and a number of other PfDHODH inhibitors have also been designed and synthesised utilising the understanding of target mechanism [59,[69][70][71][72][73]. Altogether, these efforts have not only validated PfDHODH as a clinical target but have resulted in desirable clinical candidates.…”

Molecular docking analysis of Plasmodium falciparum dihydroorotate dehydrogenase pfDHODH from towards the design of effective inhibitors

“…The compound formed strong H-bond with residues His185 (2.45 Å), Arg265 (2.05 Å), Leu531 (2.07 and 2.34 Å) and Tyr528 (2.34 Å). These residues have been reported to be essential in inhibition of PfDHODH [ 19 ]. The third benzene ring (R3) in fisetin, which harbours two OH- groups efficiently, twists optimally to engage in a hydrogen trade-off with catalytic important Leu531, thus disrupting the pocket's alignment.…”