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Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria.

Sreekanth KokkondaXiaoyi DengKaren L WhiteFarah El MazouniJohn WhiteDavid M ShacklefordKasiram KatneniFrancis C K ChiuHelena BarkerJenna McLarenElly CrightonGong ChenInigo Angulo-BarturenMaria Belen Jimenez-DiazSantiago FerrerLeticia Huertas-ValentinMaria Santos Martinez-MartinezMaria Jose Lafuente-MonasterioRajesh ChittimallaShatrughan P ShahiSergio WittlinDavid WatersonJeremy N BurrowsDave MatthewsDiana TomchickPradipsinh K RathodMichael J PalmerSusan A CharmanMargaret A Phillips
Published in: Journal of medicinal chemistry (2020)
Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.
Keyphrases
  • plasmodium falciparum
  • cardiovascular disease
  • high resolution
  • type diabetes
  • cardiovascular events
  • magnetic resonance
  • high throughput
  • molecular dynamics simulations
  • replacement therapy
  • electron microscopy