Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antimalarials / chemical synthesis
-
Antimalarials / metabolism
-
Antimalarials / pharmacokinetics
-
Antimalarials / therapeutic use*
-
Cell Line, Tumor
-
Crystallography, X-Ray
-
Dihydroorotate Dehydrogenase
-
Dogs
-
Enzyme Inhibitors / chemical synthesis
-
Enzyme Inhibitors / metabolism
-
Enzyme Inhibitors / pharmacokinetics
-
Enzyme Inhibitors / therapeutic use*
-
Female
-
Humans
-
Malaria, Falciparum / drug therapy*
-
Male
-
Mice, SCID
-
Microsomes, Liver / metabolism
-
Molecular Structure
-
Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
-
Oxidoreductases Acting on CH-CH Group Donors / metabolism
-
Parasitic Sensitivity Tests
-
Plasmodium falciparum / drug effects
-
Plasmodium falciparum / enzymology
-
Plasmodium vivax / drug effects
-
Plasmodium vivax / enzymology
-
Protein Binding
-
Pyrroles / chemical synthesis
-
Pyrroles / metabolism
-
Pyrroles / pharmacokinetics
-
Pyrroles / therapeutic use*
-
Rats
-
Structure-Activity Relationship
Substances
-
Antimalarials
-
Dihydroorotate Dehydrogenase
-
Enzyme Inhibitors
-
Pyrroles
-
Oxidoreductases Acting on CH-CH Group Donors