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.
Subject(s)
Antimalarials/therapeutic use , Enzyme Inhibitors/therapeutic use , Malaria, Falciparum/drug therapy , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Pyrroles/therapeutic use , Animals , Antimalarials/chemical synthesis , Antimalarials/metabolism , Antimalarials/pharmacokinetics , Cell Line, Tumor , Crystallography, X-Ray , Dihydroorotate Dehydrogenase , Dogs , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacokinetics , Female , Humans , Male , Mice, SCID , Microsomes, Liver/metabolism , Molecular Structure , 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 , Rats , Structure-Activity RelationshipABSTRACT
In the course of optimizing a novel indazole sulfonamide series that inhibits ß-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis, a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.
Subject(s)
3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/antagonists & inhibitors , Aniline Compounds/pharmacology , Mycobacterium tuberculosis , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Binding Sites , DNA Damage , Mycobacterium tuberculosis/enzymologyABSTRACT
Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group.
