ABSTRACT
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
Decaprenylphosphoryl-ß-d-ribose 2'-epimerase (DprE1) is an essential enzyme in Mycobacterium tuberculosis and has recently been studied as a potential drug target, with inhibitors progressing to clinical studies. Here we describe the identification of a novel series of morpholino-pyrimidine DprE1 inhibitors. These were derived from a phenotypic high-throughput screening (HTS) hit with suboptimal physicochemical properties. Optimization strategies included scaffold-hopping, synthesis, and evaluation of fragments of the lead compounds and property-focused optimization. The resulting optimized compounds had much improved physicochemical properties and maintained enzyme and cellular potency. These molecules demonstrated potent efficacy in an in vivo tuberculosis murine infection model.
Subject(s)
Alcohol Oxidoreductases/antagonists & inhibitors , Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Mycobacterium tuberculosis/drug effects , Pyrimidines/pharmacology , Tuberculosis/drug therapy , Alcohol Oxidoreductases/metabolism , Animals , Antitubercular Agents/chemistry , Antitubercular Agents/therapeutic use , Bacterial Proteins/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Humans , Male , Mice , Morpholines/chemistry , Morpholines/pharmacology , Morpholines/therapeutic use , Mycobacterium tuberculosis/enzymology , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Tuberculosis/microbiologyABSTRACT
Our findings reported herein provide support for the benefits of including functional group complexity (FGC) within fragments when screening against protein targets such as Mycobacterium tuberculosis InhA. We show that InhA fragment actives with FGC maintained their binding pose during elaboration. Furthermore, weak fragment hits with functional group handles also allowed for facile fragment elaboration to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization.