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J Med Chem ; 57(12): 5419-34, 2014 Jun 26.
Article in English | MEDLINE | ID: mdl-24871036

ABSTRACT

4-Aminoquinolone piperidine amides (AQs) were identified as a novel scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the minimum inhibitory concentrations, followed by whole genome sequencing of mutants raised against AQs, identified decaprenylphosphoryl-ß-d-ribose 2'-epimerase (DprE1) as the primary target responsible for the antitubercular activity. Mass spectrometry and enzyme kinetic studies indicated that AQs are noncovalent, reversible inhibitors of DprE1 with slow on rates and long residence times of ∼100 min on the enzyme. In general, AQs have excellent leadlike properties and good in vitro secondary pharmacology profile. Although the scaffold started off as a single active compound with moderate potency from the whole cell screen, structure-activity relationship optimization of the scaffold led to compounds with potent DprE1 inhibition (IC50 < 10 nM) along with potent cellular activity (MIC = 60 nM) against Mtb.


Subject(s)
Amides/chemistry , Antitubercular Agents/chemistry , Bacterial Proteins/antagonists & inhibitors , Mycobacterium tuberculosis/drug effects , Oxidoreductases/antagonists & inhibitors , Piperidines/chemistry , Quinolones/chemistry , Alcohol Oxidoreductases , Amides/pharmacokinetics , Amides/pharmacology , Animals , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/pharmacology , Catalytic Domain , Cell Line, Tumor , Drug Resistance, Bacterial , Genome, Bacterial , Humans , Kinetics , Microbial Sensitivity Tests , Molecular Docking Simulation , Mutation , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/genetics , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protein Binding , Quinolones/pharmacokinetics , Quinolones/pharmacology , Rats, Wistar , Stereoisomerism , Structure-Activity Relationship
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