ABSTRACT
Structure-activity relationship (SAR) exploration on the left-hand side (LHS) of a novel class of bacterial topoisomerase inhibitors led to a significant improvement in the selectivity against hERG cardiac channel binding with concomitant potent antimycobacterial activity. Bulky polar substituents at the C-7 position of the naphthyridone ring did not disturb its positioning between two base pairs of DNA. Further optimization of the polar substituents on the LHS of the naphthyridone ring led to potent antimycobacterial activity (Mtb MIC = 0.06 µM) against Mycobacterium tuberculosis (Mtb). Additionally, this knowledge provided a robust SAR understanding to mitigate the hERG risk. This compound class inhibits Mtb DNA gyrase and retains its antimycobacterial activity against moxifloxacin-resistant strains of Mtb. Finally, we demonstrate in vivo proof of concept in an acute mouse model of TB following oral administration of compound 19.
ABSTRACT
DNA gyrase is a clinically validated target for developing drugs against Mycobacterium tuberculosis (Mtb). Despite the promise of fluoroquinolones (FQs) as anti-tuberculosis drugs, the prevalence of pre-existing resistance to FQs is likely to restrict their clinical value. We describe a novel class of N-linked aminopiperidinyl alkyl quinolones and naphthyridones that kills Mtb by inhibiting the DNA gyrase activity. The mechanism of inhibition of DNA gyrase was distinct from the fluoroquinolones, as shown by their ability to inhibit the growth of fluoroquinolone-resistant Mtb. Biochemical studies demonstrated this class to exert its action via single-strand cleavage rather than double-strand cleavage, as seen with fluoroquinolones. The compounds are highly bactericidal against extracellular as well as intracellular Mtb. Lead optimization resulted in the identification of potent compounds with improved oral bioavailability and reduced cardiac ion channel liability. Compounds from this series are efficacious in various murine models of tuberculosis.
Subject(s)
Antitubercular Agents/chemical synthesis , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Mycobacterium tuberculosis/drug effects , Piperidines/chemical synthesis , Topoisomerase II Inhibitors/chemical synthesis , Acute Disease , Administration, Oral , Animals , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Biological Availability , Chronic Disease , DNA Gyrase/genetics , DNA Gyrase/metabolism , Drug Resistance, Bacterial , ERG1 Potassium Channel , Fluoroquinolones/pharmacology , Humans , Macrophages/drug effects , Macrophages/microbiology , Mice, Inbred BALB C , Microbial Sensitivity Tests , Molecular Docking Simulation , Mutation , Mycobacterium tuberculosis/enzymology , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protein Subunits/genetics , Protein Subunits/metabolism , Rats , Stereoisomerism , Structure-Activity Relationship , Topoisomerase II Inhibitors/pharmacokinetics , Topoisomerase II Inhibitors/pharmacology , Tuberculosis, Pulmonary/drug therapyABSTRACT
A pharmacophore-based search led to the identification of thiazolopyridine ureas as a novel scaffold with antitubercular activity acting through inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration of the side chains at the thiazolopyridine ring C-5 position to access the ribose/solvent pocket. Potent compounds with GyrB IC50 ≤ 1 nM and Mtb MIC ≤ 0.1 µM were obtained with certain combinations of side chains at the C-5 position and heterocycles at the C-6 position of the thiazolopyridine core. Substitutions at C-5 also enabled optimization of the physicochemical properties. Representative compounds were cocrystallized with Streptococcus pneumoniae (Spn) ParE; these confirmed the binding modes predicted by the homology model. The target link to GyrB was confirmed by genetic mapping of the mutations conferring resistance to thiazolopyridine ureas. The compounds are bactericidal in vitro and efficacious in vivo in an acute murine model of tuberculosis.
