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1.
J Med Chem ; 58(5): 2195-205, 2015 Mar 12.
Article in English | MEDLINE | ID: mdl-25658376

ABSTRACT

To identify new agents for the treatment of multi-drug-resistant Pseudomonas aeruginosa, we focused on siderophore-conjugated monocarbams. This class of monocyclic ß-lactams are stable to metallo-ß-lactamases and have excellent P. aeruginosa activities due to their ability to exploit the iron uptake machinery of Gram-negative bacteria. Our medicinal chemistry plan focused on identifying a molecule with optimal potency and physical properties and activity for in vivo efficacy. Modifications to the monocarbam linker, siderophore, and oxime portion of the molecules were examined. Through these efforts, a series of pyrrolidinone-based monocarbams with good P. aeruginosa cellular activity (P. aeruginosa MIC90 = 2 µg/mL), free fraction levels (>20% free), and hydrolytic stability (t1/2 ≥ 100 h) were identified. To differentiate the lead compounds and enable prioritization for in vivo studies, we applied a semi-mechanistic pharmacokinetic/pharmacodynamic model to enable prediction of in vivo efficacy from in vitro data.


Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/pharmacokinetics , Drug Discovery , Monobactams/pharmacology , Monobactams/pharmacokinetics , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/drug effects , Siderophores/metabolism , Animals , Humans , Male , Monobactams/chemistry , Pseudomonas Infections/microbiology , Rats , Rats, Wistar , Structure-Activity Relationship , beta-Lactamases/chemistry
2.
Antimicrob Agents Chemother ; 58(9): 5325-31, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24957839

ABSTRACT

New therapeutic strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis are urgently required to combat the global tuberculosis (TB) threat. Toward this end, we previously reported the identification of 1,4-azaindoles, a promising class of compounds with potent antitubercular activity through noncovalent inhibition of decaprenylphosphoryl-ß-D-ribose 2'-epimerase (DprE1). Further, this series was optimized to improve its physicochemical properties and pharmacokinetics in mice. Here, we describe the short-listing of a potential clinical candidate, compound 2, that has potent cellular activity, drug-like properties, efficacy in mouse and rat chronic TB infection models, and minimal in vitro safety risks. We also demonstrate that the compounds, including compound 2, have no antagonistic activity with other anti-TB drugs. Moreover, compound 2 shows synergy with PA824 and TMC207 in vitro, and the synergy effect is translated in vivo with TMC207. The series is predicted to have a low clearance in humans, and the predicted human dose for compound 2 is ≤1 g/day. Altogether, our data suggest that a 1,4-azaindole (compound 2) is a promising candidate for the development of a novel anti-TB drug.


Subject(s)
Antitubercular Agents/therapeutic use , Indoles/therapeutic use , Pyridines/therapeutic use , Tuberculosis, Pulmonary/drug therapy , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacokinetics , Dogs , Drug Therapy, Combination , Female , Humans , Indoles/chemical synthesis , Indoles/pharmacokinetics , Male , Mice , Mice, Inbred BALB C , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats
3.
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
4.
J Med Chem ; 57(13): 5728-37, 2014 Jul 10.
Article in English | MEDLINE | ID: mdl-24874895

ABSTRACT

In a previous report, we described the discovery of 1,4-azaindoles, a chemical series with excellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. Herein, we report lead optimization of this series, culminating in potent, metabolically stable compounds that have a robust pharmacokinetic profile without any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles in a rat chronic TB infection model. We believe that compounds from the 1,4-azaindole series are suitable for in vivo combination and safety studies.


Subject(s)
Antitubercular Agents/chemical synthesis , Indoles/chemical synthesis , Alcohol Oxidoreductases , Animals , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists & inhibitors , Disease Models, Animal , Humans , Indoles/pharmacokinetics , Mice , Mycobacterium tuberculosis/drug effects , Oxidoreductases/antagonists & inhibitors , Rats , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 24(3): 870-9, 2014 Feb 01.
Article in English | MEDLINE | ID: mdl-24405701

ABSTRACT

Scaffold hopping from the thiazolopyridine ureas led to thiazolopyridone ureas with potent antitubercular activity acting through inhibition of DNA GyrB ATPase activity. Structural diversity was introduced, by extension of substituents from the thiazolopyridone N-4 position, to access hydrophobic interactions in the ribose pocket of the ATP binding region of GyrB. Further optimization of hydrogen bond interactions with arginines in site-2 of GyrB active site pocket led to potent inhibition of the enzyme (IC50 2 nM) along with potent cellular activity (MIC=0.1 µM) against Mycobacterium tuberculosis (Mtb). Efficacy was demonstrated in an acute mouse model of tuberculosis on oral administration.


Subject(s)
Mycobacterium tuberculosis/drug effects , Pyridones/chemical synthesis , Thiazoles/chemical synthesis , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Urea/chemical synthesis , Urea/pharmacology , Administration, Oral , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Disease Models, Animal , Inhibitory Concentration 50 , Mice , Microbial Sensitivity Tests , Molecular Structure , Pyridones/chemistry , Pyridones/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , Topoisomerase II Inhibitors/chemistry , Urea/chemistry
6.
J Med Chem ; 56(21): 8834-48, 2013 Nov 14.
Article in English | MEDLINE | ID: mdl-24088190

ABSTRACT

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.


Subject(s)
Antitubercular Agents/pharmacology , DNA Gyrase/metabolism , Mycobacterium tuberculosis/drug effects , Pyridines/pharmacology , Topoisomerase II Inhibitors/pharmacology , Tuberculosis/drug therapy , Urea/pharmacology , Animals , Antitubercular Agents/administration & dosage , Antitubercular Agents/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Mycobacterium tuberculosis/enzymology , Pyridines/administration & dosage , Pyridines/chemistry , Structure-Activity Relationship , Topoisomerase II Inhibitors/administration & dosage , Topoisomerase II Inhibitors/chemistry , Urea/analogs & derivatives , Urea/chemistry
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