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Thuỳ An Hoàng

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Papers by Thuỳ An Hoàng

Research paper thumbnail of Novel 3-fluoro-6-methoxyquinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV

Bioorganic & medicinal chemistry letters, Aug 1, 2017

Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emergin... more Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC90=0.125μg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC50 of 85.9μM and a favorable profile in the anesthetized guinea pig model.

Research paper thumbnail of Pyridone-Conjugated Monobactam Antibiotics with Gram-Negative Activity

Journal of Medicinal Chemistry, 2013

Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated mo... more Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogs with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli. Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogs suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P.aeruginosa strain PAO1.

Research paper thumbnail of Novel monobactams utilizing a siderophore uptake mechanism for the treatment of gram-negative infections

Bioorganic & Medicinal Chemistry Letters, 2012

Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MD... more Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.

Research paper thumbnail of Novel quinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV

Bioorganic & Medicinal Chemistry Letters, 2013

Research paper thumbnail of Preparation, Gram-Negative Antibacterial Activity, and Hydrolytic Stability of Novel Siderophore-Conjugated Monocarbam Diols

ACS Medicinal Chemistry Letters, 2011

Research paper thumbnail of Quantification of rifapentine, a potent antituberculosis drug, from dried blood spot samples using liquid chromatographic-tandem mass spectrometric analysis

Antimicrobial agents and chemotherapy, 2014

The quantification of antituberculosis drug concentrations in multinational trials currently requ... more The quantification of antituberculosis drug concentrations in multinational trials currently requires the collection of modest blood volumes, centrifugation, aliquoting of plasma, freezing, and keeping samples frozen during shipping. We prospectively enrolled healthy individuals into the Tuberculosis Trials Consortium Study 29B, a phase I dose escalation study of rifapentine, a rifamycin under evaluation in tuberculosis treatment trials. We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying rifapentine in whole blood on dried blood spots (DBS) to facilitate pharmacokinetic/pharmacodynamic analyses in clinical trials. Paired plasma and whole-blood samples were collected by venipuncture, and whole blood was spotted on Whatman protein saver 903 cards. The methods were optimized for plasma and then validated for DBS. The analytical measuring range for quantification of rifapentine and its metabolite was 50 to 80,000 ng/ml in whole-blood DBS. The...

Research paper thumbnail of Novel 3-fluoro-6-methoxyquinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV

Bioorganic & medicinal chemistry letters, Aug 1, 2017

Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emergin... more Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC90=0.125μg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC50 of 85.9μM and a favorable profile in the anesthetized guinea pig model.

Research paper thumbnail of Pyridone-Conjugated Monobactam Antibiotics with Gram-Negative Activity

Journal of Medicinal Chemistry, 2013

Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated mo... more Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogs with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli. Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogs suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P.aeruginosa strain PAO1.

Research paper thumbnail of Novel monobactams utilizing a siderophore uptake mechanism for the treatment of gram-negative infections

Bioorganic & Medicinal Chemistry Letters, 2012

Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MD... more Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.

Research paper thumbnail of Novel quinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV

Bioorganic & Medicinal Chemistry Letters, 2013

Research paper thumbnail of Preparation, Gram-Negative Antibacterial Activity, and Hydrolytic Stability of Novel Siderophore-Conjugated Monocarbam Diols

ACS Medicinal Chemistry Letters, 2011

Research paper thumbnail of Quantification of rifapentine, a potent antituberculosis drug, from dried blood spot samples using liquid chromatographic-tandem mass spectrometric analysis

Antimicrobial agents and chemotherapy, 2014

The quantification of antituberculosis drug concentrations in multinational trials currently requ... more The quantification of antituberculosis drug concentrations in multinational trials currently requires the collection of modest blood volumes, centrifugation, aliquoting of plasma, freezing, and keeping samples frozen during shipping. We prospectively enrolled healthy individuals into the Tuberculosis Trials Consortium Study 29B, a phase I dose escalation study of rifapentine, a rifamycin under evaluation in tuberculosis treatment trials. We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying rifapentine in whole blood on dried blood spots (DBS) to facilitate pharmacokinetic/pharmacodynamic analyses in clinical trials. Paired plasma and whole-blood samples were collected by venipuncture, and whole blood was spotted on Whatman protein saver 903 cards. The methods were optimized for plasma and then validated for DBS. The analytical measuring range for quantification of rifapentine and its metabolite was 50 to 80,000 ng/ml in whole-blood DBS. The...

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