ArticleBioorganic & medicinal chemistry2012
Antitubercular nitrofuran isoxazolines with improved pharmacokinetic properties.
Article in Bioorganic & medicinal chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Structure, Mutation, Functional Domain Roles and Medical Implications of Glycerol Kinase.The protein journal · 2026Review
- Both Nitro Groups Are Essential for High Antitubercular Activity of 3,5-Dinitrobenzylsulfanyl Tetrazoles and 1,3,4-Oxadiazoles through the Deazaflavin-Dependent Nitroreductase Activation Pathway.Journal of medicinal chemistry · 2024Article
- Nitrile Oxide, Alkenes, Dipolar Cycloaddition, Isomerization and Metathesis Involved in the Syntheses of 2-Isoxazolines.Molecules (Basel, Switzerland) · 2023Review
- Synthesis and biological evaluation of selective survivin inhibitors derived from the MX-106 hydroxyquinoline scaffold.European journal of medicinal chemistry · 2021Article
- Design, Synthesis, and Biological Evaluation of Stable Colchicine-Binding Site Tubulin Inhibitors 6-Aryl-2-benzoyl-pyridines as Potential Anticancer Agents.Journal of medicinal chemistry · 2021Article
- Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds.Pharmaceuticals (Basel, Switzerland) · 2017Review
- Structure-Activity Relationships of Spectinamide Antituberculosis Agents: A Dissection of Ribosomal Inhibition and Native Efflux Avoidance Contributions.ACS infectious diseases · 2017Article
- Identification and Characterization of CINPA1 Metabolites Facilitates Structure-Activity Studies of the Constitutive Androstane Receptor.Drug metabolism and disposition: the biological fate of chemicals · 2016Article
- Synthesis and antibacterial evaluation of macrocyclic diarylheptanoid derivatives.Bioorganic & medicinal chemistry letters · 2016Article
- Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes.The Journal of antimicrobial chemotherapy · 2016Article
- Nitrofuranyl Methyl Piperazines as New Anti-TB Agents: Identification, Validation, Medicinal Chemistry, and PK Studies.ACS medicinal chemistry letters · 2015Article
- Syntheses and Antituberculosis Activity of 1,3-Benzothiazinone Sulfoxide and Sulfone Derived from BTZ043.ACS medicinal chemistry letters · 2015Article
- Article
- Synthesis, structure-activity relationship studies, and antibacterial evaluation of 4-chromanones and chalcones, as well as olympicin A and derivatives.Journal of medicinal chemistry · 2014Article
- Chemical modulation of the biological activity of reutericyclin: a membrane-active antibiotic from Lactobacillus reuteri.Scientific reports · 2014Article
- Pentacyclic nitrofurans with in vivo efficacy and activity against nonreplicating Mycobacterium tuberculosis.PloS one · 2014Article
- Progress in targeting cell envelope biogenesis in Mycobacterium tuberculosis.Future microbiology · 2013Review
Corrections and comments
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Authors and funding
14 authors.
Funding
Abstract
A series of tetracyclic nitrofuran isoxazoline anti-tuberculosis agents was designed and synthesized to improve the pharmacokinetic properties of an initial lead compound, which had potent anti-tuberculosis activity but suffered from poor solubility, high protein binding and rapid metabolism. In this study, structural modifications were carried on the outer phenyl and piperidine rings to introduce solubilizing and metabolically blocking functional groups. The compounds generated were evaluated for their in vitro antitubercular activity, bacterial spectrum of activity, solubility, permeability, microsomal stability and protein binding. Pharmacokinetic profiles for the most promising candidates were then determined. Compounds with phenyl morpholine and pyridyl morpholine outer rings were found to be the most potent anti-tuberculosis agents in the series. These compounds retained a narrow antibacterial spectrum of activity, with weak anti-Gram positive and no Gram negative activity, as well as good activity against non-replicating Mycobacterium tuberculosis in a low oxygen model. Overall, the addition of solubilizing and metabolically blocked outer rings did improve solubility and decrease protein binding as designed. However, the metabolic stability for compounds in this series was generally lower than desired. The best three compounds selected for in vivo pharmacokinetic testing all showed high oral bioavailability, with one notable compound showing a significantly longer half-life and good tolerability supporting its further advancement.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.