ArticleChemMedChem2014
Time-dependent diaryl ether inhibitors of InhA: structure-activity relationship studies of enzyme inhibition, antibacterial activity, and in vivo efficacy.
Article in ChemMedChem, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
22 citing papers in PubMed, 56 citations in OpenAlex.
- Is Mycobacterial InhA a Suitable Target for Rational Drug Design?ChemMedChem · 2025Review
- Imidazoquinoline Derivatives as Potential Inhibitors of InhA Enzyme andMolecules (Basel, Switzerland) · 2024Article
- Evaluating the Impact of the Tyr158 pBiochemistry · 2023Article
- Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections.International journal of molecular sciences · 2022Article
- Antibiotic-Derived Radiotracers for Positron Emission Tomography: Nuclear or "Unclear" Infection Imaging?Angewandte Chemie (International ed. in English) · 2022Review
- Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA.International journal of molecular sciences · 2022Article
- Advances in Key Drug Target Identification and New Drug Development for Tuberculosis.BioMed research international · 2022Review
- New InhA Inhibitors Based on Expanded Triclosan andPharmaceuticals (Basel, Switzerland) · 2021Article
- A Long Residence Time Enoyl-Reductase Inhibitor Explores an Extended Binding Region with Isoenzyme-Dependent Tautomer Adaptation and Differential Substrate-Binding Loop Closure.ACS infectious diseases · 2021Article
- Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular agents.Molecular diversity · 2020Article
- Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening.Nature communications · 2017Article
- Rationalizing the Binding Kinetics for the Inhibition of the Burkholderia pseudomallei FabI1 Enoyl-ACP Reductase.Biochemistry · 2017Article
- Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA Inhibitors.Journal of the American Chemical Society · 2017Article
- Formulation studies of InhA inhibitors and combination therapy to improve efficacy against Mycobacterium tuberculosis.Tuberculosis (Edinburgh, Scotland) · 2016Article
- Correlating Drug-Target Kinetics andChemical science · 2016Article
- Selectivity of Pyridone- and Diphenyl Ether-Based Inhibitors for the Yersinia pestis FabV Enoyl-ACP Reductase.Biochemistry · 2016Article
- Radiolabelling and positron emission tomography of PT70, a time-dependent inhibitor of InhA, the Mycobacterium tuberculosis enoyl-ACP reductase.Bioorganic & medicinal chemistry letters · 2015Article
- Aqueous Molecular Dynamics Simulations of the M. tuberculosis Enoyl-ACP Reductase-NADH System and Its Complex with a Substrate Mimic or Diphenyl Ethers Inhibitors.International journal of molecular sciences · 2015Article
- Direct inhibitors of InhA are active against Mycobacterium tuberculosis.Science translational medicine · 2015Article
- Slow-Onset Inhibition of Mycobacterium tuberculosis InhA: Revealing Molecular Determinants of Residence Time by MD Simulations.PloS one · 2015Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
The diaryl ethers are a novel class of antituberculosis drug candidates that inhibit InhA, the enoyl-ACP reductase involved in the fatty acid biosynthesis (FASII) pathway, and have antibacterial activity against both drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. In the present work, we demonstrate that two time-dependent B-ring modified diaryl ether InhA inhibitors have antibacterial activity in a mouse model of TB infection when delivered by intraperitoneal injection. We propose that the efficacy of these compounds is related to their residence time on the enzyme, and to identify structural features that modulate drug-target residence time in this system, we have explored the inhibition of InhA by a series of B-ring modified analogues. Seven ortho-substituted compounds were found to be time-dependent inhibitors of InhA, where the slow step leading to the final enzyme-inhibitor complex (EI*) is thought to correlate with closure and ordering of the InhA substrate binding loop. A detailed mechanistic understanding of the molecular basis for residence time in this system will facilitate the development of InhA inhibitors with improved in vivo activity.
Indexed as
Identifiers
What OpenQuestion holds
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.