ArticleJournal of medicinal chemistry2013
Optimization of benzoxazole-based inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase.
Article in Journal of medicinal chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 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
28 citing papers in PubMed, 81 citations in OpenAlex.
- Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition inJournal of bacteriology · 2024Article
- Fragment-Based Lead Discovery Strategies in Antimicrobial Drug Discovery.Antibiotics (Basel, Switzerland) · 2023Review
- Novel amides of mycophenolic acid and some heterocyclic derivatives as immunosuppressive agents.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- The Enzymatic Activity of Inosine 5'-Monophosphate Dehydrogenase May Not Be a Vulnerable Target forACS infectious diseases · 2021Article
- Molecular Basis of P131 Cryptosporidial-IMPDH Selectivity-A Structural, Dynamical and Mechanistic Stance.Cell biochemistry and biophysics · 2021Article
- A probable means to an end: exploring P131 pharmacophoric scaffold to identify potential inhibitors of Cryptosporidium parvum inosine monophosphate dehydrogenase.Journal of molecular modeling · 2021Article
- Mycophenolic anilides as broad specificity inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitors.Bioorganic & medicinal chemistry letters · 2020Article
- Evaluation of Bronopol and Disulfiram as PotentialMolecules (Basel, Switzerland) · 2020Article
- Genetic ablation of purine salvage inProceedings of the National Academy of Sciences of the United States of America · 2019Article
- Inhibitors of inosine 5'-monophosphate dehydrogenase as emerging new generation antimicrobial agents.MedChemComm · 2019Review
- Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis.Nature communications · 2019Article
- Article
- Expanding Benzoxazole-Based Inosine 5'-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure-Activity As Potential Antituberculosis Agents.Journal of medicinal chemistry · 2018Article
- Fragment-Based Approach to Targeting Inosine-5'-monophosphate Dehydrogenase (IMPDH) from Mycobacterium tuberculosis.Journal of medicinal chemistry · 2018Article
- Benzoxazoles, Phthalazinones, and Arylurea-Based Compounds with IMP Dehydrogenase-Independent Antibacterial Activity against Francisella tularensis.Antimicrobial agents and chemotherapy · 2017Article
- Inhibition of Inosine-5'-monophosphate Dehydrogenase from Bacillus anthracis: Mechanism Revealed by Pre-Steady-State Kinetics.Biochemistry · 2016Article
- A QSAR model of benzoxazole derivatives as potential inhibitors for inosine 5`-monophosphate dehydrogenase from Cryptosporidium parvum.Bioinformation · 2016Article
- A Proposed Target Product Profile and Developmental Cascade for New Cryptosporidiosis Treatments.PLoS neglected tropical diseases · 2015Article
- Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity.Acta crystallographica. Section F, Structural biology communications · 2015Article
- Structural Genomics Support for Infectious Disease Drug Design.ACS infectious diseases · 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 1 country.
Funding
Abstract
Cryptosporidium parvum is an enteric protozoan parasite that has emerged as a major cause of diarrhea, malnutrition, and gastroenteritis and poses a potential bioterrorism threat. C. parvum synthesizes guanine nucleotides from host adenosine in a streamlined pathway that relies on inosine 5'-monophosphate dehydrogenase (IMPDH). We have previously identified several parasite-selective C. parvum IMPDH (CpIMPDH) inhibitors by high-throughput screening. In this paper, we report the structure-activity relationship (SAR) for a series of benzoxazole derivatives with many compounds demonstrating CpIMPDH IC50 values in the nanomolar range and >500-fold selectivity over human IMPDH (hIMPDH). Unlike previously reported CpIMPDH inhibitors, these compounds are competitive inhibitors versus NAD(+). The SAR study reveals that pyridine and other small heteroaromatic substituents are required at the 2-position of the benzoxazole for potent inhibitory activity. In addition, several other SAR conclusions are highlighted with regard to the benzoxazole and the amide portion of the inhibitor, including preferred stereochemistry. An X-ray crystal structure of a representative E·IMP·inhibitor complex is also presented. Overall, the secondary amine derivative 15a demonstrated excellent CpIMPDH inhibitory activity (IC50 = 0.5 ± 0.1 nM) and moderate stability (t1/2 = 44 min) in mouse liver microsomes. Compound 73, the racemic version of 15a, also displayed superb antiparasitic activity in a Toxoplasma gondii strain that relies on CpIMPDH (EC50 = 20 ± 20 nM), and selectivity versus a wild-type T. gondii strain (200-fold). No toxicity was observed (LD50 > 50 μM) against a panel of four mammalian cells lines.
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.