ArticleJournal of medicinal chemistry2018
Development of (6 R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5 H-imidazo[2,1- b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis.
Article in Journal of medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Identification of a Benzenesulfonylpiperazine Derivative With In Vivo Efficacy Against Visceral Leishmaniasis.Chemical biology & drug design · 2026Article
- Exploring Novel Nitrofuryl-1,3,4-Thiadiazole-Based Derivatives: Design, Synthesis, and Evaluation of In Vitro Leishmanicidal and Trypanocidal Activity.Archiv der Pharmazie · 2026Article
- Validated LC-MS/MS Method for Quantifying the Antiparasitic Nitroimidazole DNDI-0690 in Preclinical Target Site PK/PD Studies.Biomedical chromatography : BMC · 2025Article
- Synthesis and biological evaluation of 4,7,9-trisubstituted benzoxazepines as antileishmanial agents.Bioorganic & medicinal chemistry letters · 2024Article
- Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents.Journal of medicinal chemistry · 2024Article
- Green Synthetic Methods of Oxazine and Thiazine Scaffolds as Promising Medicinal Compounds: A Mini-review.Current organic synthesis · 2024Review
- Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides.Journal of medicinal chemistry · 2023Article
- Further Investigations of Nitroheterocyclic Compounds as Potential Antikinetoplastid Drug Candidates.Biomolecules · 2023Review
- Discovery of pyrazolopyrrolidinones as potent, broad-spectrum inhibitors ofFrontiers in tropical diseases · 2023Article
- Review
- Current leishmaniasis drug discovery.RSC medicinal chemistry · 2022Review
- Recent Progress in the Synthesis of Drugs and Bioactive Molecules Incorporating Nitro(het)arene Core.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Nitroaromatic Antibiotics as Nitrogen Oxide Sources.Biomolecules · 2021Review
- Novel Linker Variants of Antileishmanial/Antitubercular 7-Substituted 2-Nitroimidazooxazines Offer Enhanced Solubility.ACS medicinal chemistry letters · 2021Article
- Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility.Journal of medicinal chemistry · 2020Article
- Recent Progress in the Discovery and Development of 2-Nitroimidazooxazines and 6-Nitroimidazooxazoles to Treat Tuberculosis and Neglected Tropical Diseases.Molecules (Basel, Switzerland) · 2020Review
- Novel 2D and 3D Assays to Determine the Activity of Anti-Leishmanial Drugs.Microorganisms · 2020Article
- Leishmaniasis immunopathology-impact on design and use of vaccines, diagnostics and drugs.Seminars in immunopathology · 2020Review
- Highly Enantioselective, Hydrogen-Bond-Donor Catalyzed Additions to Oxetanes.Journal of the American Chemical Society · 2020Article
- Improved Prediction of Aqueous Solubility of Novel Compounds by Going Deeper With Deep Learning.Frontiers in oncology · 2020Article
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Authors and funding
15 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1- b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1- b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1- b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6 R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads ( R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds ( R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.
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