ArticleJournal of medicinal chemistry2017
7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis.
Article in Journal of medicinal chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 57 citations in OpenAlex.
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- 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
- 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
- Field-Deployable Treatments For Leishmaniasis: Intrinsic Challenges, Recent Developments and Next Steps.Research and reports in tropical medicine · 2023Review
- Review
- Current leishmaniasis drug discovery.RSC medicinal chemistry · 2022Review
- Replacement of Less-Preferred Dipolar Aprotic and Ethereal Solvents in Synthetic Organic Chemistry with More Sustainable Alternatives.Chemical reviews · 2022Review
- 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
- Antileishmanial assessment of isoxazole derivatives againstRSC medicinal chemistry · 2020Article
- Novel benzoxaborole, nitroimidazole and aminopyrazoles with activity against experimental cutaneous leishmaniasis.International journal for parasitology. Drugs and drug resistance · 2019Article
- Design, Synthesis, and Biological Evaluation of 2-Nitroimidazopyrazin-one/-es with Antitubercular and Antiparasitic Activity.Journal of medicinal chemistry · 2018Article
- Novel Aminoquinoline Derivatives Significantly Reduce Parasite Load inACS medicinal chemistry letters · 2018Article
- 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.Journal of medicinal chemistry · 2018Article
- Addressing the Metabolic Stability of Antituberculars through Machine Learning.ACS medicinal chemistry letters · 2017Article
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Authors and funding
15 authors at 7 institutions in 6 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.
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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.