ArticleBioorganic & medicinal chemistry letters2018
Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides.
Article in Bioorganic & medicinal chemistry letters, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 27 citations in OpenAlex.
- Synthesis and in vitro antitrypanosomatid activity of novel 5-nitroindole-rhodanine conjugates.Future medicinal chemistry · 2025Article
- 2-(Nitroaryl)-5-Substituted-1,3,4-Thiadiazole Derivatives with Antiprotozoal Activities: In Vitro and In Vivo Study.Molecules (Basel, Switzerland) · 2022Article
- Functionalized Nitroimidazole Scaffold Construction and Their Pharmaceutical Applications: A 1950-2021 Comprehensive Overview.Pharmaceuticals (Basel, Switzerland) · 2022Review
- 2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling.PLoS neglected tropical diseases · 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
- Design, Synthesis, and Biological Evaluation of 2-Nitroimidazopyrazin-one/-es with Antitubercular and Antiparasitic Activity.Journal of medicinal chemistry · 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
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Authors and funding
12 authors at 7 institutions in 4 countries.
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No grant is acknowledged in the PubMed record.
Abstract
A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.
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