6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]thiazoles: Facile synthesis and comparative appraisal against tuberculosis and neglected tropical diseases
| Autor: | Sujata S. Shinde, Louis Maes, Yuehong Wang, Andrew M. Thompson, Delphine Launay, Eric Chatelain, Adrian Blaser, Baojie Wan, Brian D. Palmer, Scott G. Franzblau, Robert F. Anderson, William A. Denny, Zhenkun Ma |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Tuberculosis Stereochemistry Clinical Biochemistry Antitubercular Agents Pharmaceutical Science Microbial Sensitivity Tests 01 natural sciences Biochemistry Mycobacterium tuberculosis Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Drug Discovery medicine Animals Structure–activity relationship Chagas Disease Thiazole Oxazoles Molecular Biology Oxazole biology 010405 organic chemistry Pharmacology. Therapy Organic Chemistry biology.organism_classification medicine.disease 0104 chemical sciences Disease Models Animal Thiazoles Chemistry 030104 developmental biology chemistry Nitroimidazoles Pretomanid Nitro Molecular Medicine Delamanid medicine.drug |
| Zdroj: | Bioorganic and medicinal chemistry letters |
| ISSN: | 0960-894X |
| Popis: | As part of a quest for backups to the antitubercular drug pretomanid (PA-824), we investigated the unexplored 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]-thiazoles and related-oxazoles. The nitroimidazothiazoles were prepared in high yield from 2-bromo-4-nitroimidazole via heating with substituted thiiranes and diisopropylethylamine. Equivalent examples of these two structural classes provided broadly comparable MICs, with 2-methyl substitution and extended aryloxymethyl side chains preferred; albeit, S-oxidised thiazoles were ineffective for tuberculosis. Favourable microsomal stability data for a biaryl thiazole (45) led to its assessment in an acute Mycobacterium tuberculosis mouse model, alongside the corresponding oxazole (48), but the latter proved to be more efficacious. In vitro screening against kinetoplastid diseases revealed that nitroimidazothiazoles were inactive versus leishmaniasis but showed interesting activity, superior to that of the nitroimidazooxazoles, against Chagas disease. Overall, "thio-delamanid" (49) is regarded as the best lead. (C) 2017 Elsevier Ltd. All rights reserved. |
| Databáze: | OpenAIRE |
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