6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]thiazoles: Facile synthesis and comparative appraisal against tuberculosis and neglected tropical diseases |
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| Authors: | Andrew M. Thompson Adrian Blaser Brian D. Palmer Robert F. Anderson Sujata S. Shinde Delphine Launay Eric Chatelain Louis Maes Scott G. Franzblau Baojie Wan Yuehong Wang Zhenkun Ma William A. Denny |
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| Affiliation: | 1. Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;2. Department of Chemistry, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;3. Drugs for Neglected Diseases Initiative, 15 Chemin Louis Dunant, 1202 Geneva, Switzerland;4. Laboratory for Microbiology, Parasitology and Hygiene, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium;5. Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA;6. Global Alliance for TB Drug Development, 40 Wall St, New York 10005, USA |
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| Abstract: | 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. |
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| Keywords: | KZFRULYIWSGDHV-UHFFFAOYSA-N ZLFWFIZYALOODH-UHFFFAOYSA-N MFDANUGWANIOOJ-UHFFFAOYSA-N SKMAQZSSDQYMHA-UHFFFAOYSA-N JLIZCKIDPGDOOM-UHFFFAOYSA-N Tuberculosis Chagas disease Delamanid Nitroimidazole |
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