6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]thiazoles: Facile synthesis and comparative appraisal against tuberculosis and neglected tropical diseases

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

Research output: Research - peer-reviewArticle

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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.

LanguageEnglish (US)
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number11
DOIs
StatePublished - Jun 1 2017

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Neglected Diseases
Thiazoles
Tuberculosis
Oxazoles
2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo(2,1-b)(1,3)oxazine
Antitubercular Agents
Leishmaniasis
Chagas Disease
Mycobacterium tuberculosis
Heating
Lead
In Vitro Techniques
4-nitroimidazole
OPC-67683
ethylene sulfide
Screening
Substitution reactions

Keywords

  • Chagas disease
  • Delamanid
  • In vivo efficacy
  • JLIZCKIDPGDOOM-UHFFFAOYSA-N
  • KZFRULYIWSGDHV-UHFFFAOYSA-N
  • MFDANUGWANIOOJ-UHFFFAOYSA-N
  • Nitroimidazole
  • SKMAQZSSDQYMHA-UHFFFAOYSA-N
  • Tuberculosis
  • ZLFWFIZYALOODH-UHFFFAOYSA-N

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]thiazoles : Facile synthesis and comparative appraisal against tuberculosis and neglected tropical diseases. / Thompson, Andrew M.; Blaser, Adrian; Palmer, Brian D.; Anderson, Robert F.; Shinde, Sujata S.; Launay, Delphine; Chatelain, Eric; Maes, Louis; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 27, No. 11, 01.06.2017.

Research output: Research - peer-reviewArticle

Thompson, AM, Blaser, A, Palmer, BD, Anderson, RF, Shinde, SS, Launay, D, Chatelain, E, Maes, L, Franzblau, SG, Wan, B, Wang, Y, Ma, Z & Denny, WA 2017, '6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]thiazoles: Facile synthesis and comparative appraisal against tuberculosis and neglected tropical diseases' Bioorganic and Medicinal Chemistry Letters, vol 27, no. 11. DOI: 10.1016/j.bmcl.2017.03.069
Thompson, Andrew M. ; Blaser, Adrian ; Palmer, Brian D. ; Anderson, Robert F. ; Shinde, Sujata S. ; Launay, Delphine ; Chatelain, Eric ; Maes, Louis ; Franzblau, Scott G. ; Wan, Baojie ; Wang, Yuehong ; Ma, Zhenkun ; Denny, William A./ 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]thiazoles : Facile synthesis and comparative appraisal against tuberculosis and neglected tropical diseases. In: Bioorganic and Medicinal Chemistry Letters. 2017 ; Vol. 27, No. 11.
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AU - Anderson,Robert F.

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AU - Launay,Delphine

AU - Chatelain,Eric

AU - Maes,Louis

AU - Franzblau,Scott G.

AU - Wan,Baojie

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