Structure-activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis

Anja Meissner, Helena I. Boshoff, Mahalakshmi Vasan, Benjamin P. Duckworth, Clifton E. Barry, Courtney Aldrich

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37 Scopus citations


A series of 2-aminothiazoles was synthesized based on a HTS scaffold from a whole-cell screen against Mycobacterium tuberculosis (Mtb). The SAR shows the central thiazole moiety and the 2-pyridyl moiety at C-4 of the thiazole are intolerant to modification. However, the N-2 position of the aminothiazole exhibits high flexibility and we successfully improved the antitubercular activity of the initial hit by more than 128-fold through introduction of substituted benzoyl groups at this position. N-(3-Chlorobenzoyl)-4-(2-pyridinyl) -1,3-thiazol-2-amine (55) emerged as one of the most promising analogues with a MIC of 0.024 μM or 0.008 μg/mL in 7H9 media and therapeutic index of nearly ∼300. However, 55 is rapidly metabolized by human liver microsomes (t1/2 = 28 min) with metabolism occurring at the invariant aminothiazole moiety and Mtb develops spontaneous low-level resistance with a frequency of ∼10-5.

Original languageEnglish (US)
Pages (from-to)6385-6397
Number of pages13
JournalBioorganic and Medicinal Chemistry
Issue number21
StatePublished - Nov 1 2013

Bibliographical note

Funding Information:
This research was supported by a National Institutes of Health Grant AI070219 (to C.C.A.) and the Intramural Research Program of the NIAID, NIH.


  • Aminothiazole
  • Antibacterial agent
  • High-throughput screening
  • Mycobacterium tuberculosis

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