Abstract
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 language | English (US) |
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Pages (from-to) | 6385-6397 |
Number of pages | 13 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 21 |
Issue number | 21 |
DOIs | |
State | Published - 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.
Keywords
- Aminothiazole
- Antibacterial agent
- High-throughput screening
- Mycobacterium tuberculosis