Structure-activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis.
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 0.024μM or 0.008μg/mL in 7H9 media and therapeutic index of nearly ∼300. However, 55 is rapidly metabolized by human liver microsomes (t1/2=28min) with metabolism occurring at the invariant aminothiazole moiety and Mtb develops spontaneous low-level resistance with a frequency of ∼10(-5).
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
Anja
A
Meissner
Helena I
HI
Boshoff
Mahalakshmi
M
Vasan
Benjamin P
BP
Duckworth
Clifton E
CE
Barry
Courtney C
CC
Aldrich
D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014709:Vero Cells
D000995:Antitubercular Agents; C588114:N-(3-chlorobenzoyl)-4-(2-pyridinyl)-1,3-thiazol-2-amine; D011725:Pyridines; D013844:Thiazoles
Aminothiazole; Antibacterial agent; High-throughput screening; Mycobacterium tuberculosis