Synthesis and evaluation of 1,2,4-triazolo[1,5-a]pyrimidines as antibacterial agents against Enterococcus faecium.
Rapid emergence of antibiotic resistance is one of the most challenging global public health concerns. In particular, vancomycin-resistant Enterococcus faecium infections have been increasing in frequency, representing 25% of enterococci infections in intensive care units. A novel class of 1,2,4-triazolo[1,5-a]pyrimidines active against E. faecium is reported herein. We used a three-component Biginelli-like heterocyclization reaction for the synthesis of a series of these derivatives based on reactions of aldehydes, β-dicarbonyl compounds, and 3-alkylthio-5-amino-1,2,4-triazoles. The resulting compounds were assayed for antimicrobial activity against the ESKAPE panel of bacteria, followed by investigation of their in vitro activities. These analyses identified a subset of 1,2,4-triazolo[1,5-a]pyrimidines that had good narrow-spectrum antibacterial activity against E. faecium and exhibited metabolic stability with low intrinsic clearance. Macromolecular synthesis assays revealed cell-wall biosynthesis as the target of these antibiotics.
Department of Chemistry and Biochemistry and Eck Institute for Global Health, University of Notre Dame, 423 Nieuwland Hall, Notre Dame, Indiana 46556, United States.
Huan
H
Wang
Department of Chemistry and Biochemistry and Eck Institute for Global Health, University of Notre Dame, 423 Nieuwland Hall, Notre Dame, Indiana 46556, United States.
Mijoon
M
Lee
Department of Chemistry and Biochemistry and Eck Institute for Global Health, University of Notre Dame, 423 Nieuwland Hall, Notre Dame, Indiana 46556, United States.
Zhihong
Z
Peng
Department of Chemistry and Biochemistry and Eck Institute for Global Health, University of Notre Dame, 423 Nieuwland Hall, Notre Dame, Indiana 46556, United States.
Blas
B
Blázquez
Department of Chemistry and Biochemistry and Eck Institute for Global Health, University of Notre Dame, 423 Nieuwland Hall, Notre Dame, Indiana 46556, United States.
Elena
E
Lastochkin
Department of Chemistry and Biochemistry and Eck Institute for Global Health, University of Notre Dame, 423 Nieuwland Hall, Notre Dame, Indiana 46556, United States.
Malika
M
Kumarasiri
Department of Chemistry and Biochemistry and Eck Institute for Global Health, University of Notre Dame, 423 Nieuwland Hall, Notre Dame, Indiana 46556, United States.
Renee
R
Bouley
Department of Chemistry and Biochemistry and Eck Institute for Global Health, University of Notre Dame, 423 Nieuwland Hall, Notre Dame, Indiana 46556, United States.
Mayland
M
Chang
Department of Chemistry and Biochemistry and Eck Institute for Global Health, University of Notre Dame, 423 Nieuwland Hall, Notre Dame, Indiana 46556, United States.
Shahriar
S
Mobashery
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D016984:Enterococcus faecium / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D046915:Penicillin-Binding Proteins / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D046915:Penicillin-Binding Proteins; D011743:Pyrimidines; D014230:Triazoles