3 years ago

Methodology for Monobactam Diversification: Syntheses and Studies of 4-Thiomethyl Substituted β-Lactams with Activity against Gram-Negative Bacteria, Including Carbapenemase Producing Acinetobacter baumannii

Methodology for Monobactam Diversification: Syntheses and Studies of 4-Thiomethyl Substituted β-Lactams with Activity against Gram-Negative Bacteria, Including Carbapenemase Producing Acinetobacter baumannii
Rui Liu, Marvin J. Miller, Scott J. Hecker, Tomasz Glinka, Patricia A. Miller, Serena Carosso
Bromine induced lactamization of vinyl acetohydroxamates facilitated syntheses of monocyclic β-lactams suitable for incorporation of a thiomethyl and extended functionality at the C(4) position. Elaboration of the resulting substituted N-hydroxy-2-azetidinones allowed incorporation of functionalized α-amino substituents appropriate for enhancement of antibiotic activity. Evaluation of antibacterial activity against a panel of Gram-positive and Gram-negative bacteria revealed structure–activity relationships (SAR) and identification of potent new monobactam antibiotics. The corresponding bis-catechol conjugate, 42, has excellent activity against Gram-negative bacteria including carbapenemase and carbacephalosporinase producing strains of Acinetobacter baumannii, which have been listed by the WHO as being of critical concern worldwide.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b01164

DOI: 10.1021/acs.jmedchem.7b01164

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