Synthesis and biological screening of novel 2-azetidinone derivatives as antimicrobial agents

beta-lactam antibiotics are a mainstay of antimicrobical therapy and play an important role treating infections with a broad spectrum of Gram-positive and Gram-negative bacteria. These molecules exhibit their bactericidal effects by inhibiting enzymes involved in the biosynthesis of bacterial cell wall decomposing the peptide-glycan network building blocks in the cell walls. In the last years the indiscriminate use of antibiotics has highlighted an alarming increase of drug-resistant bacteria and the most commonly acquired mechanism of antibiotic resistance is the ability of bacteria to express enzymes (-lactamases) inactivating these drugs. The goal of the present work is to prepare a series of novel semi-synthetic -lactam compounds containing an azetidinone moiety joined to the amino-nitrogen of the 6-aminopenicillanic acid (6-APA).The synthetic route was designed because of the sensitivity of the 2-azetidinone towards ring-opening reaction by nucleophiles so to preserve the stability and the pharmacological activity of the 6-aminopenicillanic acid (6-APA). The general synthetic strategy involves the synthesis of structurally different -lactams derivatives by stereoselective Staudinger reaction [2+2]. The 2-azetidinones are sequently linked to the 6-APA affording the title compounds in high yield. SAR studies are performed introducing different functional groups on the azetidinone motif and all the synthesized compounds are screened as antibacterials against four human pathogenic bacteria (two Gram positive bacteria Staphilococcus aureus and Streptococcus pneumonia and two Gram negative bacteria Klebisella pneumonia and Pseudomonas Aeruginosa).