New non-β-lactam 4,4′-methylenedianiline compounds: design, synthesis and assessment of anti-β-lactamase activity

Abstract

Infectious disorders are among the dominant causes of death globally, and the β-Lactams are the most effective antibiotics for managing these disorders. Unfortunately, Antimicrobial resistance has been frequently observed internationally, represented by the bacterial β-lactamase which breaks down the β-lactam ring, consequently disabling these drugs. The use of β-lactamase inhibitors (e.g., clavulanic acid) combined with β-lactams can minimize bacterial resistance. Therefore, these challenges necessitate the exploration for new remedies with potential antimicrobial and anti-β-lactamase properties. This study utilizes docking design to synthesize and evaluate the antibacterial and anti-β-lactamase activities of new non-β-lactam 4,4'-methylenedianiline amides. The production of these amides was achieved through the reaction of carboxylic acids with 4,4'-methylenedianiline using the coupling agent N,N'-dicyclohexylcarbodiimide (DCC). After characterization of the new amides based on physical and spectral data, they were tested biologically against four strains of β-lactamase-producing Gram-positive and Gram-negative bacteria to assess their anti-β-lactamase activities and compared with that of clavulanic acid as a co-inhibitor with amoxicillin. The resulting data indicate that all the synthesized compounds exhibited varying degrees of activity against the β-lactamases of all bacterial strains. The activity against P. aeruginosa was weaker than against Staph. aureus and E. coli. The observed activities were still weaker than that of the standard clavulanic acid. It has been determined that the β-lactamase active site favors hydrophobic substituents, and halogen atoms and the nitro group enhance the binding of these hydrophobic residues and potentiate it.