Synthesis and antimicrobial activity of the hybrid molecules between amoxicillin and derivatives of benzoic acid

Due to the increasing problem of bacterial resistance worldwide, the demand for new antibiotics is becoming increasingly urgent. We wished to: (a) prepare hybrid molecules by linking different pharmacophores by chemical bonds; (b) investigate the antib acterial activity of these hybrids using drug‐sensitive and drug‐resistant pathogens in vitro and vivo. A series of hybrid molecules with a diester structure were designed and synthesized that linked amoxicillin and derivatives of benzoic acid via a methylene bridge. Synthesized compounds were evaluated for activities against Gram‐positive bacteria (Staphylococcus aureus American Type Culture Collection [ATCC] 29213, ATCC 11632; methicillin‐resistant S. aureus [MRSA] 11; Escherichia coli ATCC 25922) and Gram‐negative bacteria (Salmonella LS677, GD836, GD828, GD3625) by microdilution of broth. Synthesized compounds showed good activity against Gram‐positive and Gram‐negative bacteria in vitro. In particular, amoxicillin‐p‐nitrobenzoic acid (6d) showed good activity against Salmonella species and had better activity against methicillin‐resistant S. aureus (minimum inhibitory concentration [MIC] = 64 μg/ml) than the reference drug, amoxicillin (MIC = 128 μg/ml). Amoxicillin‐p‐methoxybenzoic acid (6b) had the best antibacterial activity in vivo (ED50 = 13.2496 μg/ml). The hybrid molecules of amoxicillin and derivatives of benzoic acid synthesized based on a diester structure can improve the activity of amoxicillin against Salmonella species and even improve the activity against MRSA.