A novel 1-benzoazepine-derived Michael acceptor and its hetero-adducts active against MRSA

Abstract

Multidrug-resistant bacterial infections continue to be a rising global health concern. Herein, we describe the development of a novel class of 3-substituted benzoazepinedione derivatives with promising antibacterial activity. The pivotal compound, benzoazepinedione carboxylate 9, represents a highly electrophilic Michael acceptor, enabling divergent access to a wide range of thia-, aza-, oxa-, and phospha-Michael adducts. Notably, most prepared compounds exhibited potent antibacterial activity against both drug-susceptible and drug-resistant strains of Staphylococcus aureus (MIC₉₀ of up to 2 μg mL⁻¹). The cytotoxicity assessment in the VERO6 cell line revealed that thia-adduct 10d (IC₅₀ of 36.5 μg mL⁻¹) exhibits lower toxicity compared to its parent electrophile 9 (IC₅₀ of 14.3 μg mL⁻¹), which is in agreement with the hypothesis of covalently modified prodrugs. Additionally, stability studies of the prepared compounds in CD₃OD and a DMSO–PBS mixture confirmed that thia-Michael adducts 10 are stable under neutral conditions while dynamic under mildly basic conditions. Moreover, 3D reconstructed tissue models (human lung epithelial EpiAirway™ and a human small intestine model) did not exhibit a viability decrease below 80% of the untreated control at all concentrations tested, indicating tolerance to higher concentrations of potential drugs and prodrugs.