Development of nitro-substituted bis-CF3 sulphonamides with potent antibacterial activity against multidrug-resistant Uropathogenic E. coli

Multidrug-resistant (MDR) Uropathogenic Escherichia coli (UPEC) is a leading cause of Urinary tract infections (UTIs) worldwide. Its resistance is growing rapidly to various conventional antibiotics and poses a severe threat to global health due to growing recurrent infections, prolonged hospitalization, treatment failure, and increasing healthcare costs. The urgent need for novel antibacterial drugs with greater effectiveness has been emphasized by the rising resistance of UPEC to commonly used antibiotics, particularly sulfonamides. Nowadays, the clinical effectiveness of well-established antibacterial sulfonamide-based drugs is compromised due to widespread resistance. Therefore, structural improvement of sulfonamide via a nitro group and electron-withdrawing fluorine substituents is an excellent strategy to enhance the target-binding affinity, lipophilicity, and antibacterial activity while potentially overcoming current mechanisms of resistance. Despite this, nitro-substituted fluorinated sulfonamide derivatives have not yet been explored against MDR UPEC. In this work, a library of sixteen sulfonamide derivatives was synthesized via nucleophilic substitution reactions and characterized using Fourier transform infrared spectroscopy (FTIR), gas chromatography–mass spectrometry (GC-MS), and nuclear magnetic resonance spectroscopy (NMR). Broth microdilution and colony-forming unit assays were used to evaluate their antibacterial activity, and field-emission scanning electron microscopy was used to examine bacterial morphology changes. Among all compounds, 4g (nitro-substituted bis-CF3 sulfonamide) exhibited promising activity with an MIC of 125 μg/mL, demonstrating an 87.5% reduction relative to the reference sulfamethoxazole concentration of 1000 μg/mL. Structure–activity relationship analysis revealed that antibacterial performance was enhanced due to the incorporation of a nitro group and trifluoromethyl functionalities. Molecular docking studies further supported these findings, using bacterial Dihydroproteorate synthase (DHPS), compound 4g demonstrated the strongest binding affinity (-8.2 kcal/mol), approximately 10.8% higher than that of sulfamethoxazole (-7.4 kcal/mol). Overall, these findings signify that nitro-substituted tri-fluorinated sulfonamide derivatives are promising antibacterial agents and offer an appropriate platform for developing next-generation drugs for effective clinical therapies against UPEC-associated urinary tract infections.