The synthesis and biological evaluation of virtually designed fluoroquinolone analogs against fluoroquinolone-resistantEscherichia coliintended for UTI treatment

Fluoroquinolones (FQs) are one of the most commonly prescribed classes of antibiotics for the treatment of urinary tract infections (UTIs), but FQ-resistantEscherichia coli(E. coli) in UTIs is widespread and increasing. In order to address the resistance-related issue, novel drug molecules with the capacity to overcomeE. coliresistance are crucial for modern healthcare. Based on this rationale, the virtually screened novel FQ analogsFQ-49,FQ-70,FQ-131,FQ-132,FQ-137,FQ-147,FQ-151,FQ-172,FQ-177, andFQ-182were synthesized using a microwave-assisted technique. These compounds possessed excellent activity against FQ-resistantE. coliand inhibited purified mutant DNA gyrase activityin vitro.A 3D-QSAR modeling study was used to identify the potent FQ analogs and calculate their molecular properties. Sequence analysis of the quinolone-resistance determining region (QRDR) of purified mutant DNA gyrase enzyme confirmed the presence of Ser83Leu and Asp87Asn mutations in FQ-resistantE. coliisolates from UTI patients. Overall, this study confirmed that ten of the synthesized novel FQ analogs exhibited extremely potent antibacterial activity against existing FQ-resistantE. coli, and they could be further successfully utilized for the treatment of UTIs.