A series of hybridized pyrrolidine compounds with a 1,2,4‐oxadiazole moiety were
synthesized to develop effective molecules against the enzymes DNA gyrase and
topoisomerase IV (Topo IV). Compounds 8–20 were developed based on a
previously disclosed series of compounds from our lab, but with small structural
modifications in the hopes of increasing the compounds' biological activity. In
comparison to novobiocin, with IC50 = 170 nM, the findings of the DNA gyrase
inhibitory assay revealed that compounds 16 and 17 were the most potent of all
synthesized derivatives, with IC50 values of 180 and 210 nM, respectively.
Compound 17 had the strongest inhibitory effect against Escherichia coli Topo IV
of all the synthesized compounds, with an IC50 value of 13 μM, which was
comparable to novobiocin (IC50 = 11 μM). Therefore, hybrids 16 and 17 appeared to
be potential dual‐target inhibitors. In the minimal inhibitory concentration (MIC)
assays, compound 17 outperformed ciprofloxacin against E. coli, with an MIC of
55 ng/ml, compared to 60 ng/ml for ciprofloxacin. Finally, the docking study, along
with the in vitro experiments, supports our promising approach to effectively
develop potent leads for further optimization as dual DNA gyrase and Topo IV
inhibitors.