Lead Identification of 8‑(Methylamino)-2-oxo-1,2-dihydroquinoline Derivatives as DNA Gyrase Inhibitors: Hit-to-Lead Generation Involving Thermodynamic Evaluation

DNA gyrase and topoisomerase IV are
well-validated pharmacological
targets, and quinolone antibacterial drugs are marketed as their representative
inhibitors. However, in recent years, resistance to these existing
drugs has become a problem, and new chemical classes of antibiotics
that can combat resistant strains of bacteria are strongly needed.
In this study, we applied our hit-to-lead (H2L) chemistry for the
identification of a new chemical class of GyrB/ParE inhibitors by
efficient use of thermodynamic parameters. Investigation of the core
fragments obtained by fragmentation of high-throughput screening hit
compounds and subsequent expansion of the hit fragment was performed
using isothermal titration calorimetry (ITC). The 8-(methylamino)-2-oxo-1,2-dihydroquinoline
derivative 13e showed potent activity against Escherichia coli DNA gyrase with an IC50 value of 0.0017 μM. In this study, we demonstrated the use
of ITC for primary fragment screening, followed by structural optimization
to obtain lead compounds, which advanced into further optimization
for creating novel antibacterial agents.