TP0480066, a selective topoisomerase II inhibitor, demonstrates excellent inhibitory activity against DNA gyrase (IC50 = 1.10 nM) and topo IV (IC50 = 62.89 nM). This compound exhibits potent efficacy against multiple bacterial species, including drug-resistant strains. Moreover, TP0480066 displays significant inhibitory activity against N. gonorrhoeae, making it suitable for research on gonorrhea [1] [2].

TOPO IV:62.89 nM, DNA gyrase:1.10 nM

TP0480066 (compound 32) has demonstrated notable antimicrobial efficacy within concentrations of 0-2048 μg/mL over 18-24 hours, showcasing robust activity against a variety of bacterial species, including drug-resistant strains like MRSA (n=24), gPRSP (n=30), and VRE (n=34), as well as against Clostridioides difficile. Moreover, within a 24-48 hour timeframe, TP0480066 has shown potent activity against N. gonorrhoeae, including those strains exhibiting decreased susceptibility or resistance to existing antimicrobial agents. Specifically, at concentrations of 1.25×10^-4, 5×10^-4, and 2×10^-3 μg/mL over 24 hours, it displayed effective time-kill activity against N. gonorrhoeae ATCC 49226, significantly reducing its viable counts. Cell viability assays further confirmed TP0480066's broad-spectrum antimicrobial potential, illustrating favorable activities against clinically isolated methicillin-resistant S. aureus, vancomycin-resistant enterococci (including E. faecium and E. faecalis), and genotype penicillin-resistant S. pneumonia with minimum inhibitory concentration (MIC) ranges indicative of high efficacy. Additionally, against various N. gonorrhoeae strains, including ATCC and NCTC lines, TP0480066 exhibited significant antimicrobial activities at exceptionally low MIC values, highlighting its potential as a formidable agent against both standard and drug-resistant bacterial pathogens.

Administered subcutaneously at a dose of 100 mg/kg, TP0480066 demonstrates significant pharmacokinetic parameters in female Slc:ICR mice, achieving a peak concentration (C max) of 12400 ng/mL at 0.250 hours (T max), with a half-life (t 1/2) of 6.79 hours, and an area under the concentration-time curve (AUC) from 0 to 24 hours of 16000 ng×h/mL. Additionally, in a dose-dependent manner, TP0480066, at dosages of 1, 3, 10, 30, and 100 mg/kg, markedly inhibits the growth of N. gonorrhoeae ATCC 49226 and NCTC 13479 in female BALB/c mice with genital tract infections, showing significant effectiveness at 30 and 100 mg/kg doses. These outcomes are drawn from studies employing subcutaneous injections in single doses across different concentrations, highlighting TP0480066's potential against N. gonorrhoeae infections.