Design, Synthesis, in silico Molecular Docking, ADMET Analysis and in vitro Antibacterial Activity of Pyranopyrazole Derivatives as Potent Glucosamine-6-Phosphate Synthase Inhibitor

Background

The need for new antibacterial medicines arises from the emergence of antibiotic-resistant bacterial strains. Pyranopyrazole derivatives, known for their diverse biological activities, are investigated for their potential to inhibit glucosamine-6-phosphate synthase, a critical enzyme in bacterial cell wall biosynthesis.

Materials and Methods

Pyranopyrazole derivatives (SW1-SW10) were synthesized via a one-pot multicomponent reaction. In silico ADME and toxicity analyses were conducted to predict pharmacokinetic profiles and potential toxicities. Molecular docking studies were conducted to evaluate binding affinities with glucosamine-6-phosphate synthase (PDB ID: 2VF5). The in vitro antibacterial activity was assessed by measuring the zones of inhibition against Escherichia coli and Staphylococcus aureus at concentrations of 25 µg/mL, 50 µg/mL and 100 µg/mL.

Results

The docking investigations indicated that SW6 and SW4 exhibited robust binding affinities, with docking scores of -9.4 and -9.0, respectively. In silico ADME analysis indicated favorable drug-likeness, with SW1, SW2, SW7 and SW10 meeting all criteria and showing bioavailability scores of 0.55. In vitro antibacterial experiments revealed that SW6 displayed the greatest efficacy, with inhibition zones measuring 9.5±0.2 mM, 14.6±0.5 mM and 20.3±0.7 mM against E. coli and 10.2±0.3 mM, 15.2±0.6 mM and 21.3±0.8 mM against S. aureus at escalating doses. SW4 exhibited comparable efficacy, with inhibition zones measuring 20.8±0.3 mM and 20.2±0.7 mM at 100 µg/mL against S. aureus and E. coli, respectively.

Conclusion

The pyranopyrazole derivatives, particularly SW6 and SW4, exhibit strong potential as antibacterial agents. Their high binding affinities and significant in vitro antibacterial activity suggest that these compounds could be promising leads for developing new antibacterial therapies targeting antibiotic-resistant strains.