Novel desfluoroquinolone–sulfonamide hybrids as potential anti-MRSA agents: synthesis, drug-likeness, molecular docking, and molecular dynamics simulation study

Abstract

The overuse of antibiotics has led to Staphylococcus aureus developing resistance to conventional antibiotics, resulting in methicillin-resistant Staphylococcus aureus (MRSA), which poses a major threat to global morbidity and mortality. DNA gyrase exerts antibacterial effects by obstructing bacterial DNA translocation, leading to DNA fragmentation, which is essential for bacterial viability. Here, we present the design and synthesis of a series of hybrid compounds with previously known antibacterial sulfonamide moieties attached to a desfluoroquinolone scaffold. Sixteen desfluoroquinolone compounds containing a sulfonamide structure were synthesized by active substructure splicing, and these compounds were then subjected to computational simulation analysis, including drug-like analysis, molecular docking, and MMGBSA simulation. The results indicated that the synthesized molecules displayed satisfactory drug-likeness and stable binding modes with DNA gyrase, proving their potential as anti-MRSA agents. Based on the MMGBSA binding affinity values, the top four hit compounds (X01, X05, X12, and X14) were identified and subjected to 100 ns molecular dynamics simulations. The dynamics of the protein–ligand complexes were analyzed, confirming the results of the molecular docking and MMGBSA analysis studies. Further examination of the free energy landscape information validated the potential of desfluoroquinolone–sulfonamide hybrids as novel anti-MRSA agents.