Novel 7-substituted Fluoroquinolone Citrate Conjugates as Powerful Antibacterial and Anticancer Agents: Synthesis and Molecular Docking Studies

摘要

In this study, the synthesis and evaluation of norfloxacin analogues of dimethyl citrate conjugates were described and their antibacterial and anticancer activities were assessed. The cognate 7-substituted norfloxacin citrate conjugates are active against various strains of bacteria, including MRSA (methicillin-resistant Staphylococcus aureus) with higher activity than ciprofloxacin. Screening results indicated that compound 10 possessed good antibacterial activity against several microorganisms, with MIC values in the range of 0.16-0.35 mg/mL and MBCs in the range of 0.55-0.84 mg/mL. Experiments indicated that 9 demonstrated the most significant activity towards the HCT-15 cell line with IC50 value 8.2 +/- 0.139 and against the HT-29 cell line with IC50 8.9 +/- 0.122. The title compounds were also evaluated for determining the molecular and phannacokinetic properties and drug-likeness model scores by using the Molinspiration-2008 and MolSoft-2007 softwares. The region isomeric conjugates followed the Lipinski's rule of five can be considered as potential antibacterial and anticancer bioavailable oral leads. Compounds 9 and 10 possessed maximum drug-likeness scores. The docking pose interactions of target compounds with the active site of enzyme PDB: 2ZCS of Staphylococcus aureus were estimated by using Autodock 4.2, to calculate the affinity, binding orientation of the ligand with the target protein and to explore the finest conformations. The target compounds, 7, 8, 9, 10, with protein, were loaded separately into Auto dock tools (ADT) and evaluated. The citrate conjugates, 8, 9, showed better docking scores with amino acids Lys17, Ser21, Va1268, Lys273 and Arg171, Arg265, Va1268, Va1273 with the binding energy -5.70, -5.57 kcal/mol and dissociation constant 66.62, 82.13 mu M respectively.