Synthesis and “In Silico” Evaluation of the Biological Activity of the New Dual Inhibitors of Gyrase DNA and Topoisomerase IV ^†

Quinolones are effective against a broad range of bacterial species and provide potent treatment options for a few infections [1,2]. Quinolones act in a highly unusual mode, and kill bacteria by converting essential enzymes, DNA gyrase or topoisomerase IV, into potent cellular toxins that generate high levels of double-stranded chromosomal breaks. In addition to their effects on the bacterial enzymes, some quinolones display high activity against a variety of eukaryotic type II topoisomerases, including human [3]. The understanding the ability of quinolones to preferentially target the different prokaryotic and eukaryotic type II topoisomerases remains a major challenge for the researchers.

The DFT/B3LYP/6-311 G* level of the basis set has been used for the computation of molecular structures. The score and hydrogen bonds formed with the amino acids from the binding site of the receptor protein are used to predict the binding modes, the binding affinities and the orientation of the docked quinolones. The quinolone compounds were synthesized and characterized by physical–chemical methods and by biological activity.

Some quinolone compounds were designed and synthesized. For these compounds there were calculations performed of characteristics and molecular properties and molecular docking studies to identify and visualize the most likely interaction ligand (quinolone) with the receptor targets, which were imported from the Protein Data Bank (PDB ID: 4P8O, 3M4I, 1ZXM, 2ZD1). The study was performed relating to some quinolone compounds known in medical therapeutics: ciprofloxacin, vosaroxin, elvitegravir. The result of the molecular docking study (docking score), (Figure 1) shows that the nature of the substituents on the quinolone nucleus influences the binding affinity and binding mode of a quinolone to the receptor protein.

The prediction of the binding affinity of a new compound to an identified target is a significant parameter in the development of a new drug and would allow restricted the synthesis to the most promising compounds.