Design Synthesis And Bioactivity Evaluation Of Novel GyrB/ParE Inhibitors And LpxC Inhibitors

The severe infection associated with bacteria has become a major threat to public health and life.Multidrug-resistant Gram-negative bacteria are more worrying and difficult to control among these pathogens,however the corresponding antimicrobial drugs are very scarce.Therefore,there is an urgent need of safe and effective anti-Gram-negative bacteria agents for clinic use.Bacteria II topoisomerase,namely DNA gyrase and topoisomerase IV,which are common constituents of all bacteria,serve as the key enzymes that are necessary for bacterial DNA replication and cell survival and are identified as important antimicrobial targets.Both enzymes are tetramers composed of two subunits?[?GyrA?₂?GyrB?₂]and[?ParC?₂?ParE?₂]?.In recent years,Gyr B/Par E double targeting inhibitors have been found to selectively act on the ATP hydrolase regions of GyrB subunit and ParE subunit by competitive inhibition of ATP hydrolysis,blocking the energy supply of the enzyme catalyzed reaction,and thus inhibiting bacterial DNA replication,leading to bacterial death,which is different from the quinolone drugs with a novel mechanism of action.Some compounds such as benzimidazole series and Tirus's tricyclic series exhibit excellent anti-Gram-negative bacteria activity,which possess a very good prospects for further research.The lipopolysaccharide?LPS?layer is a peculiar structure of the outer wall of the gram-negative bacterial cell wall,and Lipid A,one of its components,is responsible for anchoring LPS to the extracellular membrane and preventing the intrusion of environmental hazards.Studies have shown that lipid A is critical to the growth of gram-negative bacteria and that the inhibition of its synthesis can lead to bacterial death.LpxC is a key metalloproteinase in the biosynthesis of lipid A,which is widely found in gram-negative bacteria and can be inhibited by small molecule metalloproteinase inhibitors,making it a very attractive antimicrobial target.Based on the binding mode of ATPase and small molecule inhibitors in DNA gyrase and topoisomerase IV,nine GyrB/ParE inhibitors with novel structures were designed and synthesized by the combination with the amino group of Tirus's tricyclic series,which plays an important role in the anti-negative bacteria activity,utilizing the methods of pharmacophore splice,bioisosterism and etc.On the other hand,we were enlightened from the stucture of another type of metalloenzyme inhibitor—peptide deformylase?PDF?inhibitor,and designed and synthesized four compounds by introducing the N-formylhydroxylamine fragment into the existing Lpx C inhibitors,expecting to find Lpx C inhibitors with excellent activity,improved metabolic properties and less toxicity.Unfortunately,the compounds we designed did not show significant antibacterial activity against the tested strains in the in vitro antibacterial activity test,demonstrating that our strategy of modifications failed.Although the structure-based design has not been successful,our work has still contributed to the further development of these agents with considerable SAR datas.