Design,Synthesis And Bioactivity Evaluation Of Indoquinone Derivatives As Bacterial Inhibitors

The use of antibiotics is an effective method to treat a variety of bacterial or microbial infections.Bacterial resistance reduces the therapeutic effect of drugs and seriously threatens human's well-being.However,traditional antibacterial drugs have disadvantages such as large dosage needed and severe side effects,so there is urgency for more safe and efficient bacterial inhibitors.In recent years,DNA Gyrase and FabH have become the focus of antibacterial research.DNA Gyrase belongs to the topoisomerase ? type,whose homologue in human is topoisomerase ?,and is important for the growing cycle of bacteria,DNA replication,transcription,recombination,gene expression,chromosome depolymerization and other biological processes.While FabH plays a key role in controlling the biosynthesis of fatty acid by being involved in its initial steps and feedback regulation.Being able to be widely and safely applied,dual inhibition has become an promising solution for bacterial resistance.Isatin,as a Indoquinone derivative,was used as the potential inhibitor for DNA gyrase and after a 2-round-screening it was modified to become an atypical dual inhibitor for DNA Gyrase(major)and FabH(assistant)to suppress DNA replication(DNA Gyrase)and cell survival(FabH).Most of the synthetic compounds showed inhibiting effect against DNA gyrase,notably,some of the compounds performed well in inhibiting FabH as well.Compound 118(IC50= 0.025 ?M),the best-performed compound in activity among all,was comparable to that of Novobiocin(IC50= 0.040,uM),the drug used as positive control.Meanwhile it also repressed the activity of FabH(IC50=5.20 ?M)successfully.Besides,docking simulation suggested that there may be important interactional residues and binding modes between the compound and its two target proteins.This compound owned the characteristics of high efficiency,low initial toxicity and the capability of dual inhibition.The comprehensive discussion on its structure-activity relationship also provided directions for further development and clinical application of advanced compounds.Similarly,most indoquinone derivatives also have an anti-bacterial resistance towards Helicobacter pylori(Hp),a common acid-resistant pathogen induce gastritis,stomach ulcers and even stomach cancer.While ureases within catalyze the hydrolysis of urea producing ammonia and carbon dioxide so that the indispensable nitrogen can be obtained.Not only is urase essential in plants and microorganisms,it also play an important part in how gastric and peptic ulcers are induced by Hp.The concentration around Hp was elevated under the help of urase,resulting in a higher pH which benefits its survival under an acidic environment within a human's stomach.In order to inhibit ureases in Hp,a series of novel Indoquinone derivatives named S1-S20 were synthesized.Among all,S18(IC50=0.71 ?M;MIC = 0.48 ?M)stood out for its superior inhibitory activity compared to both AHA(IC50= 17.2 ?M)and Metronidazole(MIC = 31.3?M),the drug used as positive control in this study.In addition,it also had the advantage of low cytotoxicity.Molecular docking simulation revealed the potential binding model between the drug and its target enzymes.The construction of 3D-QSAR model provided guidance for the further design and optimization of inhibitors towards urease in Hp and laid foundation for the follow-up research.By structural modification combined with computer-aided drug design,a series of indoquinone derivatives was designed and synthesized in our study so as to seek possible solutions for bactarial resistance,which provided a reference for the future improvement of anti-bacterial drugs and was of great significance for the survival and development of mankind.