Design,synthesis And Bactericidal Activity Of Novel Bacteriostatic Agents Based On Topoisomerase ?

With the widespread application of antibiotics,the emergence of multi-drug resistant bacteria strains has caused serious threats to human life and health.Therefore,the optimization and modification based on the original antibiotic scaffold and the development of antibiotics with a new scaffold have become the key measures to solve this problem.This paper designed and synthesized three series of derivatives,70 coumarin-pyrazole carboxamide derivatives?A series?,24 coumarin-thiazolyl ester derivatives?B series?and48 multi-substituted benzoindole-pyrazole Schiff base derivatives?C series?by using of drug design strategy based on fragment and pharmacophores.All target compounds were characterized by ¹H NMR,¹³C NMR and MS.Some compounds were characterized by single crystal diffraction.In the paper,Novobiocin,Ciprofloxacin,Gatifloxacin,and Levofloxacin were used as control drugs.The MIC of 4 common bacteria was determined for all compounds.Some compounds were tested for IC₅₀ for 6 drug-resistant bacteria strains.The results indicated that the 8III-k?MIC=0.25?g/m L?exhibited considerable inhibitory activity than Ciprofloxacin?MIC=0.5?g/m L?against E.coli,8V-c?MIC=0.05?g/m L?exhibited excellent antibacterial activity than Ciprofloxacin?MIC=0.25?g/m L?against Salmonella;8p exhibited excellent antibacterial activity against 4 bacteria strains with MIC values of 0.05,0.05,8,and 0.05?g/m L,respectively;8I-w exhibited excellent antibacterial activity against four drug-resistant E.coli bacteria strains with IC₅₀ values of 7.0,17.0,13.5,and 1.0?M,respectively.In addition,compounds can bind well to the bacterial Topoisomerase II by interacting with various amino acid residues.In summary,a total of 142 compounds in three series were synthesized using efficient and convenient methods,and 4 compounds with excellent antibacterial activity were found.These can provide a theoretical basis for solving the harm of drug-resistant bacteria and lay a certain practical foundation for the search for a new topoisomerase II inhibitor.