Design,Synthesis And Antifungal Activity Of Novel Triazolones

1,2,4-Triazole derivatives have always been the most widely used drugs in clinical treatment of invasive fungal infections due to their advantages of broad antibacterial spectrum,low toxicity,high efficiency,and stable pharmacokinetics.However,the problem of drug resistance caused by the overuse of antibiotics has led to the decline of the efficacy of traditional antifungal agents.Hence,the development of a new generation of drug-resistant antifungal drugs has become a research hotspot for researchers.In this paper,a series of 1,2,4-triazolones derivatives were synthesized by using 1,2,4-triazole as the parent nucleus,using the computer-aided drug design method and the basic principles of drug design,combined with the structure-activity relationship of antifungal drugs.The specific work is as follows: 1、The classification,action mechanism,drug resistance mechanism of antifungal drugs and the application of 1,2,4-triazole derivatives in the field of medicine were summarized.2、Cytochrome CYP51 was selected as the fungal target enzyme(PDB:6CR2),and the designed compounds were theoretically screened by molecular simulation software such as Autodock.The potential activity of the compound was evaluated according to the difference of the minimum binding energy,so as to determine the general formula of the target compound.3、Using substituted benzoic acid as raw material,a series of substituted benzoic hydrazides were synthesized by esterification and hydrazinolysis reaction;benzoxazin-4-one intermediates were synthesized from salicylic acid or 4-trifluoromethylsalicylic acid and salicylic amide by one-pot cooking method;a series of 1,2,4-triazolones derivatives were synthesized by the ring-opening rearrangement reaction of hydrazide and imine intermediates.All compounds were confirmed by 1H NMR,13 C NMR and LC mass spectrometry.4、With voriconazole as the positive control drug,the in vitro antifungal activity of the synthesized target compounds was evaluated by micro-dilution method.The tested fungi were Candida albicans,Candida tropicalis,Candida glabrata and Aspergillus niger.The results showed that most of the compounds had potential antibacterial activity,and the MIC90 values were concentrated in the range of 16-64 μg/m L.Among them,the antibacterial activity of compound B7 against Candida tropicalis,Candida glabrata and Candida albicans is significantly better than that of voriconazole,and it can be used as a candidate compound for new antifungal drugs for further development and research.5、The interaction between some compounds and protein targets and the reasons for the differences in biological activities were visually analyzed by molecular docking technology.The results showed that trifluoromethyl is beneficial to improve the antibacterial activity of these compounds.At the same time,when the benzene ring on the side chain of the 1-position N atom of the triazole ring contains an electron-withdrawing substituent(F or Cl),the biological activity of the compound is significantly stronger than that of the electron-donating substituents(CH3 or CH3O),and para-substitution is more advantageous than ortho-substitution.