Synthesis, Characterization And Biological Activity Of S-β-D- Glucosides Of 1,2,4-Triazole Derivatives

In this paper, 3-S-2’,3’,4’,6’-tetra-O-acetyl-β-D-glucopyranosyl-4-amino-5-substitutedphenyl-1,2,4-triazole(5R1-5R9), 3-S-2’,3’,4’,6’-tetrahydroxy-β-D-glucopyranosyl-4-amino-5-substituted-phenyl-1,2,4-triazole(6R1-6R9) and 2-S-(2’,3’,4’,6’-tetra-O-acetyl-β-Dglucopyranosyl)-5-((4-substituted phenyl-5-amino-4H-1,2,4-triazol-3-ylthio) methyl)-1,3,4-oxadiazole(10R1-10R4), 22 compounds in total were rationally designed and synthesized according to the superposition principle of bioactive substructures by the combination of "ortho-hydroxyphenyl," "1,2,4-triazole," "1,3,4-oxadiazole" and " glycosylation". The structures of all target compounds were confirmed by 1H NMR, 13 C NMR, IR and HRMS spectrum.A series of potassium compounds were prepared by substituted benzoyl hydrazide and CS2 in potassium hydroxide. These compounds were converted to 4-amino-5-substituted phenyl-3-ylsulfanyl 4H-1,2,4-triazol 4 by cyclization in hydrazine hydrate. Compounds 5R1-5R9 were synthesized by glycosylation of 4 and bromo-2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside in the presence of potassium hydroxide with acetone as solvent. Compounds 6R1-6R9 were prepared from 5R1-5R9 by deacetylating in methanol-dichloromethane solvent with sodium methoxide as catalyst. Compounds 4 were used as starting materital to prepare the target compounds 10R1-10R4 by hydrazinolysis, cycliztion and condensation. This paper discusses the influence of reaction medium, temperature and the amount of alkali on the yield of the compounds 6R1-6R9. Finally the better reaction condition is found as: methanol and dichloromethane at volume ratio of 1:1, temperature at 20~25 ℃, sodium methoxide and 5R1-5R9 at molar ratio of 1~3: 1. This approach has the advantages of short reaction time, less side effects, complete removing of four acetyl and higher yield.The preliminary bioassay was carried out as U.S. National Clinical Laboratory Standards Committee(NCCLS) Minimal Inhibitory Concentration regulation, using Fluconazole and Triclosan as the reference drugs. We measured the antibacterial activity of the target compounds against Escherichia coli, Staphylococcus aureus, Bacillus subtilis and Candida albicans. The test results show that 5R1-5R9 and 10R1-10R4 have strong antibacterial activity than triclosan against Candida albicans; and have certain antibacterial effect against Escherichia coli and Staphylococcus aureus; but lack sensitive against Bacillus subtilis. Compounds 6R1-6R9 have good antibacterial effect against the four kinds of strains. After removal of the acetyl, compounds significantly increase antibacterial activity against Escherichia coli, Staphylococcus aureus and Bacillus subtilis. Compounds 10R1-10R4, containing both triazole and oxadiazole, significantly increase antibacterial activity against Escherichia coli and Staphylococcus aureus. The interaction and binding free energy of the target compounds with Fab I were studied by Autodock.QSAR analysis shows that:(1) Compounds with halogen substituents increase the antibacterial activity against Escherichia coli, Staphylococcus aureus, Bacillus subtilis and Candida albicans;(2) To compare the antimicrobial activity of the bromine and chlorine moiety on the phenyl ring, the introduction of bromine is more conducive to increase the antimicrobial activity;(3) Compounds with halogen substituents have different effect on the antibacterial activity in different locations, for example compound 6R5 with para chlorine substituted has better antibacterial activity against bacteria than compounds 6R6 with ortho chlorine substituted, but the inhibitory activity against fungi is on the contrary.;(4) Compounds containing both triazole and oxadiazole increase antibacterial activity against Escherichia coli and Staphylococcus aureus;(5) Compounds after removal of the acetyl increase antibacterial activity against Escherichia coli, Staphylococcus aureus and Bacillus subtilis.