Design,synthesis And Biological Activity Of Chiral Mandelic Acid Derivatives Containing A "1,3,4-oxadiazole Sulfide" Moiety

Mandelic acid has broad-spectrum biological activity and been used as an important chiral intermediate in drug design for many years.Its derivatives were widely used in anti-cancer,sterilization,anti-inflammation and other aspects.Mandelic acid derivatives that used as pesticides can control the diseases infected with Phytophthora infestans and Plasmopara viticola.A series of chiral mandelic acid derivatives with the structure of"1,3,4-oxadiazole sulfide"were designed and synthesized on the basis of our previous work in this work.The bioactivity of the target compounds against pathogenic fungi was tested in vitro using the mycelial growth rate method.The difference of biological activity between enantiomers were compared.And the preliminary action of mechanism were studied.Thirty-three pairs of chiral mandelic acid with the structure of"1,3,4-oxadiazolyl sulfide"were synthesized through esterification,hydrazinolysis,closed-loop reaction and thioetherification that used R/S-4-substituted mandelic acid as the starting materials.All the target compounds were confirmed by ¹H nuclear magnetic resonance（¹H NMR）,¹³C nuclear magnetic resonance(¹³C NMR),¹⁹F nuclear magnetic resonance(¹⁹F NMR),high resolution mass spectrometry（HRMS）and single crystal diffraction（X-ray）.In vitro antifungal activity of the target compounds against Gibberella saubinetii,Verticillium dahliae and Sclerotinia sclerotiorum were tested with the mycelial growth rate method.Most of the target compounds showed good inhibitory effects against the three fungi.The results revealed that when 4-position of mandelic acid was substituted by chlorine,the antifungal activity of most S-configuration compounds were better than that of their R-enantiomers.The EC₅₀ value（317.0μg/m L）of compound H₃ against Gibberella saubinetii was 16.4 times than that of H₃’（19.3μg/m L）.The EC₅₀ value（129.0μg/m L）of compound H₁₅ against Verticillium dahliae was 6.5 times than that of compound H₁₅’（19.8μg/m L）.The EC₅₀ value（203.9μg/m L）of compound H₁₅ against Sclerotinia sclerotiorum was 7.2 times than that of compound H₁₅’（28.4μg/m L）.In vivo antifungal avtivity against Sclerotinia sclerotiorum exhibited significant differences between curative and protective activities for the enantiomers H₁₅ and H₁₅’.At the concentration of 200μg/m L,the curative activity of compound H₁₅’was 72.1%,which was higher than that of H₁₅（46.4%）,mandipropamid（38.1%）and hymexazol（67.8%）.The protective activity of H₁₅ was 78.0%,which was higher than that of H₁₅’（56.2%）,mandipropamid（64.1%）,but slightly lower than that of hymexazol（85.5%）.The further mechanism of action of the enantiomers were explored by the mycelial morphology study of Gibberella saubinetii and Sclerotinia sclerotiorum which treated with the enantiomers that exhibited large differences in activity.The results indicated that the enantiomer with higher-activity can destroy the cell membrane of pathogenic fungi more seriously,change its permeability,deform the mycelium growth and inhibit its growth.This may be the main reason for the difference in activity between the enantiomers.