Synthesis And Fungicidal Activity Of Tetronic Acid Derivatives Incorporating Substituted Phenylhydrazine Moiety

Naturally occurred tetronic acids with a heterocyclic core of 4-hydroxy-furan-2(5H)-one or furan-2,4(3H,5H)-dione,isolated from sponge,fungus and streptomyces,have been found to span a wide range with a focus on antibacterial,antitumor,antifungal,antioxidant,anti-HIV-1 and insecticidal effects,which attracted the attention of chemists.Many tetronic acid derivatives were synthesized,and some of them exhibited notable bioactivities.In this paper,substituted phenylhydrazine was introduced at 3-position of 5-(un)substituted-3-alkylidene-tetronic acid to synthesize fifty-five novel tetronic acid derivatives.Their preliminary fungicidal activities were also evaluated.3-(1-Hydroxyethylidene)-5-methylfuran-2,4(3H,5H)-dione was prepared by the reactions of O-acetoacetylation and cyclization starting from L-ethyl lactate.And three 3-(1-hydropyalkylidene)furan-2,4(3H,5H)-diones and(dimethylaminomethylidene)furan-2,4(3H,5H)-dione were prepared by 4-oxyalkylation,cyclization and acylation from ethyl 4-chloroacetoacetate.These intermediates were reacted with substituted phenylhydrazine to give fifty-five novel 3-(1-(2-(substituted phenyl)hydrazinyl)alkylidene)furan-2,4(3H,5H)-diones.The structures of these target compounds were confirmed by FT-IR,1H NMR,13C NMR,EI-MS,elemental analysis and X-ray diffraction.The fungicidal activities of all target compounds against Fusarium graminearum,Botrytis cinerea,Rhizoctonia cerealis and Colletotrichum capsici were evaluated in vitro with mycelial growth rate method at the concentration of 10 ?g/mL.The EC50 values of some selected compounds were determined.The results showed that the target compounds exhibited notable fungicidal activities against the tested fungi.The compound A6 showed the best activity against F.graminearum with EC50 value of 0.1957 ?g/mL,lower than 0.3849 ?g/mL of the control drug carbendazim.The compound A8 exhibited the best activity against B.cinerea,its EC50 value of 0.1672 ?g/mL was better than 0.2398 ?g/mL of procymidone.The compound B8 gave the best activity against R.cerealis,its EC50 value 0.0585 ?g/mL was near to the value 0.0270 ?g/mL of carbendazim.The compound A8 showed the hightest activity against C.capsici,and its EC50 value was 0.1189 ?g/mL,better than 0.2875 ?g/mL of azoxystrobin.The relationship of target compound structure and the bioactivity was analysed.The relation between alkylidene at 3-position of furan-2,4(3H,5H)-dione and bioacitivity could be concluded as ethylidene>methylidene>propylidene>butylidene.When halogen was introduced at 4-position of phenyl ring,the corresponding compounds showed good fungicidal acitivities against F.graminearum and B.cinerea.When halogen was introduced at 2-postion of phenyl ring,the corresponding compounds demonstrated good antifungal activities against R.cerealis and C.capsici.In addition,the 3D-QSAR was studied.The CoMFA and CoMSIA were applied to research the relationship between target compound structure and their antifungal activities against B.cinerea.The models indicated that the bulky hydrophobic group with negative charge at phenyl ring played an importan role in improving antifungal activity against B.cinerea.