Synthesis Of ?-Arylidene Lactams And Their Antifungal Activity

The scaffolds of natural products have served as templates for a vast array of commercial pesticides.In our previous works,the structural motif ?-methylene-?-butyrolactone(MBL or tulipalin A)has been found to be the main pharmacophore of antifungal compound carabrone and this pharmacophore has potential for designing new bioactive antifungal agents.Meanwhile,a great many botanical antifungal compounds which occur ?,?-unsaturated ester or amide motif bear the cinnamoyl scaffold in addition to the MBLscaffold,which gives the opportunity to comprehensively take advantage of these two different scaffolds via scaffold hopping strategy.For the above accounts,a set of ?-arylidene-?-lactams were designed and synthesized via scaffold hopping and bioisosteric replacement strategies to investigate their antifungal activity.Furthermore,three different approaches were undertaken to optimize the scaffold of ?-arylidene-?-lactam containing changing ring size and substitution of benzo group and heteroatoms-containing groups on ? and ? sites.This study could give useful cues to further optimize the scaffold of ?-arylidene-?-lactams.The main results were as following:1.Fifty one ?-arylidene-?-lactam and four ?-methylene-?-lactam compounds were synthesized and their antifungal activities were evaluated.The antifungal test results indicated that compounds Py2,Py15 and Py16 were the potent compounds against Colletotrichum orbiculare with EC50 values of 21.4 ?g/mL,19.7 ?g/mL and 19.9 ?g/mL,respectively;and Py2 possesses the highest antifungal activity against Gaeumannomyces gramini with EC50 value of 46.9 ?g/mL.Structure-activity relationship(SAR)analysis revealed that introduction of F and CF3 groups on arylidene could increase the potency.Compounds Py15 and Py23 had in vivo protective efficacy against cucumber anthracnose disease with control rates 68.7% and 57.7% respectively at the concentration of 500 ?g/mL,showing higher efficacy than that of carbendazim(61.5%).Compound Py2 displayed lower than carbendazim at 1000 ?g/mL.Compound Py34 showed comparable in vivo protective efficacy at the concentration of 500 ?g/mL with triadimefon at the concentration of 150 ?g/mL.2.Thirty two ?-arylidene-?-lactams and twenty eight ?-arylidene-?-lactams were synthesized and their antifungal activities were tested.The antifungal test results indicated that these compounds were less potent against the testing fungi and only compounds Pi13,Pi18,Az26 and Az27 have higher antifungal activity against G.gramini with EC50 values of 86.5 ?g/mL,55.6 ?g/mL,65.7 ?g/mL and 64.5 ?g/mL,respectively.The systemic SAR analysis revealed that the ?-arylidene-?-lactam scaffold was beneficial for the potency than ?-arylidene-? and ?-lactam scaffolds.3.Twenty eight 3-benzylideneindolin-2-ones were synthesized and their antifungal activities were evaluated.The antifungal test results indicated that compounds Ox10,Ox12 and Ox27 were the potent compounds against G.gramini with EC50 values of 41.0 ?g/mL,37.0 ?g/mL and 24.9 ?g/mL,respectively;and Ox24 and Ox25 possesses the highest antifungal activity against B.cinerea with EC50 value of 49.5 ?g/mL and 46.5 ?g/mL respectively.SAR analysis revealed that introduction of F,Cl and CH3 groups on 5-site of indolin-2-one were beneficial for the potency.Compounds Ox10 and Ox28 had higher in vivo protective efficacy than carbendazim against wheat taken-all disease with control rates of 62.2% and 61.4% respectively at the concentration of 1000 ?g/mL.These results demonstrates that introduction of benzo group at ? and ? sites could increase the potency against G.gramini and B.cinerea.4.Compound Ma1 showed higher inhibition rates of mycelium growth against C.orbiculare and B.cinerea than compounds Hy,Tho,Tha and Rh.Therefore,twenty five 3-benzylidenepyrrolidine-2,5-diones were synthesized and their antifungal activities were evaluated.The antifungal test results indicated that compounds Ma23 and Ma26 were the potent compounds against C.orbiculare with EC50 values of 15.6 ?g/mL and 24.3 ?g/mL,respectively;and Ma18,Ma23 and Ma26 possesses the highest antifungal activity against B.cinerea with EC50 value of 35.1 ?g/mL,25.4 ?g/mL and 28.7 ?g/mL.SAR analysis revealed that introduction of different substituents on benzylidene led to limited increase in potency and incorporation of benzyl into N atom could result in a significant increase in potency.Compounds Ma23 and Ma26 had comparable in vivo protective efficacy with carbendazim against cucumber anthracnose disease with control rates 63.5% and 57.6% respectively at the concentration of 500 ?g/mL.Compound Ma26 showed comparable in vivo protective efficacy with carbendazim against tomato grey mold disease.These results verified that introduction of heteroatomic group at ? and ? sites could increase the potency against C.orbiculare and B.cinerea.In conclusion,173 ?-arylidene lactams were synthesized and the results revealed that ?-arylidene-?-lactam scaffold was beneficial for the potency than ?-arylidene-? and ?-lactam scaffolds.Through the optimization of ?-arylidene-?-lactams,compounds Ox27 and Ma23 showed good in vitro and in vivo antifungal activities against G.gramini and C.orbiculare respectively.These results revealed that ?-arylidene-?-lactam possesses the potential for further investigation.