Design,Synthesis,and Biological Activities Of Novel Isobutyrophenone Derivatives

The agricultural diseases and insect pests caused to decrease the production and quality of cash crops,led to significantly threaten the agricultural economy.The excessive use of synthetic pesticides not only resulted in the environment pollution but also affected to the human healthy and animals.Natural products and their analogs are important sources to discovery of biologically active compounds and new drug lead compounds.Acetophenone isolated from the higher fungus Polyporus picipes exhibits antifungal and antibacterial properties.Our pervious studies,isobutyrophenone which is one of acetophenone derivative displayed have good antifungal activity,so,in this study focused on the discovery and structural optimization of potential targets related to isobutyrophenone.The antifungal activities of all synthesis compounds were tested against seven phytopathogenic fungi.The potential targets for their antifungal activity were confirmed as inhibitor type II fructose-1,6-bisphosphate aldolase for the first time.Their α-glucosidase inhibitory activities were evaluated and the structure-antifungal relationships were also discussed.The main results are as follows:1.A series 46 compounds of 1-(2,4-dihydroxy-5-methylphenyl)-2-methylpropan-1-one(3)derivatives were designed and synthesized.The antifungal activity of synthetic compounds were evaluated for against seven phytopathogenic fungi including Botrytis cinerea,Alternaria solani,C.gloeosporiodes,Fusarium solani,F.Graninearum,Cytospora sp(Valsa mali)and Magnaporthe grisea.Compounds 4a,5a,5c,5d,5e exhibited as a good antifungal activities.Antifungal properties of compound 5a exhibited strong with relatively high selectivity to against B.Cinerea,C.Gloeosporiodes and,Fusarium solani with EC50 values 4.12,6.56 and 9.87 μg/m L,respectively,5c has the best inhibitory activity against Cytospora sp,EC50 is 1.42 μg/m L;5d had the best inhibitory activity against F.Graninearum and Fusarium solani,with EC50 of 6.51 and 2.67 μg/m L,respectively,5e also had a good inhibitory activity against Fusarium graminearum with an EC50 of 2.49 μg/m L.This compounds also exhibited potential Mg-Fba enzyme inhibitory activity with IC50 data in the range of 28.91-69.82 μM.2.The 3,4 and 5-modified derivatives were synthesized with the isobutyrophenone skeleton.The structure-activity relationship(SAR)study showed that the introduction of a bromo group at the 3 to 5 position of the benzene ring and the esterification of the 4-hydroxy group with the chloroacetyl group can significantly improve the antifungal activity and broad spectrum of the compound.Among them,compound 12 b were showed the best antifungal activity against 7 plant pathogenic fungi,with the EC50 ranged from 1.22 to 39.44 μg/m L.Moreover,it has exhibited the highest type II fructose-1,6-bisphosphate aldolase inhibitory activity with IC50 of 3.63 μM,which is higher nearly 7.9 times than compound 5e(IC50 = 28.91 μM).In vivo fruit tests showed that compound 12 b has the practical potential to protect fruits(or plants)from pathogens,and its protective ability is similar to that of azoxystrobin.Cytotoxicity results of synthesized compounds on normal cells line NIH3T3 and 293 T and silkworms shown that all compounds were non-toxicity and safe with living environment of the organism.Therefore,compounds 12 b are well worth the consideration as a safe and effective fungicidal product to control plant diseases.3.α-glucosidase inhibitory activity of 76 new isobutyrylphenol derivatives were evaluated.Structure-activity relationship(SAR)studies have shown that the introduction of the bromine atom on the 3-phenyl,iodomethyl group at 4 position and the methyl group on the 5-phenyl ring were play an important role to increase the inhibitory of α-glucosidase activity.Among them,compound 12 d exhibits the best α-Glucosidase inhibitory activity with an IC50 of 0.57 μM.The interaction mechanism of the inhibitors with α-glucosidase showed that compound 12 d could bind to other site of α-glucosidase enzyme with hydrogen bonds interactions.The everts intestinal sleeves in vitro and the sucrose loading test in vivo on the rat α-glucosidase inhibition of the lead compound proved that they have significant postprandial hypoglycemic effects.These compounds may serve as lead for the future research in order to identify a potent and safer therapy for the treatment of diabetes mellitus.