Design,Synthesis And Structure-activity Study Of Acetophenene Derivatives

Fungi-derived natural products with unique skeletons and bioactivities provide considerable drug leads and candidates,thereby constituting a hotspot in the field of drug discovery.In a study aiming to discover new antifungal agents and anti-cancer drugs,we focused our interest on naturally occurring substance with multiple bioactivities as starting material for the rational design of new compounds.2,4-dihydroxy-5-methyl acetophenone is a secondary metabolite isolated from the higher fungus Poluporus picipes Fr,although it has been reported to have a wide range of significant biological activities such as antimicrobial activity,cytotoxic activity,antioxidant activity etc.Few studies about the influence of the substitutes and acetophenone skeleton on its antifungal and anticancer activities were reported.Here in,a series of 2,4-dihydroxy-5-methyl acetophenone derivatives were rationally designed and synthesized;their antimicrobial and anticancer activities were evaluated,the structure-activity relationship of the target compounds was also studied.The results of this dissertation are listed as follows:1.Three different strategies were applied to obtain the natural product2,4-dihydroxy-5-methyl acetophenone,the reaction mechanisms were explored and two new possible reduction mechanisms were proposed;the factors such as reaction temperature,reaction time and solvent influencing on yield were discussed as well.2.A series of acetophenone derivatives were designed on the basis of naturally occurring substance?2,4-dihydroxy-5-methyl acetophenone?.One hundred and sixty-four acetophenone analogues?seven classes?were conveniently synthesized by multiple synthetic procedures;115 of them were reported for the first time.Their structures were elucidated by ¹H-NMR,¹³C-NMR and EI-MS analysis.3.In vitro antifungal activities against a panel of important phytopathogenic fungi including Cytospora sp.,Glomerella cingulated,Pyricularia oryzaecar,Botrytis cinerea and Alternaria solani.were tested by mycelia growth rate assay at 100?g/mL.Compounds displayed optimal activities against tested fungi were further investigated their half maximal inhibitory concentration(IC₅₀),together with the lipophilicity values of the compounds?log P?,we discussed the structure-activity relationship.The results showed that most synthesized molecules exhibited a broad spectrum of antifungal activities against tested organisms;some of them appeared significant more effective than the positive control Thiabendazole.The most active ketone derivatives have a log P values ranging from 1.71 to 2.54,an increase in the chain length of linear alkyl ketones led to enhanced antifungal activities,the IC₅₀0 of?-7 against Pyricularia oryzaecar was 17.28?g/mL;Active ethers have a log P value in the range of 1.32-1.55 and 2.01-2.5,?-1 and?-10 showed stronger activities than Thiabendazole;oximes possessed a broad spectrum of antifungal activity,in particular?-2,?-3 and?-11?log P 1.97-2.84?were found to be active against all the phytopathogenic fungi;isoxazole and benzophenone derivatives were inactive against tested fungi;DAPG derivatives had specific antifungal property,?-12 exerted remarkable antifungal activity against Glomerella cingulate and Pyricularia oryzaecar with IC₅₀ values of 1.26?g/mL and1.52?g/mL,respectively.Besides,those DAPG derivatives??-2,?-3,?-10 and?-11?have a log P values ranging from-0.53 to 0.98 also exerted notable in vitro activities with IC₅₀ value less than 10?g/mL,much lower than positive control Thiabendazole.The compounds mentioned above might be promising leads for agricultural fungicides.4.In vitro antimicrobial activity of the isoxazoles against Bacillus subtills,Staphylococcus aureus,Escherichia coli and Pseudomonas aeruginosa were examined by paper filtering method and TTC microdilution method.The results suggested that isoxazole derivatives?-2,?-7 and?-11 had specific antimicrobial activity,and displayed certain inhibition against Gram negative Bacillus subtills and Staphylococcus aureus.5.Cytotoxic activity assay against brine shrimp?Artemia salina?demonstrated that ketone derivatives?-10,?-11 and?-17 had a reasonable cytotoxicity against brine shrimp,with LC₅₀ value of 20.8,19.6 and 20.4?g/mL,respectively.Ether compound?-20exerted a comparable activity to positive control Sannastatin;Oxime and isoxazole derivatives were found to be inactive against Artemia salina;as for benzophenone derivatives,SAR study revealed that 3-methyl is essential to the cytotoxic activity,the introduction of substituents on the aromatic ring enhance the activity,especially compounds?-15 and?-26,bearing 2-iodine and-3,4,5-trimethoxyl group were found to be the most active ones.6.Antitumor activity of target compounds was studied by SRB assay through determining the inhibition effect on the proliferation of Chinese hamster ovary?CHO?,human gastric carcinoma cells?SGC-7901?,human cervical carcinoma cell line?HeLa?and human prostate cancer cell line?PC-3?in vitro.The results indicated that among the ketone and ether derivatives,?-10,?-11,?-12,?-20 and?-24 had potent antitumor effects,with IC₅₀ values less than 15?M against tested cell lines;benzophenone derivatives displayed remarkable in vitro activity,in particular,compound?-15 was found active against HeLa and PC-3 with IC₅₀0 of 0.52?M and 5.74?M,?-15 also had an outstanding cytotoxic activity,IC₅₀:1.14?M?HeLa?,5.12?M?PC-3?and 6.83?M?CHO?;compound?-26 showed good cytotoxic activities against all the cancer cells with IC₅₀ values of 5.62?M?HeLa?,7.35?M?PC-3?and 11.15?M?CHO?,respectively.7.The results obtained from structure-activity relationship?SAR?of acetophenone derivatives on antifungal and anticancer activities suggested that some synthetic compounds can be considered promising candidates in the development of new antifungal and antitumor agents.