Design,Synthesis And Activity Evaluation Of Novel Derivants Ofacacetin

Acacetin,chemical name 5,7-dihydroxy-4'-methoxyflavone and also known as locustanin or acacia,obtained from chrysanthemum,natural locust,snow lotus and other plants,is a classic and natural flavonoids.Acacetin has a wide range of biological activities,such as anti-oxidation,anti-cancer,anti-virus,anti-asthma,anti-neuritis,anti-cardiovascular disease and so on,but its efficiency is low and the exact mechanism remains unclear.In recent years,new studies have shown that acacetin showed stronger activities(IC50)than clinical commonly used drugs in anti-atrial fibrillation,anti-gout and analgesia.However,as a flavonoid compound,the planar structure of the large conjugated region of the flavonoid ring leads to poor water solubility,low oral absorption,low bioavailability in vivo and poor chemical resistance.In our previous research,a series of novel acacetin derivatives were designed and synthesized.On the one hand,the introduction of active pharmacophore improved the efficacy of specific therapy,such as anti gout andanalgesia.On the other hand,amino acid prodrugs were designed based on the prodrug strategy,which were used amino or carboxyl to form salt,to improve the water solubility and bioavailability.The biological evaluation indicated that Aca-Z12,an acacetin derivative that the 7th hydroxyl hydrogen in acacetin was substituted by acetamino,is a high active compound whose analgesic activity was significantly higher than that of acacetin(89.41% VS 69.79%),and the water solubility was also significantly improved.The results stated above show that the introduction of acylamino groups has an important role of improving the activity of 7th acacetin,and providing conditions for further research of designing the new higher activity derivatives.Based on keeping the amide pharmacophore activity and used Aca-Z12 as the lead compound,the novel drugs were designed to determine the influence of different alkyl chain length of carbon atoms containing amide groups on the biological activity of acacetin.At the same time,the new 7-and 5-substituted acacetin derivatives with ether and ester bond as a connecting key and containing different amide group were designed to improve the water solubility by introducing PEG(polyethylene glycol)and piperidyl respectively.The molecular weight and chemical structure of the target compounds were confirmed by ESI-MS and 1H-NMR,and the melting point of the compounds were also determined.Three kinds of pain models containing the mouse acetic acid writhing model,the mouse formalin licking model and the mouse hot plate model were used to evaluate the analgesic activity of the compounds,and the preliminary structure-activity relationship was analyzed.The evaluation results of acetic acid writhing model in mice showed that the new designed and synthesized compounds have a certain degree of analgesic activity.The analgesic effect of intraperitoneal administration was stronger thanthat of oral administration.Intraperitoneal injection results showed that acacetin and its derivatives had good analgesic effect on acetic acid writhing model in mice.Analgesic activity was significantly stronger than diclofenac and basically the same as the early active detection compound Aca-Z12.The activity of intragastric administration was significantly lower than that of intraperitoneal injection,possibly due to the low solubility and poor absorption of acacetin and its derivatives.Three new compounds,Aca-L08,Aca-L09 and Aca-L12,were found to be comparable or slightly stronger than the positive control compound Aca-Z12 in both intraperitoneal injection and intraperitoneal administration.The preliminary structure-activity relationship analysis showed that the aliphatic carbon chain length of the amide-based acacetin derivatives had no significant effect on the activity.The intraperitoneal injection of Aca-L01,Aca-L02,Aca-L03,Aca-L14 and Aca-L15 showed significant or slightly elevated activity compared with acacetin,but decreased than that of Aca-Z12.Intraperitoneal injection of the new compound Aca-L12 showed a significantly higher activity than diclofenac,acacetin(Aca)and Aca-Z12,indicating that the acetylamino as functional groups may be specific for the activity of the acacetin derivatives and provided a reference for the next optimized design.The number of amide groups and the type of amide alkyl chain of a liphatic side chains have some effect on the activity and the activity of t he substitutes side chain is better than that of the straight chain and the ring chain.The activity of 7-substituted acacia derivatives that introduced PEG fragment were higher than that of the acacetin,but not as high as the activity of the precursor Aca-Z12.In addition,the substituents in dif ferent positions also had different effect on the activity and the 5-substitu ted products had a higher activity compared with the 7-substituted compounds.The results of the detailed structure-activity relationship study are st ill remained to be supported by more compound activity data.The results of the mouse formalin licking model showed that the new compounds showed a certain degree of neuralgia inhibitory activity at a dose of10 mg/kg for intraperitoneal administration,which was comparable to that of the positive drug Ralfinamide or better than Ralfinamide,indicating that acacia compounds also has an inhibitory effect on neuropathic pain.The research reports are few and it is worth further in-depth study.Although the results of the hot plate method showed the new compounds have a certain analgesic effect,the abnormal behavior,jumping behavior rather than licking,of the mice in the experiment showed that the hot plate method may not be suitable for the activity evaluation of acacin compounds.In this study,a series of new strains of acacia derivatives were designed and synthesized based on the active primers in previous studies.Through three kinds of mice analgesic model evaluation,we found a new structure of acacia derivatives with better analgesic activity.The activity of the three new compounds is comparable to that of the positive control and can be used as a new natural source of active leader analgesic drugs.