Study On The Synthesis And Biological Activity Of Carnosic Acid Derivatives

Objective:To synthesize novel camosic acid(CA)derivatives,which were expected to have improved neuroprotective ability.Methods:In the study,we synthesized a total of 42 novel derivatives by reduction,oxidation and condensation reaction.Compound 1 was acquired by conducting a ketalization reaction between the phenolic hydroxyl groups in CA and acetone.In the next step,compound 1 was reduced to produce compound 2 using lithium aluminium hydride(LAH).Compound 2 was then oxidized using Dess-Martin periodinane(DMP),and compound 3 was acquired as a result.Compound 1 and the respective amines were converted into a series of amides a1-a19 with the method in which HATU was used as the condensation agent.An intermediate was generated during the synthesis process of amides a1-a19.Another series of amides b1-b19 were obtained by taking off protective isopropyl groups.The yields of all the CA derivatives were quite satisfying with the.method.All the CA derivatives produced in this study were reported for the first time,and the structures of all the CA derivatives were characterized using various spectroscopic techniques.Then,we used an H2O2-induced hippocampal neuron damage model to test the neuroprotective effects of CA derivatives by using cell counting kit-8(CCK-8).Results:Experimental results showed that the neuron viability of the most samples that are pretreated with CA derivatives increased compared with the H2O2-induced group(*P<0.05).It was also discovered that amides a6,a10,a11,a18 and ester 4 had higher activity than that of their parent compound CA compared with positive control group of CA(AP<0.05).The aromatic substituted amides tended to be more effective than heterocyclic or straight chain substituted amides were.The para-methyl-or ortho-chloro-substituted amides were found to be more active among the various benzyl-substituted amides,and the ethyl-phenyl-substituted amide was the most effective one.Conclusions:The catechol hydroxyl groups and carboxyl groups might not be truly necessary for the neuroprotective activity of CA,and choosing suitable substituents helps to further improve the activity and physicochemical properties of the compounds.CA and its derivatives are worthy of developing into neuroprotective agents,owing to their promising in vitro efficacy.The findings of this study provide more basis for future research into CA and its derivatives.