Design, Synthesis And Activity Study Of Creatine Derivatives

Cerebral creatine deficiency is a disease caused by AGAT and GAMT defects and SLC6A8 gene mutations.SLC6A8 gene mutations can lead to creatine transport deficiency.At present,the therapeutic drugs widely studied are mainly creatine esters and creatine amide precursors,which cross the cell membrane in a transporter-independent manner and are crucial for the treatment of creatine transporter deficiency.Creatine esters and creatine amide derivatives were designed with benzyl creatine as the lead compound.According to the blood-brain barrier penetration strategy and using Chemdraw to calculate the physical and chemical properties of the designed compounds,the lipid-water partition coefficients of the selected creatine esters(1.84-3.29)were better than benzyl creatine ester(Log P=1.13),and the lipid-water partition coefficients of the selected creatine amide derivatives(1.28-2.47)were higher than creatine benzyl ester and reported compounds.In this paper,14 creatine derivatives were synthesized,including 5 creatine esters(2a-e)and 9 creatine amide derivatives(4a-i).By reading and summarizing the literature,the route was determined to use N,N’-di-tert-butoxycarbonyl-S-methylisothiourea and sarcosine as the starting materials to generate Boc group-protected creatine(intermediate1).Then,Steglich esterification method was used to react with different benzyl alcohol substrates.During the reaction,the synthesis of intermediate 1a was taken as the research object.Different carbodiimide condensation agents,the feed ratio of condensation agent,solvent and reaction material ratio were studied,and the optimum process parameters were determined.Finally,the Boc protecting group was removed under acidic conditions,and five creatine esters were synthesized.Creatine amide derivatives were synthesized by amide condensation reaction of intermediate 1 with different aromatic amine substrates.The activated ester method and the carbodiimide condensation agent method were selected for the reaction.During the period,the synthesis of intermediate 3f was taken as the research object,and the condensation agent and material ratio were studied to determine the optimal reaction conditions.The prepared compounds 4a,2b,2e were tested for neuroprotection in rats.Methods:The middle cerebral artery occlusion(MCAO)model of rats was established by suture method.The rats were randomly divided into sham operation group,MCAO group,drug4a(283 mg/kg)group,drug 2b(100 mg/kg)group and drug 2e(100 mg/kg)group.The area of cerebral infarction was detected by TTC method.Conclusion: Compounds 4a(30.76±3.81%)and 2e(35.59±5.57%)can improve the symptoms of neurological deficits after cerebral infarction in MCAO rats.There was statistical significance between each dose group and sham operation group(P<0.05).