Design, Synthesis And Anti-ischemic Activities Of Linarinic Acid Derivatives

(-)-Linarinic acid is a new compound isolated from the ethanol extract of the whole herb of L.vulgaris Mill.We used the PASS programe to predict the activity of Linarinic acid.The result showed that the Linarinic acid had significant activity of stimulating cardiovascular.Preliminary pharmacological evaluations showed that Linarinic acid dose-dependently reduced the content of MDA in liver of elder rat in vitro.So Linarinic acid was chosen as a lead compound to study its anti-brain ischemia activity.Based on the lead compound,four kinds of Linarinic acid derivatives including benzene-ring-substituted Linarinic acid derivatives,1-substituted Linarinic acid derivatives,9-oxo-substituted Linarinic acid derivatives,and 3-benzylidene- substituted Linarinic acid derivatives were designed.Totally 59 target compounds were synthesized,and their structures were confirmed by MS and ¹H-NMR.Among them,58 compounds were not reported in literatures. Twenty seven target compounds were screened by a pharmacological test in vitro.The result showed that twenty- four compounds could reduce the content of MDA in liver of elder rat.The result of in vitro pharmacological test showed that seventeen compounds had stronger inhibition than Linarinic acid.Among them,nine compounds（LA-005,LA-007,LA-010,LA-012,LA-017,LA-020, LA-023,LA-027,LA-036）showed excellent activities with IC₅₀below 1nmol/L. Benzylidene group at 3 position of Linarinic acids with their poor water solubility were screened in vivo pharmacological test,The result showed that they could effectively extend survival time of the rats,and also reduced the content of MDA in liver and cerebra of rats.So their anti-brain ischemia activities were recommended.The pharmacological tests of other derivatives are under progress.In the synthetic progress of synthesis of Linarinic acid,another kind of compounds named pyrrolo[2,1-c][1,4]benzodiazepines were obtained.This kind of compound also has anti-ischemic activitiy in literature.Twenty four pyrrolo[2,1-c][1,4]benzodiazepine derivatives were synthesized.Their structures were confirmed by MS and ¹H-NMR.Among them,23 compounds were not reported in literature.Due to their poor water solubility,only two compounds （PBD-007 and PBD-008）were screened by a pharmacological test in vivo.The result showed that they could effectively extend survival time of the rats,and could also reduce the content of MDA in liver and cerebra of rats.Preliminary SARs of Linarinic acid derivatives were summarized.Linarinic acid 7-halogen or 7-amino substitutions could increase anti-brain ischemia activity;while 6,7-dimethoxyl or 7-nitro substitutions might decrease the activities;1-substituted（by ester,amido,hydroxymethyl）derivatives and 3-benzylidene derivatives showed anti-brain ischemia activity.9-Oxo-substituted derivatives did not show the anti-brain ischemia activity.In conclusion,Linarinic acid derivatives and pyrrolo[2,1-c][1,4]benzodiazepine-3, 11-dione derivatives have definite anti-brain ischemia activities more or less, and some of them are promising for developing new anti-brain ischemia agents.