Synthesis And Anticonvulsant, Antidepressant Activity Of Isatin Derivatives

Isatin (Isatin, ISA), is a new kind of natural marine medicine which is necessary tomaintain lobster’s and palaemon’s survival. Isatin is a kind of endogenous active factor inhuman and animal body. Isatin owns a clear chemical structure, a variety of biologicalactivity and low toxicity. A series of synthesized Isatin derivatives have high biologicalactivity and application value. It has a great important significance for the research anddevelopment of new drugs. In this article, we designed a series of Isatin derivative andused aniline as the starting material.Synthesis of Isatin according to Sandmeyer and itsstructure modified by amidation reaction, nucleophilic substitution reaction. Wesynthesized a total of32Isatin derivatives and we evaluated their anticonvulsant activity，the antidepressant activity of Isatin derivatives (4a-q).Research methods: We gained two series of designed Isatin derivatives whichincluded2-(2,3-Dioxoindolin-1-yl)-N-phenylacetamide(3a-q)and2-(6-Methyl-2,3-dioxoindolin-1-yl)-N-Phenylacetamide (4a-q) by conventional synthesis method.Experiments were detected thin layer chromatography(TLC)technique. Those finalcompounds were purified recrystallization and their structures were characted by meltingpoint test，spectral analysis technique (IR,1H-NMR,13C-NMR, MS) and elementalanalysis technique. Their neurotoxicity was measured by rotarod test and theiranticonvulsant activity was evaluated by the maximal electroshock seizure andpentylenetetrazole model test. Antidepressant activity of Isatin derivatives (4a-q) wasstudied by the forced swimming test.Research results:(1)The anticonvulsant activities of14Isatin derivatives(3a-n) was evaluated byMES test: Ten compounds showed the anticonvulsant activity. The lead compound Isatinexhibited anti-MES effect only at300mg/kg dose level, nine compounds (3a-3d,3f,3g,3i,3l and3n) exhibited anti-MES effect at100mg/kg, the compound3m showed anti-MESeffect at300mg/kg dose level. Whereas four compounds (3e,3h,3j and3k) did not havethe anticonvulsant activity at300mg/kg dose level. All these compounds did not show theneurotoxicity at at the same dose levels. Six compounds (3a-3d and3f,3i) which exhibitedthe better anti-MES activity were then subjected to phase II trials for quantification of their anticonvulsant activity and neurotoxicity：the electron-donor substituted phenyl derivatives(3b-3d), the potency order was the activity order was p-CH3>-H>o-CH3>m-CH3, in whichthe compound3d was the most anticovulsant activity with an ED50of91.3mg/kg, TD50of>1000mg/kg, a higher protective index (PI=TD50/ED50,>11) was gained than referencedrug phenobarbital and carbamazepine. Anti-MES activity order of the halogen substitutedderivatives：p-F>p-Cl>p-Br, however, the compound3f was the most anticonvulsantactivity with an ED50of88.0mg/kg, TD50of>800mg/kg, a higher protective index(PI=TD50/ED50,>9.1) was gained than reference drug phenobarbital.(2)The study of18Isatin derivatives(4a-q)on pentylenetetrazole convulsant modeland forced swimming test：Pentylenetetrazole convulsant experimental results showed thatall the compounds presented no neurotoxicity at the doses of100mg/kg,12compoundsexhibited anticonvulsant activity. Compounds4a，4f and4p owned the best anticonvulsantactivity and their test results were consistent with antiepileptic drug carbamazepine (100mg/kg). Forced swimming test showed4Isatin derivatives (I,4m,4p,4q) showed goodantidepressant activity compared with the blank group at the dose of100mg/kgconcentration.Conclusion: Based on the lead compound Isatin, we had structural modification,synthesized a series of Isatin derivatives in our study and related research on theiranticonvulsant activity and antidepressant activity was finished. The preliminaryevaluation of their anticonvulsant activity and antidepressant activity was finished.Compounds with good anticonvulsant activity were were then subjected to phase II trialsfor their structure activity relationship. Our work was helpful for the development of higheffect and low toxicity anticonvulsant and antidepressants medicine.