Studies On Synthesis And Anticonvulsant Activities Of Novel Cyclopropane Derivatives

The urgent demands for novel AEDs will be long-standing for the complexity and severity of epilepsy and the side effects of the currently marketed AEDs. The definitions and the pathogenesis of epilepsy were introduced in the foreword. The rules and experiences in AEDs searching were summarized after an overview on the development history of the utilized AEDs. Based on these analyses, three series of novel cyclopropane-containing compounds were designed to combine different pharmacophores existing in effective anticonvulsant agents.Nine cyclopropanespirohydantoin derivatives were prepared as attempts to combine the well-known hydantoin core and sulfonamide fragments in one molecular. Ethylenediamine was chosen as the linker after comprehensively considering on the stability and synthetic process of the products. Meanwhile, the hydantoin ring-opening analogues of those above-mentioned compounds were synthesized to verify the importance of the hydantoin core and probe into the antiepileptic potential of the ring-opening analogues.The second series of cyclopropane-containing compounds was obtained after the condensation of 2,2-dimethylcyclopropane-1,1-dicarboxylic acid with sulfanilamide and amines to accomplish the combination between CA inhibitors and valproate amide derivatives. Some molecules containing two propyl chains were prepared to investigate the influence of cyclopropane fragment on anticonvulsant activities. In the carbonic anhydrase tests, the most active one among the selected compounds was compound ?-9 (IC50=0.77 ?M (acetazolamide,0.49 ?M)).We reported some novel cyclopropane-containing semicarbazones as the last series of pharmacophore-combined agents because of the fantastic anticonvulsant properties possessed by the simple semicarbazone structure. We found a way to mash up hydantoin core with semicarbazone. In other words, some atoms in those agents would not only be a part of the hydantoin core but also be a member of the semicarbazone group. It was exciting to check the viability of this strategy to obtain more effective AEDs.The MES and scPTZ screens were chosen for the appraising of the anticonvulsant profile of those cyclopropane-containing compounds. The most active one among the hydantoin-sulfonamide compounds was II-7f (ED50=28.1 mg/kg, PI=20).The most active one among the amide-sulfonamide compounds was ?-10b (ED50=16.4mg/kg, PI=24.8). The PI value of III-4c (PI=20.4) and ?-4d (PI>19.8) were also higher than PHT. Most cyclopropane-containing semicarbazone compounds exhibited serious neurotoxicity or fatal toxicity except IV-5a-d.Compound ?-5d showed the best antiproliferative activity against Hela cells (IC50=23.7?M) while it's hydantoin-containing analogues ?-1d showed the best antitumor activity against HepG-2 cells (IC50=26.7?M).In summary, the combination principles were used in the present study to design series of novel anti-epilepsy agents. Compounds ?-7e, ?-7f, ?-10b, ?-4c and ?-4d showed exciting potential to act as novel anti-epilepsy drugs and the SAR summarized in this paper provided some useful information for subsequent research.