Design,Synthesis And Biological Evaluateion Of Triazole Derivatives As Anticonvulsant,Antiinflammatory And Antitumor Agents

Research and development in drugs innovation,micromolecule scaffold was favoured by medicinal chemists in recent years.Triazole could be independent of the peripheral structure and interacted with the hydrogen bond donor as a hydrogen bond acceptor.It also could be inserted into a structure as a bond bridge performing connection function.Besides,triazole-containing derivatives have widely biological activities,such as anticonvulsant,anti-inflammatory,anti-bacteria,anti-tumor.In present study,a new library of 84 compounds,3,4-dihydroisoquinolin derivatives containing heterocycle Z-(1-3),perimidine derivatives containing triazole Z-4 and triazoles linked to xanthotoxin Z-(4-5),was sunthesized and designed with the principle of combination.Their structures were characterized by IR,1H-NMR,13C-NMR,and mass spectral data.We expect to obtain the potential anticonvulsant,anti-inflammatory and anti-cancer agents with low toxicity.In part 1,three novel series of 3,4,dihydroisoquinolin with heterocycle derivatives were synthesized using 6-methoxyl-l-indanone as the starting material based on Schmidt rearangement,thionation,hydrazine,cyclization and reduction reaction.Their anticonvulsant activity and neurotoxicity using maximal electroshock(MES)test,pentylenetetrazole(PTZ)-induced seizure test and the rotarod test.Among them,9-(exyloxy)-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinolin-3(2H)-one(Z-3a)showed significant anticonvulsant activity in MES tests with an ED50 value of 63.31 mg/kg and it showed wide margins of safety with protective index(PI>7.9).It showed much higher anticonvulsant activity than that of valproate.It also demonstrated potent activity against PTZ-induced seizures.A docking study of compound Z-3 a in the benzodiazepine(BZD)-binding site of ?-aminobutyric acid A(GABAA)receptor revealed it's mechanism of action of anticonvulsant was possible related with the BZD receptor.Future research needs to examine whether the compound combine with the BZD-receptor.In part 2,a series of perimidine derivatives containing was designed.Firstly,the anti-inflammatory properties of the synthesized perimidine derivatives were evaluated in a lipopolysaccharide(LPS)-stimulated inflammation model.And then,we found compound 7-(3-methylbenzyl)-7H-[1,2,4]triazolo[4,3-a]perimidine(Z-4h)and compound 7-(2-fluorobenzyl)-7H-[1,2,4]triazolo[4,3-a]perimidine(Z-4n)caused a reduction in the levels of the pro-inflammatory cytokines-tumor necrosis factor(TNF)-a and interleukin(IL)-6-in RAW264.7 cells by Elisa.The anti-inflammatory potential of compounds Z-4n was also evaluated in vivo in a xylene-induced ear inflammation model.It showed the most potent anti-inflammatory activity with an inhibition of 49.26%at a dose of 50 mg/kg.This activity is more potent than that of the reference drug ibuprofen(28.13%),and slightly less than that of indometacin(49.36%).To further elucidate the mechanisms underlying these inhibitory effects,LPS-induced nuclear factor-icB(NF-?B)activation and mitogen-activated protein kinase(MAPK)phosphorylation were studied.The results of western blotting showed that the extract obtained from compound Z-4n inhibited NF-?B activation and MAPK phosphorylation in a dose-dependent manner.Moreover,the results of a docking study of compound Z-4n into the COX-2 binding site revealed that its mechanism was possibly similar to that of naproxen,a COX-2 inhibitor.The effect of compound Z-4n on COX-2 antibody was showed it could significantly inhibit COX-2 activity.Two series of xanthotoxin-triazole derivatives were designed,synthesized,and studied for their antiproliferative properties in part 3.The in vitro cytotoxicity of the compounds in the AGS cancer cell line and the L02 normal cell line was evaluated via MTT assay.Among the synthesized compounds,9-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-7H-furo[3,2-g]chromen-7-one(Z-5p)was found to have the greatest antiproliferative activity against AGS cells(IC50 = 7.5 pM)and showed better activity than the lead compound(xanthotoxin,IC50>100 ?M)and the reference drug(5-fluorouracil,IC50 = 29.6 ?M)did.The IC50 value of Z-5p in L02 cells was 13.3 times higher than that in the AGS cells.Therefore,the compound exhibited better therapeutic activity and specificity compared with the positive control 5-fluorouracil.Cell cycle analysis revealed that compound Z-5p inhibited cell growth via the induction of S/G2 phase arrest in AGS cells.In summary,three novel compounds—an anticonvulsant compound(Z-3a)with a high safety,an anti-inflammatory compounds(Z-4n),which could inhibit the COX-2 expression and an anticancer compound(Z-5p)with a high selectivity towards the AGS cells,had been obtained.They were identified as a promising lead compound for the further development and identification of triazole-based anticonvulsant,anti-inflammatory and anticancer agents.This study might provide an experimental basis for the development of new candidates with high efficiency and low toxicity in the field of epilepsy,inflammation and tumor.