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Imidazo[4',5':4,5]benzo[d][1,2,3]triazole-4,8-dione 유도체의 합성 및 항진균 작용 연구

Title
Imidazo[4',5':4,5]benzo[d][1,2,3]triazole-4,8-dione 유도체의 합성 및 항진균 작용 연구
Authors
강다영
Issue Date
2016
Department/Major
대학원 약학과
Publisher
이화여자대학교 대학원
Degree
Master
Advisors
유충규
Abstract
Quinone 유도체들은 항진균, 항암, 항균, 항종양 등 다양한 생리활성을 나타낸다. 본 연구에서는 quinone 유도체 중 우수한 생리활성이 예상되는 Imidazo[4',5':4,5]benzo[d][1,2,3]triazole-4,8-dione등의 다양한 유도체들을 합성하여 항진균 작용 및 그 생리활성을 검색하였다. 5,6-Dichloro-2-methyl-4,7-benzimidazoledione (DMBC)에 sodium azide 와 triphenylphosphine을 반응시켜 6-methyl-2-((triphenylphos phoranylidene)amino)imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8 (2H,5H)-dione (DMBPPH3)를 합성하였다. 이 화합물에 aryl or aliphatic aldehyde를 반응시켜 6-methyl-2-(methyleneamino)imidazo[4',5':4,5] benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione (DMBAs) 유도체 16개를 합성하였다. 또한 5,6-dichloro-2-methyl-4,7-benzimidazoledione (DMBC)에 ethyl iodide를 넣어 1-ethyl-4,7-dimethoxy-2-methyl-1H-benzo[d]imidazole (DMEC)를 만들었다. 이 화합물에 sodium azide와 triphenylphosphine 을 반응시켜 5-ethyl-6-methyl-2-((triphenylphos phoranylidene)amino)imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8 (2H,5H)-dione (DMEPPH3)를 합성하였고, 이 화합물에 각각의 arylaldehyde 및 aliphatic aldehyde 를 반응시켜 5-ethyl-6-methyl-2-(methyleneamino)imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8 (2H,5H)-dione (DEBAs) 유도체 10개를 얻었다. 5,6-Dichloro-2-(trifluoromethyl)-1H-benzo[d]imidazole-4,7-dione (DTFC) 화합물에 sodium azide 와 triphenylphosphine 을 반응시켜 6-(trifluoromethyl)-2-((triphenylphosphoranylidene)amino)imidazo[4',5':4,5] benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione (DTFPPH3)를 합성하였다. 이 화합물에 각각의 arylaldehyde, aliphatic aldehyde 를 반응시켜 2-(methyleneamino)-6-(trifluoromethyl)imidazo[4',5':4,5]benzo[1,2-d] [1,2,3]triazole-4,8(2H,5H)-dione (DTFAs) 유도체 10개를 합성하였다. 5,6-Dichloro-4,7-dioxoindazole (INC)을 합성하여 sodium azide와 triphenylphosphine 을 반응시켜 2-((triphenylphosphoranylidene)amino) -4a,5-dihydro-[1,2,3]triazolo[4,5-f]indazole-4,8(2H,7aH)-dione (INPPH3)을 합성하였다. 여기에 다양한 aryl aldehyde 및 aliphatic aldehyde 를 반응시켜 2-(methyleneamino)-[1,2,3]triazolo[4,5-f]indazole-4,8(2H,5H)-dione (INAs) 유도체 15개를 합성하였다. 2,3-Dichloro-1,4-naphthoquinone (NQC)에 sodium azide, triphenylphosphine 을 반응시켜 2-((triphenylphosphoranylidene)amino) -2H-naphtho[2,3-d][1,2,3]triazole-4,9-dione (NQPPH3)을 합성 하였다. 여기에 다양한 aryl aldehyde를 반응시켜 2-(methyleneamino)-[1,2,3]triazolo[4,5-f]indazole-4,8(2H,5H)-dione (NQAs) 유도체 10개를 얻었다. naphthoquione (NQ)에 여러가지 azide와의 aza-Wittig 반응을 통해 1-ethyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione (NQAzs) 유도체 7개를 합성하였다. 2,3-Dimethyldcyclohexa-2,5-diene-1,4-dione (BQ)에 다양한 azide 와의 aza-Wittig반응을 통해 1-ethyl-5,6-dimethyl-1H-benzo[d][1,2,3]triazole -4,7-dione (BQAZs) 유도체 13개를 합성하였다. 신약 개발의 중요한 lead compound인 2-chloro-5-methyl-1,4-benzoquinone 에 pyridine 과 ethylacetoacetate 를 반응시켜 ethyl 2-methyl -1,4-dioxo-1,4-dihydropyrido[1,2-a]indole-10-carboxylate (EDI)를 얻었다. 여기에 다양한 aryl, aliphatic thiol 을 반응시켜 ethyl 3-mercapto-2-methyl-1,4-dioxo-1,4-dihydropyrido[1,2-a]indole-10-carboxylate (EDITs) 유도체 17개를 합성하였다. 합성한 화합물 8a-p (DMBAs), 13a-j (DMEAs), 18a-j (DTFAs), 25a-o (INAs), 29a-j (NQAs), 31a-g (NQAzs), 34a-m (BQAzs), 38a-q (EDITs) 들에 대해서 항진균 작용을 알아보기 위해서 병원성 진균의 대표적인 지표가 되는 6가지 병원균주인 C. albicans, C. tropicalis, C. krusei, C. neoformans, A. niger 및 A. flavus에 대한 항진균 작용을 검색하였다. 각 화합물에 대한 minimum inhibitory concentration (MIC)는 액체 배지 희석법 (two fold broth dilution method)으로 하였고 대조 약물로는 fluconazole, flucytosine을 사용하였다. 화합물 8f (DMBA6), 8n (DMBA14), 8o (DMBA15), 13j (DMEA10), 25e (INA5) 및31e (NQAz5)이 대부분의 균주에 대하여 fluconazole보다 좋고, flucytosine과 비슷하거나 좋은 효과를 나타내어 합성한 유도체들 중에서 가장 우수한 항진균 효과를 나타냈다;Quinone compounds have various pharmacological activities as antifungal, antitumor, antimalarial and so forth. Especially, compounds containing the hetero cyclic quinone group represent an important class of biologically active compounds. Based on this consideration, imidazo[4',5':4,5]benzo[d][1,2,3]triazole-4,8-dione derivatives were synthesized and evaluated for their antifungal activities. 5,6-Dichloro-2-methyl-4,7-benzimidazoledione (DMBC), which has been starting material of 6-methyl-2-((triphenylphosphoranylidene)amino)imidazo[4',5':4,5]benzo [1,2-d][1,2,3]triazole-4,8(2H,5H)?dione (DMBPPH3) and 5-ethyl-6-methyl-2-((triphenylphosphoranylidene)amino)imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8 (2H,5H)?dione (DMEPPH3). And then, 6-methyl-2-(methyleneamino)imidazo [4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)?dione (DMBAs) and 5-ethyl-6-methyl-2-(methyleneamino)imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione (DMEAs) were synthesized from DMBPPH3, DMEPPH3 with aryl/ aliphatic aldehyde. 2-(Methyleneamino)-6-(trifluoromethyl)imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8(2H,5H) ?dione (DTFAs) derivatives were synthesized from 6-(trifluoromethyl)-2-((triphenylphosphoranylidene)amino)imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione (DTFPPH3) with aryl/ aliphatic aldehyde. 2-((Triphenylphosphoranylidene)amino)-4,5-dihydro-[1,2,3]triazolo[4,5-f]indazole-4,8(2H,7aH)-dione (INPPH3) was synthesized by reaction with 5,6-dichloro-1H-indazole-4,7-dione (INC), sodium azide and triphenylphosphine. 2-(methyleneamino)-[1,2,3]triazolo[4,5-f]indazole-4,8(2H,5H)-dione (INAs) derivates were synthesized by INPPH3 with various aldehydes. And a lot of derivatives which were synthesized by substitution of NQPPH3 and aryl aldehyde. 1-Ethyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione (NQAzs) and 1-ethyl-5,6-dimethyl -1H-benzo[d][1,2,3]triazole-4,7-dione (BQAzs) were synthesized from 1,4-naphthoquinone (NQ) and 2,3-dimethylbenzoquinone (BQ) with various azides. Ethyl 3-mercapto-2-methyl-1,4-dioxo-1,4-dihydropyrido[1,2-a]indole-10-carboxylate (EDITs) were synthesized by substitution of aryl/ aliphatic thiol and ethyl 2-methyl-1,4-dioxo-1,4-dihydropyrido[1,2-a]indole-10-carboxylate (EDI) synthesized using the reaction with 2-chloro-5-methyl-1,4-benzoquinone, pyridine, ethylacetoacetate. The antifungal activities of all the synthesized compounds were evaluated using the two fold broth dilution method against C. albicans, C. tropicalis, C. neoformans, C. krusei, A. flavus and A. niger. Their MIC (minimum inhibitory concentration) values were determined and compared with positive controls, fluconazole and flucytosine. Among newly synthesized compounds, 8f (DMBA6), 8n (DMBA14), 8o (DMBA15), 13j (DMEA10), 25e (INA5) and 31e (NQAz5) generally showed relatively potent antifungal activities compared to fluconazole and flucytosine.
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