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

Abstract

항진균, 항암, 항균, 항종양 등에 대한 다양한 생리활성을 Quinone 유도체들에서 볼 수 있다. 본 연구에서는 quinone 유도체 중 우수한 생리활성이 예상되는 imidazo[4',5':4,5]benzo[1,2-d][1,2,3] triazole-4,8(2H,5H)-dione와 1H-benzo[d]imidazole-4,7-dione 등의 다양한 유도체들을 합성하여 항진균 작용 및 그 생리활성을 검색하였다. 5,6-Dichloro-2-(furan-2-yl)-1H-benzo[d]imidazole-4,7-dione 에 sodium azide 와 triphenylphosphine을 반응시켜 6-(furan-2-yl)-2-((triphenylphosphoranylidene)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 2-(ethylideneamino)-6-(furan-2-yl) imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8(2H,5H) –dione (DMBAs) 유도체 7개를 합성하였다. 또한 5,6-dichloro-2-(furan-2-yl)-1H-benzo[d] imidazole-4,7-dione 에 aryl aniline 혹은 aliphatic aniline 를 넣어 5-chloro-2-(furan-2-yl)-6-methyl-1H-benzo[d] imidazole-4,7-dione (DMBAMs) 유도체 4 개를 합성하였다. 5,6-Dichloro-2-(thiophen-2-yl)-1H-benzo[d]imidazole-4,7-dione 화합물에 sodium azide 와 triphenylphosphine 을 반응시켜 6-(thiophen-2-yl)-2-((triphenylphosphoranylidene)amino)imidazo[4',5':4,5] benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione (DMB2PPH3)를 합성하였다. 이 화합물에 각각의 aryl aldehyde, aliphatic aldehyde 를 반응시켜 2-(ethylideneamino)-6-(thiophen-2-yl) imidazo[4',5':4,5] benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione (DMB2As) 유도체 6개를 합성하였다. 또한 5,6-dichloro-2-(thiophen-2-yl)-1H-benzo[d] imidazole-4,7-dione 에 aryl aniline 혹은 aliphatic aniline 를 넣어 5-chloro-6-methyl-2-(thiophen-2-yl)-1H-benzo[d]imidazole-4,7-dione (DMB2AMs) 유도체 7 개를 합성하였다. 2-(5-Bromothiophen-2-yl)-5,6-dichloro-1H-benzo[d]imidazole-4,7-dione 화합물에 sodium azide 와 triphenylphosphine 을 반응시켜 6-(5-bromothiophen-2-yl)-2-((triphenylphosphoranylidene)amino) imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione (DMBrPPH3)를 합성하였다. 이 화합물에 각각의 aryl aldehyde, aliphatic aldehyde 를 반응시켜 6-(5-bromothiophen-2-yl)-2-(ethylideneamino) imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione (DMBrAs) 유도체 14 개를 합성하였다. 또한 2-(5-bromothiophen-2-yl)-5,6-dichloro-1H-benzo[d]imidazole-4,7-dione 에 aryl aniline 혹은 aliphatic aniline 를 넣어 2-(5-bromothiophen-2-yl)-5-chloro-6-methyl-1H-benzo[d]imidazole-4,7-dione (DMBrAMs) 유도체 4 개를 합성하였다. 2,3-Dimethylcyclohexa-2,5-diene-1,4-dione (BQ) 화합물에 sodium azide 와 triphenylphosphine 을 반응시켜 5,6-dimethyl-2-((triphenylphosphoranylidene)amino)-2H-benzo[d][1,2,3]triazole-4,7-dione (BQPPh3)를 합성하였다. 이 화합물에 각각의 arylaldehyde, aliphatic aldehyde 를 반응시켜 5,6-dimethyl-2-(methyleneamino)-2H-benzo[d][1,2,3]triazole-4,7-dione (BQAs)유도체 9 개를 합성하였다. 합성한 화합물 4a-d (DMBAMs), 7a-g (DMBAs), 10a-g (DMB2AMs), 13a-f (DMB2As), 16a-d (DMBrAMs), 19a-n (DMBrAs), 23a-i (BQAs) 들에 대해서 항진균 작용을 알아보기 위해서 병원성 진균의 대표적인 지표가 되는 5가지 병원균주인 C. albicans, C. tropicalis, C. krusei, A. niger 및 A. flavus에 대한 항진균 작용을 검색하였다. 합성한 각 화합물에 대한 minimum inhibitory concentration (MIC)는 액체 배지 희석법 (two fold broth dilution method)으로 하였고 대조 약물로는 fluconazole와 flucytosine을 사용하였다.;Quinone compounds have known for various pharmacological activities such as antifungal, antitumor, antimalarial and others. Including hetero cyclic quinone group of compounds provide an important class of biologically active compounds. Based on this consideration, this study has been gone through focusing on imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione. At last largely seven kinds of derivatives were synthesized step by step and evaluated for their antifungal activities. 5,6-Dichloro-2-(furan-2-yl)-1H-benzo[d]imidazole-4,7-dione (DMB) has been synthesized to be the starting material of 6-(furan-2-yl)-2-((triphenylphosphoranylidene)amino)imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione (DMBPPH3). 5-Chloro-2-(furan-2-yl)-6-methyl-1H-benzo[d]imidazole-4,7-dione (DMBAMs) and 2-(Ethylideneamino)-6-(furan-2-yl)imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione (DMBAs) were synthesized from DMB and DMBPPH3 with aryl/ aliphatic aldehyde and aryl/ aliphatic aniline. 5,6-Dichloro-2-(thiophen-2-yl)-1H-benzo[d]imidazole-4,7-dione (DMB2) has been synthesized to be the starting material of 6-(Thiophen-2-yl)-2-((triphenylphosphoranylidene)amino)imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione (DMB2PPH3). 5-Chloro-6-methyl-2-(thiophen-2-yl)-1H-benzo[d]imidazole-4,7-dione (DMB2AMs) and 2-(Ethylideneamino)-6-(thiophen-2-yl)imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione (DMB2As) were synthesized from DMB2 and DMB2PPH3 with aryl/ aliphatic aldehyde and aryl/ aliphatic aniline. 2-(5-Bromothiophen-2-yl)-5,6-dichloro-1H-benzo[d]imidazole-4,7-dione (DMBr) has been synthesized to be the starting material of 6-(5-Bromothiophen-2-yl)-2-((triphenylphosphoranylidene)amino)imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione (DMBrPPH3). 2-(5-Bromothiophen-2-yl)-5-chloro-6-methyl-1H-benzo[d]imidazole-4,7-dione (DMBrAMs) and 6-(5-Bromothiophen-2-yl)-2-(ethylideneamino)imidazo[4',5':4,5]benzo[1,2-d][1,2,3]triazole-4,8(2H,5H)-dione (DMBrAs) were synthesized from DMBr and DMBrPPH3 with aryl/ aliphatic aldehyde and aryl/ aliphatic aniline. 2,3-Dichloro-5,6-dimethylcyclohexa-2,5-diene-1,4-dione (BQ) has been synthesized to be the starting material of 5,6-Dimethyl-2-((triphenylphosphoranylidene)amino)-2H-benzo[d][1,2,3]triazole-4,7-dione (BQPPH3). 5,6-Dimethyl-2-(methyleneamino)-2H-benzo[d][1,2,3]triazole-4,7-dione (BQAs) were synthesized from BQPPH3 with aryl/ aliphatic aldehyde. The antifungal activities of all the synthesized compounds were evaluated using the two fold broth dilution method against C. albicans, C. tropicalis, 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, nothing has shown much potent antifungal activities to flucytosine. But 17a(DMBrAM1), 17b(DMBrAM2), 19c(DMBrA3), 19h(DMBrA8), 23b(BQA2) and 23d(BQA4) compounds generally showed relatively potent antifungal activities compared to fluconazole. By analysing the structure, 4a-d(DMBAMs), 10a-g(DMB2AMs), 16a-d(DMBrAMs), 23a-i(BQAs), 7a-g(DMBAs), 13a-f(DMB2As) and 19a-n(DMBrAs) compounds were synthesized normally to ring form of aldehyde or aniline. And also 19a-n (DMBrAs) showed the highest synthetic rate among 4a-d(DMBAMs), 10a-g(DMB2AMs), 16a-d(DMBrAMs), 7a-g(DMBAs), 13a-f(DMB2As) and 19a-n(DMBrAs) derivates. Compounds through 23a-i(BQAs) were difficult to synthesize alkyl form of aldehyde but they showed better potent than ring form.