6,7-Dichloro-5,8-quinolindione과 methyl 5,6-dichloro-4,7-dioxo-4,7-dihydrobenzo[b]thiophene-2-carboxylate 유도체의 합성 및 항진균 작용 연구

Abstract

Quinone 유도체들은 항진균, 항암, 항균, 항말라리아 등 다양한 생리활성을 나타낸다. 본 연구에서는 quinone 유도체 중 우수한 생리활성이 예상되는 phthalazine-5,8-dione, methyl 4,7-dioxo-4,7-dihydrobenzo[b]thiophene-2-carboxylate 및quinoline-5,8-dione의 다양한 유도체들을 합성하여 항진균 작용 및 그 생리활성을 검색하였다. 처음으로 phthalazine을 출발 물질로 하여 phthalazine-5,8-dione (PQ)를 합성한 뒤, azide와의 aza-Wittig 반응을 통해 1-substituded-1H-[1,2,3]triazolo[4,5-g]phthalazine-4,9-diones (PQAzs) 유도체 2개를 합성하였다. 두번째로 5-amino-8-hydroxyquinoline dihydrochloride을 출발 물질로 하여 6,7-dichloroquinoline-5,8-dione (QQCl)을 합성한 뒤, 중간 유도체인 2-((triphenylphosphoranylidene)amino)-2H-[1,2,3]triazolo[4,5-g]quinoline-4,9-dione (QQPPh)와 2-amino-2H-[1,2,3]triazolo[4,5-g]quinoline-4,9-dione (QQNH2)를 합성하였다. QQPPh에 다양한 aldehyde와 ketone chloride를 반응시켜 2-(amino)-2H-[1,2,3]triazolo[4,5-g]quinoline-4,9-diones (QQAls) 유도체 6개와 N-(4,9-dioxo-4,9-dihydro-2H-[1,2,3]triazolo[4,5-g]quinolin-2-yl) amides (QQChs) 유도체 2개를 합성하였다. 또한, QQNH2에 다양한 ketone을 반응시켜 2-(2-ylideneamino)-2H-[1,2,3]triazolo[4,5-g]quinoline-4,9-diones (QQKes) 유도체 2개를 합성하였다. 세번째로 2,5-dimethoxybenzaldehyde을 출발 물질로 하여 methyl 4,7-dioxo-4,7-dihydrobenzo[b]thiophene-2-carboxylate (QSCl)을 합성한 뒤, 중간 유도체인 methyl 4,8-dioxo-2-((triphenylphosphoranylidene)amino)-4,8-dihydro-2H-thieno[2',3':4,5]benzo[1,2-d][1,2,3]triazole-6-carboxylate (QSPPh)를 합성하였다. 이 유도체와 다양한 aldehydes를 반응시켜 methyl 4,8-dioxo-2-(amino)-4,8-dihydro-2H-thieno[2',3':4,5]-benzo[1,2-d][1,2,3]triazole-6-carboxylates (QSAls) 유도체 13개를 합성하였다. 또한, 7-methyl-8-nitroquinoline을 출발 물질로 하여 7-methylquinolin-8-amine (MQI)을 합성한 뒤, 중간 유도체인 7-methylquinoline-5,8-dione (MQ)를 합성하였다. MQ와 다양한 arylamines을 반응시켜 6-arylamino-7-methylquinoline-5,8-diones(MQArs) 유도체 19개를 합성하였다. 합성한 화합물 11 (QQNH2), 12a-f (QQAls), 13a-b (QQChs), 14a-b (QQKes) 및 20a-m (QSAls)들에 대해서 항진균 작용을 알아보기 위하여 병원성 진균의 대표적인 지표가 되는 6가지 병원균주인 C. albicans, C. tropicalis, C. krusei, C. neoformans, A. niger 및 A. flavus 에 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. 물질 12d (QQAl4)와 20d (QSAl4)는 대부분의 균주에 대해 fluconazole과 flucytosine보다 높거나 비슷한 효과를 나타내어 합성된 유도체중 가장 좋은 항진균 작용을 나타내었다.;Quinones have various pharmacological activities such as antifungal, anticancer and antimalarial activities. Especially, compounds containing the heterocyclic quinone group represent an important class of biologically active compounds. Based on this consideration, phthalazine-5,8-dione, methyl 4,7-dioxo-4,7-dihydrobenzo[b]thiophene-2-carboxylate and quinoline-5,8-dione derivatives were synthesized and evaluated for their antifungal activities. 6,7-Dichloroquinoline-5,8-dione (QQCl), which has been starting material of 2-((triphenylphosphoranylidene)amino)-2H-[1,2,3]triazolo[4,5-g]quinoline-4,9-dione (QQPPh) and 2-amino-2H-[1,2,3]triazolo[4,5-g]quinoline-4,9-dione (QQNH2), were synthesized from 5-amino-8-hydroxyquinoline dihydrochloride. And then, 2-(amino)-2H-[1,2,3]triazolo[4,5-g]quinoline-4,9-diones (QQAls) and N-(4,9-dioxo-4,9-dihydro-2H-[1,2,3]triazolo[4,5-g] quinolin-2-yl) amides (QQChs) were synthesized from QQPPh with various aldehydes and ketone chlorides. Also, 2-(2-ylideneamino)-2H-[1,2,3]triazolo[4,5-g]quinoline-4,9-diones (QQKes) were synthesized from QQNH2. Methyl 4,7-dioxo-4,7-dihydrobenzo[b]thiophene-2-carboxylate (QSCl), which has been starting material of methyl 4,8-dioxo-2-((triphenylphosphoranylidene) amino)-4,8-dihydro-2H-thieno[2',3':4,5]benzo[1,2-d][1,2,3]triazole-6-carboxylate (QSPPh), were synthesized from 2,5-dimethoxybenzaldehyde. And then, methyl4,8-dioxo-2-(amino)-4,8-dihydro-2H-thieno[2',3':4,5]-benzo [1,2-d][1,2,3]triazole-6-carboxylates (QSAls) were synthesized from QSPPh with various aldehydes. 7-methylquinolin-8-amine (MQI), which has been starting material of 7-methylquinoline-5,8-dione, was synthesized from 7-methyl-8-nitroquinoline. And then 6-arylamino-7-methylquinoline-5,8-diones(MQArs) were synthesized from MQ with various arylamines. 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, 12d (QQAl4) and 20d (QSAl4) generally showed relatively potent antifungal activities compared to fluconazole and flucytosine.