4,7-Dioxobenzo[b]thiophene 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 4,7-dioxobenzo[b]thiophene 유도체를 합성하여 항진균 작용 및 그 생리활성을 검색하였다. 4,7-Dioxobenzo[b]thiophene의 pyridine 유도체들은 2,5-dimethoxybenzaldehyde를 c-HNO3로 nitration 시킨 후 methyl thioglycolate와 반응시킨 후 c-HCl, c-HNO3를 이용하여 산화 및 염소화 시켜 5,6-dichloro-4,7-dioxo-4,7-dihydro-benzo[b]thiophene-2-carboxylic acid methyl ester를 합성하였고 다양한 pyridine과 반응시켜 1-(6-chloro-2-methoxycarbonyl-4,7-dioxo-4,7-dihydro-benzo[b]thiophen-5-yl)-pyridinium (QSPs) 유도체 5개를 합성하였다. 5,6-dichloro-4,7-dioxo-4,7-dihydro-benzo[b]thiophene-2-carboxylic acid methyl ester 와 다양한 pyridine을 반응 시킨 후 acetylacetone, methyl acetoacetate, ethyl acetoacetate와 반응시켜 9-acetyl-4,10-dioxo-4,10-dihydo-1-thia-4b-aza-cyclopenta[b]fluorene-2-carboxylic acid methyl ester (QSPPs) 유도체 15개를 얻었다. 2-Amino-5-hydroxy-4-phenylsulfanyl-1-oxa-6-thia-as-indacene-3,7-dicarboxylic acid 3-methyl or ethyl ester 7-methyl ester (QSMCs, QSECs) 유도체들은 5,6-dichloro-4,7-dioxo-4,7-dihydro-benzo[b]thiophene-2-carboxylic acid methyl ester를 methyl cyanoacetate, ethylcyanoacetate와 반응시켜 2-amino-4-chloro-5 hydroxy-1-oxa-6-thia-as-indacene-3,7-dicarboxylic acid 3-methyl or ethyl ester 7-methyl ester를 합성하였고, 다양한 arylthiol과 반응시켜 2-amino-5-hydroxy-4-phenylsulfanyl-1-oxa-6-thia-as-indacene-3,7-dicarboxylic acid 3-methyl ester 7-methyl ester (QSMCs) 유도체 8개와 2-amino-5-hydroxy-4-phenylsulfanyl-1-oxa-6-thia-as-indacene-3,7-dicarboxylic acid 3-ethyl ester 7-methyl ester (QSECs) 유도체 12개를 합성하였다. 합성한 물질 5a-e (QSPs), 6a-o (QSPPs), 9a-h(QSMCs), 10a-l(QSECs) 의 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, fluorocytosine을 사용하였다. 물질 5e (3-Cl), 6f (6-Cl, 9-COCH3), 6g (6-Br, 9-COCH3), 6n (6-Cl, 9-CO2C2H5), 6o (6-Br, 9-CO2C2H5), 9h (3,4-F, 7-CO2CH3), 10k (3,4-F, 7-CO2C2H5), 10l (3,4-Cl, 7-CO2C2H5)이 대부분의 균주에 대해 fluconazole과 fluorocytosine보다 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, 4,7-dioxobenzo[b]thiophene derivatives were synthesized and evaluated for their antifungal activites. 1-(6-Chloro-2-methoxycarbonyl-4,7-dioxo-4,7-dihydro-benzo[b]thiophen-5-yl)-pyridinium (QSPs) were synthesised by substitution of 5,6-dichloro-4,7-dioxo-4,7-dihydro-benzo[b]thiophene-2-carboxylic acid methyl ester with pyridines. And 9-acetyl-4,10-dioxo-4,10-dihydo-1-thia-4b-aza-cyclopenta[b]fluorene-2-carboxylic acid methyl ester (QSPPs) were synthesised by substitution of 1-(6-chloro-2-methoxycarbonyl-4,7-dioxo-4,7-dihydro-benzo[b]thiophen-5-yl)-pyridinium with acetylacetone, methyl aceoacetate or ethyl acetoacetate. 2-Amino-4-chloro-5-hydroxy-1-oxa-6-thia-as-indacene-3,7-dicarboxylic acid 3-methyl or ethyl ester 7-methyl ester were obtained by substitution of 5,6-dichloro-4,7-dioxo-4,7-dihydro-benzo[b]thiophene-2-carboxylic acid methyl ester with methyl or ethyl cyanoacetate. And 2-amino-5-hydroxy-4-phenylsulfanyl-1-oxa-6-thia-as-indacene-3,7-dicarboxylic acid 3-methyl or ethyl ester 7-methyl ester (QSMCs, QSECs) were synthesized by substitution of 2-amino-4-chloro-5-hydroxy-1-oxa-6- thia-as-indacene-3,7-dicarboxylic acid 3-methyl or ethyl ester 7-methyl ester with arylthiol. The antifungal activities of all the compounds have synthesized 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, 5e (3-Cl), 6f (6-Cl, 9-COCH3), 6g (6-Br, 9-COCH3), 6n (6-Cl, 9-CO2C2H5), 6o (6-Br, 9-CO2C2H5), 9h (3,4-F, 7-CO2CH3), 10k (3,4-F, 7-CO2C2H5), 10l (3,4-Cl, 7-CO2C2H5) generally showed relatively potent antifungal activities compared to fluconazole and flucytosine.