1H-Benzo[f]indole-4,9-dione 과 1H-pyrrolo[3,2-g]quinoline-4,9-dione 합성 및 항진균 작용 연구

Abstract

Quinone 유도체들은 항진균, 항암, 항균, 항말라리아 등 다양한 생리활성을 나타낸다. 본 연구에서는 quinone 유도체 중 우수한 생리활성이 예상되는 quinone 유도체를 합성하여 항진균 작용 및 그 생리활성을 검색하였다. 1,4-Naphthoquinone을 ZnCl2를 촉매로 하여 ethyl benzoylacetate와 aryl thiol과 반응시켜 ethyl 5-oxo-2-phenyl-4-(phenylthio)-5,9b-dihydronaphtho[1,2-b]furan-3-carboxylate (NQMSs) 유도체 2개를 합성하였다. 2,3-Dichloro-5-hydroxynaphthalene-1,4-dione은 5-hydroxynaphthalene-1,4-dione를 Cl2 gas 와 반응시켜 합성하였고, 다양한 pyridine derivatives와 active methylene derivatives와 반응시켜 10-hydroxybenzo[f]pyrido[1,2-a]indole-6,11-dione (JQPMs) 유도체 9개를 합성하였다. 또 2,3-dichloro-5-hydroxynaphthalene-1,4-dione과 ethyl cyanoacetate를 반응시키고 다양한 arylamine을 반응시켜 ethyl 2-amino-8-hydroxy-4,9-dioxo-1-phenyl-4,9-dihydro-1H-benzo[f]indole-3-carboxylate (JQCAs) 유도체 10개를 합성하였다. Methyl 6-chloro-4,7-dioxo-5-(phenylthio)-4,7-dihydrobenzo[b]thiophene-2-carboxylate (QSSs)는 1-(2,5-Dimethoxyphenyl)ethanone을 c-HNO3로 nitration시켜 합성한 1-(3,6-dimethoxy-2-nitrophenyl)ethanone을 K2CO3와 methyl thioglycolate를 반응시켜 methyl 4,7-dimethoxybenzo[b]thiophene-2-carboxylate를 합성하였다. 이것을 c-HCl, c-HNO3와 반응시켜 methyl 5,6-dichloro-4,7-dioxo-4,7-dihydrobenzo[b]thiophene-2-carboxylate를 합성하였다. 이를 다양한 arylthiol과 반응시켜 methyl 6-chloro-4,7-dioxo-5-(phenylthio)-4,7-dihydrobenzo[b]thiophene-2-carboxylate (QSSs) 유도체 4개를 합성하였다. Quinoline 유도체는 6,7-dichloroquinoline-5,8-dione를 cyanoacetate derivatives와 arylamine과 반응시켜 2-amino-4,9-dioxo-1-phenyl-4,9-dihydro-1H-pyrrolo[3,2-g]quinoline-3-carboxylate (QQCAs) 유도체 14개를 합성하였다. 합성한 물질 3a-b (NQMSs), 7a-i (JQPMs), 9a-j (JQCAs), 14a-d (QQSs), 18a-n (QQCAs)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, flucytosine을 사용하였다. 물질 7d (4-OCH3, 7-H), 9j (3,4-F), 14d (4-F)이 대부분의 균주에 대해 fluconazole과 flucytosine보다 높거나 비슷한 효과를 나타내어 합성된 유도체 중 가장 좋은 항진균 작용을 나타내었다.;Quinones have been reported with 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, naphthoquinone, 4,7-dioxobenzo[b]thiophene and quinolinedione derivatives were synthesized and evaluated for their antifungal activites. Ethyl 5-oxo-2-phenyl-4-(phenylthio)-5,9b-dihydronaphtho[1,2-b]furan-3-carboxylate (NQMSs) were obtained by substitution of 1,4-naphthoquinone with ethyl benzoylacetate and aryl thiols. 10-Hydroxybenzo[f]pyrido[1,2-a] indole-6,11-dione (JQPMs) were obtained by substitution of 2,3-dichloro-5-hydroxynaphthalene-1,4-dione with pyridine derivatives and active methylene derivatives (acetylacetone, nitromethane, nitroethane). Ethyl 2-amino-8-hydroxy-4,9-dioxo-1-phenyl-4,9-dihydro-1H-benzo[f] indole-3-carboxylate (JQCAs) were obtained by substitution of 2,3-dichloro-5-hydroxynaphthalene-1,4-dione with ethyl cyanoacetate and arylamines. Methyl 6-chloro-4,7-dioxo-5-(phenylthio)-4,7-dihydrobenzo[b]thiophene-2-carboxylate (QSSs) were obtained by substitution of methyl 5,6-dichloro-4,7-dioxo-4,7-dihydrobenzo[b]thiophene-2-carboxylate (QS3) with arylthiols. 2-Amino-4,9-dioxo-1-phenyl-4,9-dihydro-1H-pyrrolo[3,2-g]quinoline-3-carboxylate (QQCAs) were obtained by substitution of 6,7-dichloroquinoline-5,8-dione with cyanoacetate derivatives (2-methoxyethyl 2-cyanoacetate, isopropyl 2-cyanoacetate) and arylamines. The antifungal activities of all 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 minimum inhibitory concentration (MIC) values were determined and compared with positive controls, fluconazole and flucytosine. In naphthoquinone compounds, 10-hydroxybenzo[f]pyrido[1,2-a]indole-6,11-dione (JQPMs) showed relatively potent antifungal activities against C. albicans, C. tropicalis, C. neoformans, C. krusei, A. flavus and A. niger compared to flucytosine. And methyl 6-chloro-4,7-dioxo-5-(phenylthio)-4,7-dihydrobenzo[b]thiophene-2-carboxylate (QSSs) showed potent antifungal activity compared to flucytosine. Finally, 2-amino-4,9-dioxo-1-phenyl-4,9-dihydro-1H-pyrrolo[3,2-g]quinoline-3-carboxylate (QQCAs) did not show antifungal activity against flucytosine.