4,7-Dioxobenzoselenazole 화합물의 유도체 합성 및 항진균 작용 연구

Abstract

Quinones have been reported with various pharmcological activities such as antifungal, anticancer and antimalarial activities. Especially, 5,8- quinolinediones and 4,7-dioxobenzothiazoles have been shown for their potent antifungal activity and cytotoxicity against human cancer cell with novel mechanisms. Based on this consideration, 4,7-dioxobenzoselenazole, 1H-benzo[d][1,2,3]triazole-4,7-dione, 2-thioxobenzo[d][1,3]dithiole-4,7-dione a bioisostere of 5,8-quinolinedione and 4,7-dioxobenzothiazole, were synthesized and evaluated for their antifungal activities. 5-Arylamino-2-methyl-4,7-dioxobenzoselenazoles (SeQNs) and 6-arylthio- 5-methoxy-2-methyl-4,7-dioxobenzoselenazoles (SeQSs) were obtained by the substitution of 5-methoxy-2-methyl-4,7-dioxobenzoselenazole with the appropriate arylamines or arylthiols in the presence of CeCl3. 5- Methoxy-2-methyl-4,7-dioxobenzoselenazole was prepared by treating 5-methoxy-2-methylbenzselenazole with nitration, reduction and oxidation by Fremy's salt. 5,6-Dichloro-1H-benzo[d][1,2,3]triazole-4,7-dione was prepared by treating 4,7-dimethoxy-1H-benzo[d][1,2,3]triazole with HCl and HNO3. 5-Arylamino-6-chloro-1H-benzo[d][1,2,3]triazole-4,7-diones (3NQNs) and 5,6-bis(arylthio)-1H-benzo[d][1,2,3]triazole-4,7-diones (3NQSs) were obtained by the substitution of 5,6-dichloro-1H-benzo[d][1,2,3]triazole-4,7-dione with the appropriate arylamines or arylthiols in the presence of CeCl3. 2-Thioxobenzo[d][1,3]dithiole-4,7-dione was prepared by treating 4,7-dihydroxybenzo[d][1,3]dithiole-2-thione with CAN. 5-Arylamino-2- thioxobenzo[d][1,3]dithiole-4,7-diones (3SQNs) and 5,6-bis(arylthio)-2- thioxobenzo[d][1,3]dithiole-4,7-diones (3SQSs) were obtained by the substitution of 2-thioxobenzo[d][1,3]dithiole-4,7-dione with the appropriate arylamines or arylthiols in the presence of CeCl3. The antifungal activities of 5-arylamino-2-methyl-4,7-dioxobenzoselenazoles (SeQNs), 6-arylthio-5-methoxy-2-methyl-4,7-dioxobenzoselenazoles (SeQSs), 5-arylamino-6-chloro-1H-benzo[d][1,2,3]triazole-4,7-diones (3NQNs), 5,6-bis (arylthio)-1H-benzo[d][1,2,3]triazole-4,7-diones (3NQSs), 5-arylamino-2- thioxobenzo[d][1,3]dithiole-4,7-diones (3SQNs) and 5-arylthio-2-thioxobenzo[d] [1,3]dithiole-4,7-diones (3SQSs) were evaluated using the two fold broth dilution method against Candida albicans, C. tropicalis, C. krusei, Aspergillus niger and A. flavus. The minimum inhibitory concentration (MIC) values of test compounds were determined, and compared with positive controls, fluconazole and fluorocytosine. Newly synthesized compounds generally showed potent antifungal activities compared to fluconazole against C. tropicalis and C. krusei and A. flavus.;Quinone 유도체는 항진균, 항암, 항균, 항말라리아, nitric oxide synthase 저해작용 등 여러 가지 생리활성을 나타낸다. 이에 본 연구에서는 quinone 유도체 중 우수한 항진균 작용이 예상되는 4,7-dioxobenzoselenazole, 1H- benzo[d][1,2,3]triazole-4,7-dione과 2-thioxobenzo[d][1,3]dithiole-4,7-dione 유도체를 새로이 합성하여 그 항진균 작용을 검색하였다. 4,7-Dioxobenzoselenazole 유도체는 5-methoxy-2-methylbenzselenazole을 니트로화한 후 환원시키고 Fremy's salt를 이용해 산화시켜 5-methoxy-2- methyl-4,7-dioxobenzoselenazole을 합성하고 다양한 arylamine과 반응시켜 5-arylamino-2-methyl-4,7-benzoselenazole (SeQNs) 유도체를 얻었고, arylthiol과 반응시켜 6-arylthio-5-methoxy-2-methyl-4,7-dioxobenzoselenazole (SeQSs) 유도체를 합성했다. 1H-Benzo[d][1,2,3]triazole-4,7-dione 유도체는 1,4-dimethoxybenzene을 니트로화한 후 PtO₂을 촉매 하에 수소로 환원시키고 NaNO₂와 반응시켜 4,7-dimethoxy-1H-benzo[d][1,2,3]triazole을 합성했다. 그 후 HCl과 HNO₃을 사용하여 quinonoid form으로 산화 및 염소화시켜 5,6-dichloro-1H-benzo[d] [1,2,3]triazole-4,7-dione으로 합성한 뒤 다양한 arylamine과 arylthiol을 반응시켜 각각 5-arylamino-6-chloro-1H-benzo[d][1,2,3]triazole-4,7-dione (3NQNs) 와 5,6-bis(arylthio)-1H-benzo[d][1,2,3]triazole-4,7-dione (3NQSs) 유도체를 합성했다. 2-Thioxobenzo[d][1,3]dithiole-4,7-dione 유도체는 dithiocarbamate salt에 p-benzoquinone을 가하여 2,5-dihydroxyphenyl pyrrolidine-1-carbodithioate을 합성하였다. 그 후 p-benzoquinone와 더 반응시킨 후 Na₂S·9H₂O 반응시켜 4,7-dihydroxybenzo[d][1,3]dithiole-2-thione을 합성하고 CAN을 이용해 2- thioxobenzo[d][1,3]dithiole-4,7-dione으로 만든 후 arylamine과 arylthiol을 반응시켜 각각 5-arylamino-2-thioxobenzo[d][1,3]dithiole-4,7-dione (3SQNs)와 5,6-bis(arylthio)-2-thioxobenzo[d][1,3]dithiole-4,7-dione (3SQSs) 유도체를 합성했다. 합성한 4,7-dioxobenzoselenazole (SeQNs, SeQSs), 1H-benzo[d][1,2,3] triazole-4,7-dione (3NQNs, 3NQSs)와 2-thioxobenzo[d][1,3]dithiole-4,7-dione (3SQNs, 3SQSs) 유도체들에 대해 5가지 균주, Candida albicans, C. tropicalis, C. krusei, Aspergillus niger, A. flavus에 대한 항진균 작용을 검색하였다. 각 화합물에 대한 MIC (minimum inhibitory concentration)는 액체 배지 희석법 (two fold broth dilution method)으로 대조약물로는 fluconazole, flucytosine을 사용하였다. 최소 발육저지 농도, 즉 MIC (minimum inhibitory concentration)을 측정한 결과 fluconazole보다는 효과가 좋았으며, 몇몇 유도체의 경우 fluorocytosine보다 효과가 좋았으나 대부분의 유도체는 fluorocytosine보다 그 효과가 비슷하거나 약하였다.