Quinolinedionoid 유도체 합성 및 항진균 작용 평가

Abstract

Quinolinedione 계열 물질은 항진균, 항균, 항암, 항말라리아 작용이 있다. Quinolinedione 유도체 중 우수한 항진균작용이 예상되는 5,8-quinolinedione 모핵에 N-phenylamino, 7-thiomethyl, 7-thiocyano, 6-thioalkyl가 치환된 새로운 유도체를 80%이상의 수득율로 합성하여 in vitro에서 항진균작용을 검색하였다. 8-Hydroxyquinoline을 NaN0_(2) 로 nitroso화, reduction, oxidation, chlorination 시켜 6,7-dichloro-5,8-quinolinedione 을 얻은 후 이 물질에 다양한 arylamine 또는 alkylamine을 CeCI_(3) 촉매하에서 반응시켜 선택적으로 6 위치에만 치환된 6-(N-substituted)-7-chloro-5,8-quinolinedione 유도체를 합성한 후 Na_(2)S와 (CH_(3))_(2)SO_(4) 또는 NH_(4)SCN을 가해 7번 위치를 thioalkylation, thiocyanation시켜서 RCK 101-150을 얻었다. 또한 5-amino-8-hydroxyquinoline에 HCI과 NaCIO_(3)로 oxidation 및 chlorination 시켜 합성한 6,7-dichloro-5,8-quinolinedione을 CeCI_(3) 촉매하에서 각각 Na_(2)S 와 alkyl bromide를 반응시켜 션택적으로 6위치에만 치환된6-substituted-7-chloro-5,8-quinolinedione (SQ101-110)을 얻었다. 위에서 얻은 유도체와 6-(N-substituted)-7-bromo-5,8-quinolinedione및 6-(N-substituted)-7-chloro-5,8-quinolinedione 유도체들을 병원성 진균인 pathogenic yeast의 대표적인 지표가 되는 Candida albicans Berkout KCTC 1940, Candida krusei Berkout KCTC 7213, Candida tropicalis Berkout KCTC 1195, Candida glabrata Anderson KCTC 1714, Candida parapsilosis Ashford KCTC 7214에 대한 항진균 작용을 검색하였다. 각 화합물에 대한 최소발육저지농도, 즉 MIC (minimum inhibitory concentration)는 고체 배지 희석법 (twofod agar dilution method)로 fluconazole을 대조약물로 하여 결정하였다. 그 결과 많은 quinolinedione계열물결들은 우수한 항진균작용을 나타내었다. 그 중 RCK 101, 114, 116, 117, 120, 129, SQ 106, 109 BQ 102, 103, QQ104는 MIC가 기존의 fluconazole보다 Candida sp.에 대해서 수배 내지 수십배 우수한 항진균작용을 나타내었다. CI, Br, F 등과 같이 halophenylamino 기가 6번 위치에 치환된 화합물의 항진균작용이 우수했다.;New 6-(N-substituted)-7-methylthio-5,8-quionolinedione, 6-(N-substituted)-7-cyanothio-5,8-quinolinedione and 6-substituted-7-chloro-5,8-quionlinedione derivatives were synthesized in order to evaluate the antifungal activities of quionlinedione derivatives. 6,7-Dichloro-5,8-quionlinedione was prepared by treating 5-amino-8-hydroxyquinoline with NaClO_(3) in HCl. 6-(N-substituted)-7-chloro-5,8-quinolinediones were prepared by substitution of 6,7-dichloro-5,8- quinolinedione with arylamine or alkylamine in ethanol in 90% yield. 6-Substituted-7-methylthio-5,8-quinolinediones and 6-substituted-7-cyano- thio-5,8-quinolinediones were synthesized by treating them with Na_(2)S and (CH_(3))SO_(4) or NH_(4)SCN, respectively. Substitution of 6,7-dichloro- 5,8-quinolinedione with Na_(2)S and alkylbutane in ethanol offorded 6-substituted-7-chloro-5,8-quinolinedione. These derivatives were evaluated for antifungal activities in vitro against Candida albicans Berkout KCTC 1940, Candida glbicans Anderson KCTC 7214, Candida parapsilosis Ashford KCTC 7214, Candida tropicalis Berkout KCTC 1195 and Candida krusei Berkout KCTC 7213. The MIC's were determined using the two fold agar/streak dilution method. 6-(N-Substituted)-7-methylthio-5,8-quinolinedione derivatives and 6-substituted-7-chloro-5,8-quinolinedione derivatives showed more potent antifungal activities than reference compound, fluconazole. RCK 101, 112, 114, 116, 117, 129, 136, 144 and 147 showed very potent antifungal activities. Among these, RCK 112 was the most effective in preventing the growth of Candida glabrata, Candid krusei and Candida tropioalis at MIC 0.8㎍/㎖. 6-Substituted-7-chloro-5,8-quinolinediones demonstrated stronger antifungal activities against C. krusei than other Candida strains.