4,7-Benzimidazoledione과 5,8-Quinoxalinedione 유도체 합성 및 항진균 작용 연구

Abstract

Quiones 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 cytotoxiciiy against human cancer cell with novel mechanisms. Based on this consideration, 4,7-benzimidazolediones, 5,8-quinoxlalinedione, 4,7-dioxoindazole a bioisostere of 5,8-quinolinedione and 4,7-dioxobenzothiazole, were synthesized and evaluated for their antifungal activities. 5,6-Dichloro-2-methyl-4,7-benzimidazoledione was prepared by treating 2-methyl-4,7-dimethoxybenzimidazole with HCl and HNO_(3) and 6-(arylamino)-5-chloro-4,7-benzimidazolediones (HJYs) were obtained by the substitution of 5,6-dichloro-2-methyl-4,7-benzimidazole with the appropriate arylamines in the presence of CeCl_(3). 5,6-Dichloro-2-trifluoronethyl-4,7-benzimidazoledione was synthesized by 2-trifluoronethyl-4,7-dimethoxybenzimidazole, HCl and HNO_(3) and 6-(arylamino)-5-chloro-2-trifluoronethyl-4,7-benzimidazolediones (TFQs) were derived from the same procedure with HJYs. 2,3-Dimethyl-5,8-quinoxalinedione was prepare by treating 2,3-dimethyl-5,8-dimethoxyquinoxaline with anhydrous AICI_(3) and Ag_(2)O. 6-(Arylamino)-2,3-dimethyl-5,8-quinoxalinediones (QNXs) were produced with HJYs. 5,6-Dichloro-4,7-dioxoindazole was prepared by treating 4,7-diamninoindazole with HCl and NaClO_(3). 5-(Arylthio)-6-chloro-4,7-dioxoindazoles and 5,6-Bis-(arylthio)-4,7-dioxoindazole (ISs) were obtained by the substitution of 5,6-dichloro-4,7-dioxoindazole with the appropriate arylthiol in the presence of CeCl_(3). The antifungal activities of 6-(arylamino)-5-chloro-2-methyl-4,7-benzirnidafolediones (HJYs), 6-(arylamino)-5-chloro-2-trifluoromethyl-4,7-benzimidazolediones (TFQs), 6-(arylamino)-2,3-dimethyl-5,8-dimethoxy-quinoxalinediones (QNXs) and 5-(arylthio)-6-chloro-4,7-dioxoindazoles (ISs), were evaluated using the two fold broth dilution method against Candida albicans, C. tropicalis, C. krusei and Aspergillus niger. 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. tropicalisz;Quinone 유도체들은 항진균, 항암, 항균, 항말라리아, nitric oxide synthase (NOS) 저해작용 등 여러 가지 생리활성을 나타낸다. 이에 본 연구에서는 quinone 유도체 중 우수한 항진균 작용이 예상되는 4,7-benzimidazoledione 유도체, 5,8-quinoxalinedione 유도체와 4,7-dioxoindazole 유도체를 새로이 합성하여 그 항진균 작용을 검색하였다. 4,7-Benzimidazoledione 유도체는 1,4-dimethoxybenzene을 니트로화 한 후 PtO_(2)를 촉매로 수소 환원 시키고 CH_(3)COOH 과 반응시켜 4,7-dimethoxy-2-methyl-benzimidazole을 만들었다. HCI과 HNO_(3)로 quinonoid form으로 산화 및 염소화 시켜 5,6-dichloro-2-methyl-4,7-benzimidazoledione을 합성한 후 이 물질을 다양한 arylamine과 Ce(Ⅲ)ion 촉매하에 반응시켜 선택적으로 6-(arylamino)-5-chloro-2-methyl-4,7-benzimidazoledione (HJYs ) 26개 (HJY11-37)을 합성했다. 5,6-Dichloro-2-trifluoromethyl-4,7-benzimidazoledione 유도체들은 1,4-dime thoxybenzene을 니트로화 한 후 PtO_(2)를 촉매로 수소 환원 시키고 trifluoroacetic acid와 반응시켜 HCI과 HNO_(3)로 quinonoid form으로 산화 및 염소화 시켜 5,6-dichloro-2-trifluorornethyl-4,7-benzimidazoledione을 합성한 후 이 물질을 다양한 arylamine과 Ce(Ⅲ)ion 촉매하에 반응시켜 선택적으로 6-(arylamino)-5-chloro-2-trifluorornethyl-4,7-benzimidazoledione (TFQs) 20개 (TFQ01-21)을 선택적으로 얻었다. 5,8-quinoxalinedione 유도체는 1,4-dimethoxybenzene을 니트로화 한 후 10% Pd on C을 촉매로 수소 환원시키고 2,3-butanedione과 반응시켜 5,8-dimethoxy-2,3-dimethyl-quinoxaline을 만들었다. AlCl_(3)로 demethylation 한 후 Ag_(2)O로 quinonoid form으로 산화시키고 이 물질을 다양한 arylamine과 Ce(Ⅲ)ion 촉매하에 반응시켜 선택적으로 6-(arylamino)-2,3-dimethyl-5,8-quinoxalinedione (QNXs) 10개 (QNX03-14)를 합성했다 또한, 4,7-Dioxoindazole 유도체들은 4,7-diarninoindaEole을 c-HCI과 NaClO_(3)로 산화 및 염소화시켜 5,6-dichloro-4,7-dioxoindazole을 만든 후 다양한 arylthiol과 Ce(Ⅲ)ion 촉매하에 반응시켜 5-(arylthio)-6-chloro 또는 5,6-bis-[S-(arylthio)]-4,7 -dioxoindazole (ISs) 9개 (IS01-10)을 합성했다. 합성한 benzimidazoledione 유도체 (HJYs와 TFQs), quinoxlinedione 유도체(QNXs) 및 dioxoindazole 유도체 (ISs)들에 대해 4가지 균주, Candida albicans, C. tropicalis, C. krusei, Aspergillus niger에 대한 항진균 작용을 검색하였다. 각 화합물에 대한 MIC (minimum inhibitory concentration)는 액체 배지 희석법 (two fold broth dilution method)으로 대조약물로는 fluconazole, fluorocytosine을 사용하였다. 최소 발육저지 농도, 즉 MIC (minimum inhibitory concentration)을 측정한 몇몇 유도체는 fluconazole 보다는 효과가 좋았으나 대부분의 유도체들은 fluorocytosine 보다 그 효과가 좋지 않았다. 6-(Arylamino)-5-chloro-2-methyl-4,7-benzinudazoledione (HJYs)와 6-(arylamino)-5-chloro-2-trifluoromethyl-4,7-henzimidazolediones (TFQs)는 대부분의 약물이 fluconazole과 fluorocytosine보다 효과가 약하였다. 그러나 6-(Arylamino)-2,3-dimethoxy-5,8-quinoxlinediones (QNXs) 와 5-(arylamino) -6-chloro-4,7-dioxoindazoles (ISs)는 HJYs나 TFQs 보다 좋은 효과를 나타냈으며 양성대조군으로 사용된 fluconazole과 비슷하거나 우수한 수준의 항진균 작용을 나타냈다. 또한 이 유도체들 중 몇몇은 fluorocytosine보다 좋은 효과를 나타냈다.