2-Pyridyl-4,7-benzimidazoledione과 4,7-Dioxobenzothiazole 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-benzimidazolediones, a bioisostere of 5,8-quinolinedione and 4,7-dioxobenzothiazole, were synthesized and evaluated for their antifungal activities. 5-(Arylamino)-4,7-benzimidadazoledions (CKUs) were obtained by the substitution of 4,7-behzimidadazoledion with the appropriate arylamines in the presence of CeC_(3). 4,7-benzimidazoledione was prepared by treating 4,7-dimethoxybenzimidazol with CAN. 5,6-Dichloro-2-(3-pyridyl)-4,7-benzimidazoledione was synthesized by 2-(3-pyridyl)-4,7-dimethoxybenzimidazole, HCl and HNO_(3). 6-(arylamino)-5-chloro-2-(3-pyridyl)-4,7-benzimidazoledione (3PBIQs) were produced by the same procedure with CKUs. 5,6-bis- (arylthio)-2-(3-pyridyl)-4,7-benzimidazoledione (3PSs) were obtained by the substitution with the appropriate arylthiols in the presence of CeCl_(3). 6-(arylamino)-5-chloro-2-(4-pyridyl)-4,7-benzimidazoledione (4PBIQs) and 5,6-bis-(arylthio)-2-(4-pyridyl)-4,7-benzimidazoledione(4PSs) were produced by the same procedure with 3PBIQs and 3PSs. 6-(Arylthio)-5-chloro-2-(2-pyridyl)-4,7-benzimidazoledione (PSIs) and 5,6-bis-(arylthio)-2-(2-pyridyl)-4,7-benzimidazoledione (PSIIs) were obtained by the substitution with the appropriate arylthiols in the presence of CeCl_(3). 6-(Arylamino)-2,5-dimethyl-4,7-dioxobenzothiazole were obtained by the substitution of 2,5-Dimethyl-4,7-dioxobenzothiazole with the appropriate arylamines in the presence of CeC1(3) (dMBTs), 2,5-Dimethyl-4,7-dioxobenzothiazole was prepared by treating 7-Amino-2,5-dimethyl benzothiazole with Fremy's salt. 6-Arylthio-2,5-dimethyl-4,7-dioxobenzothiazoles (dMBTSs) and 6-arylthio-5-methoxy-2-methyl-4,7-dioxobenzothiazoles (SMBTs) were obtained by the substitution with the appropriate arylthiols in the presence of CeCl(3). Some quinones were synthesized by the previous known procedure and substituted with 5,6-Dichloro-2-(2-pyridyl)-4,7-benzimidazoledione and 5-methoxy-2-methyl-4,7-dioxobenzothiazole (SMBT). The antifungal activities of 5-(Arylamino)-4,7-benzimidadazoledions(CKUs) ,6-(arylamino)-5-chloro-2-(3-pyridyl)-4,7-benzimidazoledione(3PBIQs),6-(arylamino)-5-chloro-2-(4-pyridyl)-4,7-benzimidazolediones(4PBIQa) and 5,6-bis-(arylthio)-2-(3-pyridyl)-4,7-benzimidazoledione(3PSs), 5,6-bis-(arylthio)-2-(4-pyridyl)-4,7-benzimidazoledione(4PSs),6-(arylthio)-5-chloro-2-(2-pyridyl)-4,7-benzimidazoledione(PSIs) and 5,6-bis-(arylthio)-2-(2-pyridyl)-4,7-benzimidazoledione(PSIIs),6-(arylamino)-2,5-dimethyl-4,7-dioxobenzothiazole (dMBTSs ), 6-Arylthio-2,5-dimethyl-4,7-dioxobenzothiazoles (dMBTSs) and 6-arylthio-5-methoxy-2-methyl-4,7-dioxobenzothiazoles (SMBTs) were evaluated using the two fold broth dilution method against Candidaalbicans, 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.albicans, C.tropicalis and C.krusei.;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 유도체와 4,7-dioxobehzothiazole 유도체를 새로이 합성하여 그 항진균 작용을 검색하였다. 4,7-behzimidazoledione 유도체들은 1,4-dimethoxybenzene을 니트로화 한 후 PtO_2을 촉매로 수소 환원시키고 포름산과 반응시켜 4,7-dimethoxy-benzimidazole ring을 합성한 후 cerium ammonium nitrate을 이용하여 quinonoid form으로 산화시켜 4,7-behzimidazoledione을 합성한 후, 이 물질을 다양한 arylamine과 Ce(Ⅲ)ion 촉매 하에 반응시켜 선택적으로 6-(arylamino)-4,7-benzimidazoledione(CKUs)을 합성했다. 또한 2-(3-Pyridyl)-4,7-benzimidazoledione 유도체들과 2-(4-pyridyl)-4,7-benzimidazoledione 유도체들은 1,4-dimethoxybenzene을 니트로화한 후 PtO_2을 촉매로 수소 환원시키고 각각 3,4-pyridylcarboxaldehyde와 반응시켜 2-(3-pyridyl)-4,7-dimethoxy benzimidazole과2-(4-pyridyl)-4,7-dimethoxybenzimidazole을 합성하였다. 그 후 HCI과 HNO_3을 사용하여 quinonoid form으로 산화 및 염소화시켜 5,6-dichloro-2-(3-pyridyl)-4,7-henfihddazoledione과 5,6-dichloro-2-(4-pyridyl)-4,7-benzimidazoledione으로 만든 뒤 다양한 arylamine과 arylthlol을 Ce(Ⅲ)ion 촉매 하에 반응시켜 각각 6- (arylamino) -5-chloro-2-(3-pyridyl)-4,7-benzimidazoledione (3PBIQs) 유도체 16개와 5,6-bis-(arylthio)-2-(3-Pyridyl)-4,7-henzimidazoledione (3PSs) 유도체 8개를 얻었고, 6-(arylamino)-5-chloro-2-(4-pyridyl)-4,7-benzimidazoledione (4PBIQs) 유도체 17개와 5,6-Bis-(arylthio)-2-(3-pyridyl)-4,7-benzimidazoledione (4PSs) 유도체 10개를 얻었다. 2-(2-pyridyl)-4,7-benzimidazoledione 유도체들도 같은 방법으로 6- (arylthio) -5-chloro-2- (2-pyridyl) -4,7-benzimidazoledione (PSⅠs) 7개 와5,6-Bis-(arylthio)-2-(2-pyndyl)-4,7-benzimidazoledione (PSⅡs) 8개를 합성하였다. 4,7-Dioxobenzothiazole 유도체들은 2,5-dimethyl-benzothiazole을 니트로화한 후 환원시키고 Fremy's salt를 이용해 산화시켜 2,5-dimethyl-4,7-benzothiazole을 합성하고 다양한 arylamines과 반응시켜 6-arylamino-2,5-dimethyl-benzothiazole (dMTSs)를 얻었고, arylthiols과 반응시켜 6-arylthio-2,5-dimethyl-benzothiazole (dMBTSs) 유도체 5개를 얻었다. 또한, 이미 알려진 물질인 6-methoxy-2-methyl-4,7-dioxobenzothiazole을 다양한 arylthiols과 반응시켜 6-arylthio-5-methoxy-2-methyl-4,7-dioxobenzothiazole (SMBTS) 유도체 5개를 얻었다. 충북대학교 약학대학에서 합성한 물질 2-chloro-4-methyl-5,8-quinolinedione을 다양한 arylthiols과 반응시켜 HYs 유도체 3개를 얻었다. 합성한 benzimidazolediohe 유도체 (CKUs) 및 2-(2,3,4-pyridyl)-benzimidazoledione 유도체 (3PBIQS, 4PBIQS, PSs, 3PSs, 4PSs)들과 4,7-dioxobenzothiazole 유도체 (dMBTs, dMBTSs, SMBTs), 5,8-quinolinedione 유도체 (HYs)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, flucytosine을 사용하였다. 최소 발육저지 농도, 즉 MIC (minimum inhibitory concentration)을 측정한 결과 fluconazole보다는 효과가 좋았으며, 몇몇 유도체의 경우 fluorocytosine보다 효과가 좋았으나, 몇몇 유도체의 경우 fluorocytosine보다 그 효과가 비슷하거나 약하였다. 4,7-benzimidazolediones (CKUs, 3PBIQS, 4PBIQS, 4PSs, 3PSs, PSs)는 대부분의 약물이 양성 대조군으로 사용된 fluconazole과 비슷하거나 우수한 수준의 항진균 작용을 나타냈으나 fluorocytosine보다는 그 효과가 약하였다. 그중에서 4,7-dioxobenzothiazoles (dMBTs) 유도체들은 대부분의 약물이 양성 대조군으로 사용된 fluconazole과 비슷하거나 우수한 수준의 항진균 작용을 나타냈다. 그리고 이 유도체 중 몇몇은 fluorocytosine보다 좋은 효과를 나타냈다.