Furo[2,3-f]quinolin-5-ol 및 furo[2,3-f]quinazolin-5-ol 유도체의 합성 및 항진균 작용 연구

Abstract

Quinonoid 유도체들은 항진균, 항암, 항균, 항말라리아, nitric oxide synthase 저해작용 등 다양한 생리활성을 나타낸다. 본 연구에서는 quinone 유도체 중 우수한 생리활성이 예상되는 furo[2,3-f]quinolin-5-ol , furo[2,3-f]quinazolin-5-ol 및 5,8-quinazolinedione 유도체를 합성하여 항진균 작용 및 그 생리활성을 검색하였다. 기존의 hydroxybenzofuran 유사체들은 fungal Nmt inhibitors로 알려져 있으며 이는 기존 항진균제들과 다른 약리기전을 가지므로 최근 항진균제들이 가지고 있는 단점을 극복할 수 있을 것으로 기대되고 있다. 신약 개발의 중요한 lead compound인 quinolinedione을 chlorination시켜 얻은 6,7-dichloroquinoline-5,8-dione 에 ethyl cyanoacetate를 가하여 ethyl기와 cyanoacethyl기가 치환된 ethyl 2-(7-chloro-5,8-dihydro-5,8-dioxoquinoline-6-yl)-2-cyanoacetate를 합성하였다. 여기에 arylthiol 또는 aliphatic thiol을 첨가하여 furan ring을 포함하고 있는 furo[2,3-f]quinoline 구조의 물질 4a-o (QCESs) 유도체 15개를 합성하였다. 5,8-dimethoxyquinazoline을 HCl과 HNO3로 직접 산화하여 6,7-dichloro-5,8-quinazolinedione을 합성한 후 arylthiol 또는 aliphatic thiol과 반응시켜 물질 9a-o (DQSs) 유도체 15개를 합성하였다. 또한 6,7-dichloro-5,8-quinazolinedione에 ethyl cyanoacetate를 가하여 ethyl기와 cyanoacetyl기가 치환된 ethyl 2-(7-chloro-5,8-dihydro-5,8-dioxoquinazoline-6-yl)-2-cyanoacetate를 합성하였다. 여기에 arylthiol을 첨가하여 물질 11a-g (DQESs) 유도체 7개를 합성하였다. 합성한 물질 4a-o (QCESs), 9a-o (DQSs), 11a-g (DQESs) 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, fluorocytosine을 사용하였다. 물질 4a-o (QCESs) 의 경우, 대체적으로 C. albicans와 C. tropicalis , C. krusei, A. niger, A. flavus 다섯 균주에 대해 좋은 약효를 나타냈고, 몇몇 약물은 모든 균주에 대해 좋은 항진균 효과를 나타내기도 했다. 4d (4-Cl)과 4e (4-F), 4f (4-H)은 C. neoformans를 제외한 모든 균에 대해 fluorocytosine과 fluconazole보다 나은 효과를 나타냈다. 물질 9a-o (DQSs)의 항진균 작용을 검색한 결과, 대체적으로 모든 약물이 fluconazole과 비슷하거나 나은 효과를 보였으며, 특히 9b (4-OCH3), 9c (4-Cl), 9d (4-Br)는 모든 균주에 대해 fluorocytosine과 fluconazole보다 뛰어나거나 비슷한 약효를 보였다. 주로 4번 위치에 halogen이 치환된 유도체가 항진균 효과가 좋았으며 arylthiol 유도체가 aliphatic thiol 유도체보다 더 우수한 항진균 효과를 가졌다. 물질 11a-g (DQESs) 은 대부분의 균에 대해 fluconazole과 비슷하거나 나은 효과를 나타냈지만, 11a (4-CH3), 11e (3,4-F), 11f (2,4-F) 만이 fluorocytosine과 비슷하거나 좋은 약효를 보였다.;Quinones have 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, 5,8-quinazolinediones and hydroxybenzofuran derivatives were synthesized and evaluated for their antifungal activites. Hydroxybenzofuran antifungal agents have been reported to be fungal Nmt inhibitors. Fungal Nmt is a potential target enzyme for the development of novel fungicidal drugs having a broad antifungal spectrum. In addition, the Nmt inhibitors might overcome the drawbacks of current antifungal drugs, such as resistance or drug-drug interactions. Based on this consideration, various hydroxybenzofuran analogues were synthesized and evaluated for their antifungal activites. Especially, 5,8-quinolinediones have been known for potent antifungal activity and cytotoxicity against cancer. Therefore 5,8-quinazolinediones as a bioisostere of 5,8-quinolinedione were synthesized and evaluated for their antifungal activities. Ethyl 2-(7-chloro-5,8-dihydro-5,8-dioxoquinolin-6-yl)-2-cyanoacetate (3, QCE) was obtained by substitution of 6,7-dichloroquinoline-5,8-dione with ethyl cyanoacetate. Ethyl 2-amino-5-hydroxy-4-mercaptofuro[2,3-f]quinoline-3-carboxylate 4a-o (QCESs) were obtained by substitution of QCE with the appropriate arylthiols and aliphatic thiols. 6,7-Dichloro-5,8-quinazolinedione was prepared by treating 5,8-dimethoxy quinazoline with HCl and HNO3. 6,7-bis(4-mercapto)quinazoline-5,8-dione 9a-o (DQSs) were prepared by substitution of 6,7-dichloro-5,8-quinazolinedione with arylthiols and aliphatic thiols. Ethyl 2-(7-chloro-5,8-dihydro-5,8-dioxoquinazolin-6-yl)-2-cyanoacetate (10, DNQE) was obtained by substitution of 6,7-dichloro-5,8-quinazolinedione (8, DNQ) with ethyl cyanoacetate. Ethyl 2-amino-5-hydroxy-4-mercaptofuro[2,3-f]quinazoline-3-carboxylate 11a-g (DQESs) derivatives were obtained by substitution of DNQE with the appropriate arylthiols. The antifungal activities of all the compounds have synthesized were evaluated using the two fold broth dilution method against C. albicans, C. tropicalis, C. neoformans, C. krusei, A. flavus and A. niger. Their MIC (minimum inhibitory concentration) values were determined and compared with positive controls, fluconazole and fluorocytosine. Among newly synthesized compounds, ethyl 2-amino-5-hydroxy-4-mercaptofuro[2,3-f]quinoline-3-carboxylates 4a-o(QCESs) and 6,7-bis(4-mercapto)quinazoline-5,8-diones 9a-o(DQSs) and ethyl 2-(7-chloro-5,8-dihydro-5,8-dioxoquinazolin-6-yl)-2-cyanoacetates 11a-g (DNQEs) generally showed relatively potent antifungal activities compared to fluconazole and fluorocytosine.