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Indolequinone과 Hydroxybenzofuran 유사체의 합성 및 항진균 작용 연구

Title
Indolequinone과 Hydroxybenzofuran 유사체의 합성 및 항진균 작용 연구
Authors
노지희
Issue Date
2008
Department/Major
대학원 생명·약학부약학전공
Publisher
이화여자대학교 대학원
Degree
Master
Abstract
Quinones have been reported with 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, indolequinone and ethyl 2-amino-4-chloro-5-hydroxyfuro[2,3-f]isoquinoline-3-carboxylate derivatives were synthesized and evaluated for their antifungal activites. Benzofuran 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. Reaction products of quinones and other carbonyl compounds with cysteine can be a new compounds with various pharmacological activities. The inhibitory activity of cysteine derivatives on the antifungal properties has not been reported to the best of our knowledge. Various cysteine derivatives with different substituents could exhibit the biological activities through different action and may improve the activities. Ethyl 2-(7-chloro-5,8-dihydro-5,8-dioxoisoquinolin-6-yl)-2-cyanoacetate (NQC) was obtained by substitution of 6,7-dichloroisoquinoline-5,8-dione with ethyl cyanoacetate. ethyl 2-amino-4,9-dihydro-4,9-dioxo-1H-pyrrolo [3,2-g]isoquinoline-3-carboxylate (NQNs) and ethyl 2-amino-5-hydroxy-4- mercaptofuro[2,3-f]isoquinoline-3-carboxylate (NQSs) were obtained by substitution of NQC with the appropriate arylamines and arylthiols. Ethyl 2-(7-chloro-5,8-dihydro-5,8-dioxoquinolin-6-yl)-2-cyanoacetate (QC) was obtained by substitution of 6,7-dichloroquinoline-5,8-dione with ethyl cyanoacetate. ethyl 2-amino-4,9-dihydro-4,9-dioxo-1H-pyrrolo[3,2-g] quinoline-3-carboxylate (QCNs) were obtained by substitution of QC with the appropriate arylamines Hydroxybenzofuran analogues such as NQH2, NBH2, NBMH2, QCH2, QBH2, QBMH2, MQH2, MQMH2, BQH2, BQMH2, DDH2, DDMH2, MMH2, MMMH2 were obtained by substitution of 6,7-dichloroisoquinoline-5,8- dione, 6,7-dichloroquinoline-5,8-dione, 6,7-dibromo-5,8-quinolinedione, 7-methyl-5,8-quinolinedione, 2-bromo-1,4-naphthoquinone, 2,5-dimethyl-4,7- dioxobenzothiazole and 5-methoxy-2-methyl-4,7-dioxobenzothiazole with ethyl cyanoacetate or methyl cyanoacetate. And treating equivalent amount of hydrazine hydrate as a reductant. Thiazine derivatives such as JHE, JHM, DCE, DCM, NPC-e, NPC-m were obtained by substitution of 2,3-dimethyl-5,8-quinoxalinedione, 6,7-dichloro- 5,8-dihydroxy-1,4-naphthoquinone and naphtoquinone with L-cysteine ethylester hydrochloride or L-cysteine methyl ester hydrochloride. 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 minimum inhibitory concentration (MIC) values were determined and compared with positive controls, fluconazole and fluorocytosine. Among newly synthesized compounds, ethyl 2-amino-4,9-dihydro-4,9-dioxo-1H- pyrrolo[3,2-g]isoquinoline-3-carboxylate (NQNs) and ethyl 2-amino-5- hydroxy-4-mercaptofuro[2,3-f]isoquinoline-3-carboxylate (NQSs) and ethyl 2-amino-4,9-dihydro-4,9-dioxo-1H-pyrrolo[3,2-g]quinoline-3-carboxylate (QCNs) generally showed relatively potent antifungal activities against C. albicans, C. tropicalis, C. neoformans and A. flavus compared to fluconazole and fluorocytosine. Hydroxybenzofuran analogues, especially QBH2 and MQH2 showed relatively potent antifungal activities against all tested pathgenic fungi. Thiazine derivatives showed relatively potent antifungal activities against C. albicans and C. tropicalis compared to fluconazole and fluorocytosine.;Quinonoid 유도체들은 항진균, 항암, 항균, 항말라리아, nitric oxide synthase 저해작용 등 다양한 생리활성을 나타낸다. 본 연구에서는 quinone 유도체 중 우수한 생리활성이 예상되는 1H-pyrrolo[3,2-g]isoquinoline-4,9- diones, 1H-pyrrolo[3,2-g]quinoline-4,9-diones 및 2-amino-5-hydroxy-4- mercaptofuroisoquinolines 유도체와 새로운 기전의 항진균 작용을 갖는 각종 benzofuran 유도체, thiazine 유도체를 새로이 합성하여 그 생리활성을 검색하였다. 신약 개발의 중요한 lead compound인 isoquinolinedione을 oxychlorination시켜 얻은 6,7-dichloroisoquinoline-5,8-dione 에 ethyl cyanoacetate를 가하여 ethyl기와 cyano acethyl기가 치환된 ethyl 2-(7-chloro-5,8-dihydro-5,8- dioxoisoquinolin-6-yl)-2-cyanoacetate를 합성하였다. 여기에 arylamine 또는 aliphatic amine을 첨가하여 NQNs 유도체 8개를 얻고 arylthiol를 첨가하여 NQSs 유도체 10개를 합성하였다. 또한 quinolinedione을 chlorination하고 ethyl cyanoacetate를 반응시킨 후 arylamines을 첨가하여 분자내 고리화 반응에 의해 heterocyclic indoledione구조를 갖는 QCNs 유도체 10개를 합성하였다. Hydroxybenzofuran 유사체들은 fungal Nmt inhibitors로 알려져 있으며 이는 기존 항진균제들과 다른 약리기전을 가지므로 최근 항진균제들이 가지고 있는 단점을 극복할 수 있을 것이라고 기대된다. 다양한 모핵에 ethyl cyanoacetate 또는 methyl cyanoacetate를 가하여 불안정한 중간 유도체를 얻고 여기에 분자 내 고리화 반응을 촉진시키는 hydrazine hydrate를 촉매로 첨가하여 benzofuran 구조의 NQH2, NBH2, NBMH2, QCH2, QBH2, QBMH2, MQH2, MQMH2, BQH2, BQMH2, DDH2, DDMH2, MMH2, MMMH2 유도체 14개를 합성하였다. 기존에 합성했던 다양한 quinonoid compounds에 L-cysteine ethylester 또는 L-cysteine methylester를 반응시켜 질소(N)와 황(S)을 포함하는 새로운 구조의 JHE, JHM, DCE, DCM, NPC-e, NPC-m 유도체 6개를 합성하고 그 항진균 작용을 검색하였다. 합성한 유도체 (NQNs, NQSs, QCNs, NQH2, NBH2, NBMH2, QCH2, QBH2, QBMH2, MQH2, MQMH2, BQH2, BQMH2, DDH2, DDMH2, MMH2, MMMH2, JHE, JHM, DCE, DCM, NPC-e, NPC-m)들에 대해서 6가지 병원균주인 C. albicans, C. tropicalis, C. krusei, C. neoformans, A. niger 및 A. flavus 에 대해서 항진균 작용을 검색하였다. 각 화합물에 대한 MIC (minimum inhibitory concentration)는 액체 배지 희석법 (two fold broth dilution method)으로 하였고 대조 약물로는 fluconazole, fluorocytosine을 사용하였다. NQNs 유도체들의 경우 특히 C. albicans 와 C. tropicalis 균주에 대해 모든 유도체가 fluorocytosine 보다도 좋은 항진균 효과를 보였다. 나머지 5개 균주에 대해서도 몇 개를 제외한 대부분의 유도체가 fluconazole 보다 효과가 좋았다. NQSs 유도체들의 경우 C. albicans 와 A. niger 균주에서 모든 유도체가 fluorocytosine 보다는 좋은 효과를 나타내지 못했으나 NQS4 (4-OH)는 C. tropicalis, C. krusei, C. neoformans 및 A. flavus 균주에서 fluorocytosine 보다 좋거나 비슷한 항진균 작용을 보였다. QCNs의 항진균 작용을 검색한 결과, C. albicans 와 C. tropicalis 균주에 있어서 QCN4 (4-OH), QCN9 (4-OCF3)가 fluorocytosine 보다 좋은 효과를 보였다. A. flavus 균주에 있어서는 QCN4 (4-OH), QCN6 (4-Cl)이 fluorocytosine보다 좋은 효과를 나타내는 것을 확인할 수 있었다. 그 외 C. neoformans, A. flavus 균주에 있어서는 대체로 fluconazole 보다 좋거나 비슷한 효과를 보였으나 눈에 띄게 좋은 항진균 효과를 나타내는 물질은 없었다. 또한 hydroxybenzofuran 유사체의 항진균 작용을 검색한 결과, C. albicans 와 C. tropicalis 균주에 있어서 MQH2 (ethyl, quinoline, 4-CH3)가 fluorocytosine보다 좋은 효과를 보였다. BQH2 (ethyl, naphthofuran)는 C. albicans 와 A. niger 균주에서 우수한 효과를 나타내었으며 QBH2 (ethyl, quinoline, 4-Br)는 C. krusei 및 A. niger 균주에 있어서 다른 유도체보다 좋은 효과를 보였다. Thiazole 모핵으로 합성한 DDH2 (ethyl, thiazole, 5-CH3), DDMH2 (methyl, thiazole, 5-CH3)의 경우 모든 균주에 있어서 fluconazole보다는 효과가 좋으나fluorocytosine에는 미치지 못하는 약효를 보였다. Thiazine derivatives의 경우에는 JHE (ethyl, thiazinoquinoxaline)가 C. albicans 와 C. tropicalis 균주에 있어서 fluorocytosine보다 우수한 효과를 보였으며 C. krusei 균주에 있어서는 JHM (methyl, thiazinoquinoxaline)만이 fluorocytosine보다 우수한 항진균 작용을 보였다. 종합적으로 봤을 때 thiazine 유도체는 C. albicans 및 C. tropicalis 균주에 있어서는 모든 유도체의 효과가 우수한 편이지만 그 외의 다른 진균에 있어서는 그리 뛰어난 항진균 작용을 찾아볼 수 없었다.
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