항진균성 Carbazole-1,4(9H)-dione 유도체 및 Pyrazole 유도체의 합성

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 biological active compounds. Based on this consideration, 6-hydroxy-9H-carbazole-1,4-dione derivatives and 8-hydroxydibenzo[b,d] furan-1,4-dione derivatives were synthesized and evaluated for their antifungal activities. Cabazolequinone derivatives are widely used in pharmaceuticals and mainly patented as anitcancer activities. The inhibitory activity of 6-hydroxy-9H- carbazole-1,4-dione on the antifungal properties has not been reported to the best of our knowledge. Various 6-hydroxy-9H-carbazole-1,4-dione with different substituents were synthesized to elucidate their contribution to the antifungal activityaction and would be improve the activities. 6-hydroxy-9-methyl-1H-carbazole-1,4(9H)-dione (3) were synthesized by treating equivalent amount of approporate amines (in MeOH) with 2,2’,5,5’-Biphenyldiquinone. And KBB, KBC were synthesized via the same method. 3-amino-6-hydroxy-9-methyl-1H-carbazole-1,4(9H)-dione (3a-c), 3-thio-6-hydroxy-9-methyl-1H-carbazole-1,4(9H)-dione (3d-f) and 2,3- (bis)thio-6-hydroxy-9-methyl-1H-carbazole-1,4(9H)-dione were obtained by substitution of 3 with the appropriate arylamines and arylthiols. 3-amino-6-hydroxy-9-(4-methoxybenzyl)-1H-carbazole-1,4(9H)-dione (4a-b) was obtained by substitution of 4 with the appropriate arylthiols and aliphatic thiols. 2,3-(bis)thio-9-(furan-2-ylmethyl)-6-hydroxy-1H- carbazole-1,4(9H)-dione (5a-b) was obtained by substitution of 5 with the appropriate arylthiols and aliphatic thiols. 8-hydroxydibenzo[b,d]furan-1,4-dione (6) were synthesized by treating approporate nitrobenzene (in EtOH) with 2,2’,5,5’-biphenyldiquinone. 3-amino-8-hydroxydibenzo[b,d]furan-1,4-dione (6a-b) were obtained by substitution by substitution of 6 with the appropriate arylamines. 2,3,7,9-tetrabromo-8-hydroxydibenzo[b,d]furan-1,4-dione (6c) was obtained by treating bromine under acetic acid and sod. acetate with 6. The antifungal activities of all synthesized compounds in carbazolequinone 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. In carbazolequinone compounds, 6-hydorxy-9H-carbazole-1,4-dione (3-5) showed relatively potent antifungal activities against C. albicans, C. tropicalis, C. neoformans, C. krusei, A. flavus and A. niger compared to fluconazole and fluorocytosine. 3d-f showed more potential antifungal activites than 3g-j. Especially derivarates containing fluoro showed good potential antifungal activites than others in C. albicans, C. neoformans, C. krusei, A. flavus and A. niger.. Among 4a-b, 5a-b and 6a-c, 6a-c had best antifungal activites compared to fluconazole and flucocytosine. 4a-b and 5a-b showed general or bad antifungal activites. TGF-βⅠ inhibitor have been reported with various pharmacological activities such as skar therapy, disease states involving inflammation, angiogenesis, and anticancer activities. Especially, compounds containing the heterocyclic quinone group represent an important class of biological active compounds. Based on this consideration, 1-(2-methylpyridin-3-yl)-2- (quinolin-4-yl)ethanone (9) derivatives and 2-(6-methylpyrazin-2-yl)-1- (6-methylpyridin-2-yl)ethanone (13) derivatives were synthesized. 1-(2-methylpyridin-3-yl)-2-(quinolin-4-yl)ethanone (9) were synthesized by treating equivalent amount of 2-methylnicotinate with 4-methylquinoline (in 1.0M lithium bistrimethylsilyl amide in THF) under nitrogen gas. And 13 were synthesized via the same method with 2,6-dimethylpyrazine and ethyl 6-methylpicolinate. 4-(2-(2-methylpyridin-3- yl)-1H-indol-3-yl)quinoline (10a-f) were obtained by treating equivalent amount of appropriate phenylhydrazine with 9 in acetic acid. 3-(6-methylpyrazin-2-yl)-2-(6-methylpyridin-2-yl)-1H-indole (14a-g) were obtained via the same method with 13. 4-(3-(2-methylpyridin-3-yl)-1H-pyrazol-4-yl)quinoline (10h) was obtained by treating DMFDA(N,N-dimethylformamide-dimethyl acetal) with 9, then plus hydrazine monohydrate (in EtOH). And 4-((3-(2-methylpyridin-3-yl)- 4-(quinolin-4-yl)-1H-pyrazol-1-yl)methyl)benzonitrile (10i) was obtained by treating equivalent amount of 3-(bromomethyl)benzonitril with 10h.;최근 화학요법을 이용해 치료 중인 암 환자나, 골수이식․장기이식․당뇨병․AIDS 등으로 인해 면역력이 저하되어 진균감염에 대한 감수성이 높아진 환자들에게 quinonoid 유도체들이 중요 항진균제로 사용된다. 본 연구에서는 이러한 quinonoid 유도체 중에서 우수한 생리활성이 예상되는 6-hydroxy- 9H-carbazole-1,4-dione 유도체 및 8-hydroxydibenzo[b,d]furan-1,4-dione 유도체를 합성하여 그 생리활성을 검색하였다. 항진균제 개발의 중요한 lead compound인 indolequinone의 유사구조이며 뛰어난 항암작용을 나타내는 것으로 알려진 carbazolequinone을 lead compound로 여러 유도체를 합성하였다. 서로 다른 amime을 갖는 carbazolequinone 모핵 3-5 3개를 합성하였다. Methyl기를 갖는 3a-j 4-methoxyphenyl기를 갖는 4a-b, (furan-2-yl)methan기를 갖는 5a-b를 합성하였다. 이 중 물질 3에 arylamino, arylthio 을 치환하여 3a-j 유도체 10개를 얻고, 물질 4에 aliphatic thio, arylthio 을 치환하여 유도체 2개를 합성하였다. 또한 물질 5에 aliphatic thio, arylthio 을 치환하여 유도체 2개를 합성하였다. Oxyzen을 모핵에 가지고 있는 구조인 dibenzo[b,d]furan-1,4-dione 6을 합성하였다. 뮬질 6 에 arylamino를 치환시켜 유도체를 2개 얻고, 이 구조를 bromination시켜 유도체를 1개 합성하였다. 또한 항종양 작용을 목적으로 하는 화합물을 합성하였다. 사구체 신염, 당뇨벙성 신장병, 감염에 의한 간장 기능 장애, 궤양, 모든 병인에 의한 간 섬유증, 종양 전이 성장 및 방사능에 의한 섬유증 등 ALK5 및 ALK4에 의해 매개되는 다양한 질환의 치료 및 예방에 2-피라졸이 치환된 유도체의 신규 화합물이 유용하다는 것이 밝혀졌다. 본 연구에서는 이와 유사한 구조인 2-methylpyridine이 치환된 quinoline 유도체를 합성하였다. 이러한 quinoline 유도체 중에서 우수한 생리활성이 예상되는 1-(2-methylpyridin-3-yl)-2- (quinolin-4-yl)ethanone (9) 와 구조 내에 pyrazole을 포함하는 4-(3-(2- methylpyridin-3-yl)-1H-pyrazol-4-yl)quinoline (10h) 을 합성하였다. 물질 10h를 이용해 4-((3-(2-methylpyridin-3-yl)-4-(quinolin-4-yl)-1H-pyrazol-1- yl)methyl)benzonitrile (10i)를 합성하였다. 또한 2-methylpyrazine에 2-methylpyridine이 치환된 구조의 유도체를 합성하였다. 이러한 pyrazine 구조 유도체 중에서 우수한 생리활성이 예상되는 2-(6-methylpyrazin-2-yl)-1-(6-methylpyridin-2-yl)ethanone (13) 유도체를 합성하였다. 서로 다른 phenylhydrazine 이용하여 3-(6-methylpyrazin-2-yl)- 2-(6-methylpyridin-2-yl)-1H-indole (14a-g) 7개를 합성하였다. 합성한 유도체 중 항진균 작용을 목적으로 하는 유도체 (3-5, 3a-j, 4a-b, 5a-b, 6a-c)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. 3a-j 유도체들의 경우 대부분의 유도체가 C. krusei, C. neoformans, A. niger 및 A. flavus 균주에서 fluconazole보다 좋은 항진균 효과를 보였다. 3a-j 대부분의 유도체가 fluconazole보다 좋거나 비슷한 항진균 효과를 보였으며, 3d (H), 3f (3-F), 3g (3-F), 3h (4-F)는 일부 균주에서 fluorocytosine보다 좋은 항진균 작용을 나타냈다. 3a-j 중 thio기가 치환된 유도체들이 amino기로 치환된 유도체들보다 항진균 작용이 좋은 것으로 나타났다. Thio기가 한 곳에 치환된 유도체들이 thio기가 두 곳에 치환된 유도체들보다 항진균 작용이 좋은 것으로 나타났다. 또한 arylthiol에 fluoro기가 치환된 유도체들의 항진균 활성이 다른 치환기 유도체들보다 대부분의 균주에서 좋은 것으로 나타났다. 4a-b 유도체의 경우 C. albicans 및 A. flavus 균주에서 모든 유도체가 fluconazole보다 좋거나 비슷한 효과를 나타내었으며, 5a-b 유도체의 경우 A. niger 균주에서 fluconazole과 비슷한 효과를 나타냈다. 6a-c 유도체의 경우 C. albicans, C. tropicalis, C. krusei, A. niger 및 A. flavus 균주에서 모든 유도체가 fluconazole보다 항진균 효과가 좋거나 비슷한 것으로 나타났다. 또한 6b 는 C. neoformans 균주에서 fluorocytosine과 비슷한 항진균 효과를 나타냈다. 6a-c 유도체들이 4a-b 유도체 또는 5a-b 유도체보다 좋은 항진균 효과를 나타냈다.