6,7-Dihydroisoquinoline-5,8-dione 및 6,7-dihydroquinazoline-5,8-dione 유도체의 합성 및 항진균 작용 연구

Abstract

Quinone 유도체들은 항진균, 항암, 항균, 항말라리아 등 다양한 생리활성을 나타낸다. 본 연구에서는 quinone 유도체 중 우수한 생리활성이 예상되는 다양한 isoquinoline-5,8-dione, napthoquinoline-5,8-dione 및 quinazoline-5,8-dione 유도체를 합성하여 항진균 작용 및 그 생리활성을 검색하였다. 6,7-Dichloroisoquinoline-5,8-dione (IQ)에 다양한 cyanoacetate와 aryl amine을 반응시켜 alkyl 2-cyano-2-(5,8-dioxo-6-(phenylimino)-5,6-dihydroisoquinolin-7(8H)-ylidene)acetate (IQCMs) 유도체 27개를 합성하였다. 또한 6,7-dichloroisoquinoline-5,8-dione (IQ)에 sodium azide와 triphenylphosphine을 반응시켜서 2-((triphenylphosphoranylidene)amino)-2H-[1,2,3]triazolo[4,5-g]isoquinoline-4,9-dione (IQPPH3)을 합성하였고, 이 화합물에 각각의 aryl aldehyde를 반응시켜서 2-(ethylideneamino)-2H-[1,2,3]triazolo[4,5-g]isoquinoline-4,9-dione(IQAHs) 유도체 7개를 얻었다. 6,7-Dichloroisoquinoline-5,8-dione (IQ)의 중간 유도체인isoquinoline-5,8-diamine을 oxidation 과정을 통해 isoquinoline-5,8-dione (IQO)을 합성하고, 이 화합물에 1-azido-4-ethylbenzene을 반응시켜서 6-(((4-ethylphenyl)amino)methylene)-5H-cyclopenta[c]pyridine -5,7(6H)-dione (IQOAZ) 유도체 1개를 얻었다. 또한 isoquinoline-5,8-dione (IQO)에 다양한 alkyl bromide와 반응시켜서 2-methyl-2H-pyrrolo[3,4-g]isoquinoline-4,9-dione (IQOBRs) 유도체 2개를 합성하였다. Napthoquinoline-5,8-dione을 다양한 aryl azide와 반응시킨 몇몇의derivatives가 반응을 계획하기 전부터 있었지만 항진균 작용에 대한 활성을 연구 결과가 아직 나와있지 않았기 때문에, 이미 합성되어 있는 유도체들을 제외하고 napthoquinoline-5,8-dione을 aryl azide와 반응시켜서 2-((p-tolylamino)methylene)-1H-indene-1,3(2H)-dione (NQAZs) 유도체 4개를 합성하였다. 6,7-Dichloroquinazoline-5,8-dione (DNQ)에 butyl cyanoacetate와 각각의 aryl amine을 반응시켜서 butyl 2-cyano-2-(5,8-dioxo-7-(phenylimino)-7,8-dihydroquinazolin-6(5H)-ylidene)acetate(DNQCMs) 유도체 2개를 얻었다. 또한 6,7-dichloroquinazoline-5,8-dione (DNQ)에 sodium azide와 triphenylphosphine을 반응시켜서 2-((triphenylphosphoranylidene)amino)-2H-[1,2,3]triazolo[4,5-g]quinazoline-4,9-dione (DNQPPH3)를 합성하였고, 이 화합물에 각각의 aryl aldehyde 및 aliphatic aldehyde를 반응시켜서 2-(ethylideneamino)-2H-[1,2,3]triazolo[4,5-g]quinazoline-4,9-dione (DNQAHs) 유도체 13개를 얻었다. 합성한 화합물 6a-h (IQCMs), 9a-g (IQAHs), 11 (IQOAZ), 12a-b (IQOBRs), 16a-d (NQAZs), 21a-b (DNQCMs), 24a-m (DNQAHs)들에 대해서 항진균 작용을 알아보기 위해서 병원성 진균의 대표적인 지표가 되는 6가지 병원 균주인 Candida albicans, Candida krusei, Candida tropicalis, Aspergillus niger, Aspergillus flavus 및 Crytococcus neoformans에 대해서 항진균 작용을 알아보았다. 각 화합물에 대한 minimum inhibitory concentration (MIC)는 액체 배지 희석법 (two fold broth dilution method)으로 하였고 대조 약물로는 fluconazole, flucytosine을 사용하였다. 화합물 6f-1 (IQCM16), 6f-3 (IQCM18), 6g-1 (IQCM20), 6g-2 (IQCM21), 6g-3 (IQCM22), 6h-1 (IQCM24), 9e (IQAH5), 12a (IQOBR1), 16a (NQAZ1), 24m (DNQAH13)이 대부분의 균주에 대해 fluconazole보다 좋고, flucytosine과 비슷하거나 더 좋은 효과를 나타내어 합성된 유도체들 중에서 가장 좋은 항진균 효과를 나타냈다.;Quinone compounds have various pharmacological activities as antifungal, antitumor, antimalarial and so forth. Especially, compounds containing the Hetero cyclic quinone group represent an important class of biologically active compounds. Based on this consideration, isoquinoline-5,8-dione, napthoquinoline-5,8-dione and quinazoline-5,8-dione derivatives were synthesized and evaulated for their antifugal activities. Alkyl 2-cyano-2-(5,8-dioxo-6-(phenylimino)-5,6-dihydroisoquinolin-7(8H)-ylidene)zacetate (IQCMs) derivatives were synthesized by substitution of cyanoacetate and aryl amine. and 2-((triphenylphospho- ranylidene)amino)-2H-[1,2,3]triazolo[4,5-g]isoquinoline-4,9-dione(IQPPH3) was synthesized by reaction with 6,7-dichloroisoquinoline-5,8-dione (IQ), sodium azide and triphenylphosphine. 2-(ethylideneamino)-2H-[1,2,3]triazolo[4,5-g]isoquinoline-4,9-dione (IQAHs) derivatives were synthesized by substitution of 2-((triphenylphosphoranylidene)amino)-2H-[1,2,3]triazolo[4,5-g]isoquinoline-4,9-dione (IQPPH3) and aryl aldehyde. Isoquinoline-5,8-dione (IQO) was synthesized using oxidation of isoquinoline-5,8-diamine which was intermediate of 6,7-Dichloroisoquinoline-5,8-dione (IQ). 6-(((4-ethylphenyl)amino)methylene)-5H-cyclopenta[c]pyridine-5,7(6H)-dione (IQOAZ) was synthesized by substitution of isoquinoline-5,8-dione (IQO) and 1-azido-4-ethylbenzene. Also 2-methyl-2H-pyrrolo[3,4-g]isoquinoline-4,9-dione (IQOBRs) derivatives were synthesized by substitution of isoquinoline-5,8-dione (IQO) and alkyl bromide. Although there are a lot of derivatives which were synthesized by substitution of naphthoquinoline-5,8-dione and aryl azide, those derivatives were not tested for antifungal activities yet. So we scheduled to synthesize of 2-((p-tolylamino)methylene)-1H-indene-1,3(2H)-dione (NQAZs) derivatives using the reaction with napthoquinoline-5,8-dione and aryl azide for testing derivatives as antifungal agents. 2-Cyano-2-(5,8-dioxo-7-(phenylimino)-7,8-dihydroquinazolin-6(5H)-ylidene)acetate (DNQCMs) were synthesized by substitution of 6,7-dichloroquinazoline-5,8-dione (DNQ), butyl cyanoacetate and aryl amine. Also 2-(ethylideneamino)-2H-[1,2,3]triazolo[4,5-g]quinazoline-4,9-dione (DNQAHs) were synthesized by substitution of aryl/aliphatic aldehyde and 2-((triphenylphosphoranylidene)amino)-2H-[1,2,3] triazolo[4,5-g]quinazoline-4,9-dione (DNQPPH3) synthesized using the reaction with 6,7-dichloroquinazoline-5,8-dione (DNQ), sodium azide and triphenylphosphine. The antifungal activities of all the synthesized compounds 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 flucytosine. Among newly synthesized compounds, 6f-3(IQCM18), 6g-1(IQCM20), 6g-2(IQCM21), 6g-3(IQCM22), 6h-1(IQCM24), 9e(IQAH5), 12a (IQOBR1), 16a(NQAZ1) and 24m(DNQAH13) generally showed relatively potent antifungal activities compared to fluconazole and flucytosine.