KR101164869B1 - Phenolic compound, Manufacturing method thereof and Antimicrobial Composition Having The Same - Google Patents
Phenolic compound, Manufacturing method thereof and Antimicrobial Composition Having The Same Download PDFInfo
- Publication number
- KR101164869B1 KR101164869B1 KR1020100057227A KR20100057227A KR101164869B1 KR 101164869 B1 KR101164869 B1 KR 101164869B1 KR 1020100057227 A KR1020100057227 A KR 1020100057227A KR 20100057227 A KR20100057227 A KR 20100057227A KR 101164869 B1 KR101164869 B1 KR 101164869B1
- Authority
- KR
- South Korea
- Prior art keywords
- benzo
- dioxol
- phenolic compound
- formula
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 239000000203 mixture Substances 0.000 title claims abstract description 60
- 150000002989 phenols Chemical class 0.000 title claims abstract description 59
- 230000000845 anti-microbial effect Effects 0.000 title claims abstract description 42
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 9
- 241000222122 Candida albicans Species 0.000 claims abstract description 34
- 108020003285 Isocitrate lyase Proteins 0.000 claims abstract description 28
- 229940095731 candida albicans Drugs 0.000 claims abstract description 19
- 239000004480 active ingredient Substances 0.000 claims abstract description 15
- 241000233866 Fungi Species 0.000 claims abstract description 14
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 55
- 238000000034 method Methods 0.000 claims description 26
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 claims description 22
- 201000003984 candidiasis Diseases 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- -1 2-bromo-4,5-dihydroxyphenyl Chemical group 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 229940081310 piperonal Drugs 0.000 claims description 11
- 206010007134 Candida infections Diseases 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- SEWUIZYKFWMKTO-UHFFFAOYSA-N 1,2-Bis-benzo[1,3]dioxol-5-yl-aethan Natural products C1=C2OCOC2=CC(CCC=2C=C3OCOC3=CC=2)=C1 SEWUIZYKFWMKTO-UHFFFAOYSA-N 0.000 claims description 8
- FBOYMIDCHINJKC-UHFFFAOYSA-N 5-bromo-1,3-benzodioxole Chemical compound BrC1=CC=C2OCOC2=C1 FBOYMIDCHINJKC-UHFFFAOYSA-N 0.000 claims description 7
- 125000005605 benzo group Chemical group 0.000 claims description 6
- DKSXYZJLEQAKEC-UHFFFAOYSA-N 4-bromo-5-(2-bromo-4,5-dihydroxyphenoxy)benzene-1,2-diol Chemical compound C1=C(O)C(O)=CC(Br)=C1OC1=CC(O)=C(O)C=C1Br DKSXYZJLEQAKEC-UHFFFAOYSA-N 0.000 claims description 5
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 claims description 5
- LUSZGTFNYDARNI-UHFFFAOYSA-N Sesamol Natural products OC1=CC=C2OCOC2=C1 LUSZGTFNYDARNI-UHFFFAOYSA-N 0.000 claims description 5
- USVLQGJGFKJBRW-UHFFFAOYSA-N 3,4-dibromo-5-(2,3-dibromo-4,5-dihydroxyphenoxy)benzene-1,2-diol Chemical compound BrC1=C(O)C(O)=CC(OC=2C(=C(Br)C(O)=C(O)C=2)Br)=C1Br USVLQGJGFKJBRW-UHFFFAOYSA-N 0.000 claims description 4
- OEJQEJBKJINOFJ-UHFFFAOYSA-N 4-(3,4-dihydroxyphenoxy)benzene-1,2-diol Chemical compound C1=C(O)C(O)=CC=C1OC1=CC=C(O)C(O)=C1 OEJQEJBKJINOFJ-UHFFFAOYSA-N 0.000 claims description 3
- YGXJWTJUEMFNHI-UHFFFAOYSA-N 4-bromo-5-[2-(2-bromo-4,5-dihydroxyphenyl)ethyl]benzene-1,2-diol Chemical group C1=C(O)C(O)=CC(Br)=C1CCC1=CC(O)=C(O)C=C1Br YGXJWTJUEMFNHI-UHFFFAOYSA-N 0.000 claims description 3
- NAYNTKOSEHPFKV-OWOJBTEDSA-N 5-[(e)-2-(1,3-benzodioxol-5-yl)ethenyl]-1,3-benzodioxole Chemical compound C1=C2OCOC2=CC(/C=C/C2=CC=C3OCOC3=C2)=C1 NAYNTKOSEHPFKV-OWOJBTEDSA-N 0.000 claims description 3
- PFFGMGQIRUVNFL-UHFFFAOYSA-N 5-bromo-1,3-benzodioxole Chemical compound BrC1=CC2=C(C=C1)OCO2.BrC2=CC1=C(C=C2)OCO1 PFFGMGQIRUVNFL-UHFFFAOYSA-N 0.000 claims description 3
- ZPLNNAGXAQXMKC-UHFFFAOYSA-N bis(1,3-benzodioxol-5-yl)methanol Chemical compound C1=C2OCOC2=CC(C(C=2C=C3OCOC3=CC=2)O)=C1 ZPLNNAGXAQXMKC-UHFFFAOYSA-N 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- YSMNNSKVGGGVNJ-UHFFFAOYSA-N O1COC2=C1C=CC(=C2)C(=O)C=2C=CC1=C(OCO1)C2.O2COC1=C2C=C(C=C1)C=O Chemical compound O1COC2=C1C=CC(=C2)C(=O)C=2C=CC1=C(OCO1)C2.O2COC1=C2C=C(C=C1)C=O YSMNNSKVGGGVNJ-UHFFFAOYSA-N 0.000 claims description 2
- APGDFTRTBOBDCR-UHFFFAOYSA-N O1COC2=C1C=CC(=C2)C(O)C=2C=CC1=C(OCO1)C2.O2COC1=C2C=CC(=C1)C(O)C=1C=CC2=C(OCO2)C1 Chemical compound O1COC2=C1C=CC(=C2)C(O)C=2C=CC1=C(OCO1)C2.O2COC1=C2C=CC(=C1)C(O)C=1C=CC2=C(OCO2)C1 APGDFTRTBOBDCR-UHFFFAOYSA-N 0.000 claims description 2
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- GCRKLKSGBFUJEN-UHFFFAOYSA-N 1,2-diphenylethane-1,1,2,2-tetrol Chemical group C=1C=CC=CC=1C(O)(O)C(O)(O)C1=CC=CC=C1 GCRKLKSGBFUJEN-UHFFFAOYSA-N 0.000 claims 1
- VWAVZAMMNJMAEM-UHFFFAOYSA-N 5-ethenyl-1,3-benzodioxole Chemical compound C=CC1=CC=C2OCOC2=C1 VWAVZAMMNJMAEM-UHFFFAOYSA-N 0.000 claims 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims 1
- DMWVYCLPWZIEQX-WXXKFALUSA-N O1COC2=C1C=CC(=C2)CCC2=CC1=C(OCO1)C=C2.O2COC1=C2C=CC(=C1)CCC1=CC2=C(OCO2)C=C1.O1COC2=C1C=CC(=C2)\C=C\C2=CC1=C(OCO1)C=C2 Chemical compound O1COC2=C1C=CC(=C2)CCC2=CC1=C(OCO1)C=C2.O2COC1=C2C=CC(=C1)CCC1=CC2=C(OCO2)C=C1.O1COC2=C1C=CC(=C2)\C=C\C2=CC1=C(OCO1)C=C2 DMWVYCLPWZIEQX-WXXKFALUSA-N 0.000 claims 1
- UHZZAYQKHOACNE-UHFFFAOYSA-N O1COC2=C1C=CC(=C2)OC2=CC1=C(OCO1)C=C2.O2COC=C2 Chemical compound O1COC2=C1C=CC(=C2)OC2=CC1=C(OCO1)C=C2.O2COC=C2 UHZZAYQKHOACNE-UHFFFAOYSA-N 0.000 claims 1
- QWGGKBRLOGNRAY-UHFFFAOYSA-N bis(3-bromo-4,5-dihydroxyphenyl)methanone Chemical compound BrC1=C(O)C(O)=CC(C(=O)C=2C=C(Br)C(O)=C(O)C=2)=C1 QWGGKBRLOGNRAY-UHFFFAOYSA-N 0.000 claims 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims 1
- 230000000855 fungicidal effect Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 22
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 16
- 241000894006 Bacteria Species 0.000 description 13
- 239000004599 antimicrobial Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 229940088598 enzyme Drugs 0.000 description 9
- 208000015181 infectious disease Diseases 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 241001344131 Magnaporthe grisea Species 0.000 description 7
- 150000002632 lipids Chemical class 0.000 description 7
- 241000196324 Embryophyta Species 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 240000007594 Oryza sativa Species 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
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- 230000000694 effects Effects 0.000 description 6
- 239000011888 foil Substances 0.000 description 6
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 4
- VADKRMSMGWJZCF-UHFFFAOYSA-N 2-bromophenol Chemical class OC1=CC=CC=C1Br VADKRMSMGWJZCF-UHFFFAOYSA-N 0.000 description 4
- WBLZUCOIBUDNBV-UHFFFAOYSA-N 3-nitropropanoic acid Chemical compound OC(=O)CC[N+]([O-])=O WBLZUCOIBUDNBV-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
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- 239000003242 anti bacterial agent Substances 0.000 description 4
- QTUWONBQSPLCLE-UHFFFAOYSA-N bis(3-bromo-4,5-dihydroxyphenyl)methanone Chemical group BrC=1C=C(C=C(C1O)O)C(=O)C1=CC(=C(C(=C1)O)O)Br.BrC=1C=C(C=C(C1O)O)C(=O)C1=CC(=C(C(=C1)O)O)Br QTUWONBQSPLCLE-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
본 발명은 페놀계 화합물(Phenolic compound), 그 제조방법 및 이를 유효성분으로 포함하는 항균 조성물에 대한 것으로, 특히 본 발명에 따른 페놀계 화합물은 진균류인 칸디다 알비칸(Candida albicans)의 이소시트래이트 리아제(isocitrate lyase)에 대하여 우수한 저해활성을 가지기 때문에, 유해 진균을 방제하는 살진균용 조성물로 이용될 수 있는 것이다. The present invention is a phenolic compound iso sheet ray of (Phenolic compound), a method of manufacturing the same, and as for the antimicrobial composition comprising the same as an active ingredient, in particular the phenolic compounds according to the invention are fungi of Candida albicans (Candida albicans) agent Since it has excellent inhibitory activity against isocitrate lyase, it can be used as a fungicidal composition for controlling harmful fungi.
Description
본 발명은 페놀계 화합물, 그 제조방법 및 이를 유효성분으로 포함하는 항균 조성물에 대한 것으로, 더욱 상세하게는 진균류인 칸디다 알비칸(Candida albicans)의 이소시트레이트 리아제(isocitrate lyase)에 대하여 우수한 저해활성을 가지는 항균 조성물에 관한 것이다.
The present invention relates to a phenolic compound, a method for preparing the same, and an antimicrobial composition comprising the same as an active ingredient, and more particularly, to an isocitrate lyase of the fungus Candida albicans. It relates to an antimicrobial composition having.
글리옥실레이트 사이클 (Glyoxylate cycle)은 당류가 부족한 자연환경에서 미생물이 성장할 경우에 C2 탄소원인 아세테이트와 에탄올을 C4 디카보실릭산으로 전환하여 에너지 획득 및 세포의 생합성 물질을 공급하는데 있어서 매우 중요한 대사경로이다. 이러한 생육조건하에서는 세포내 해당경로의 활성은 감소되고, 지질 및 왁스 등을 베타산화 (β-oxidation)에 의해 분해하여 아세테이트와 같은 C2 탄소원을 만들고 글리옥실레이트 사이클을 활성화하여 그 중간 생성물 숙신산(succinate)을 생합성(Biosynthesis) 경로에 제공하여 생존하게 된다.
Glyoxylate cycle is a very important metabolic pathway for the conversion of C2 carbon sources acetate and ethanol to C4 dicarbosilic acid when microorganisms grow in a natural environment that lacks saccharides. . Under these growth conditions, the activity of the glycolytic pathway in the cell is reduced, and lipids and waxes are degraded by beta-oxidation to form a C2 carbon source such as acetate, and the glyoxylate cycle is activated to produce the intermediate product succinate. ) Is provided to the biosynthesis pathway to survive.
글리옥실레이트 사이클에는 독특한 두개의 효소가 존재하는데, 이소시트레이트 리아제 (isocitrate lyase, ICL) 및 말레이트 신타제 (malate synthase)이다. 글리옥실레이트 사이클은 대부분의 세균 및 진균 (효모, 곰팡이) 그리고 식물에 존재하지만, 척추동물에는 존재하지 않는다. 식물에서도 땅콩과 같은 지질이 풍부한 씨앗의 발아시에 이용함이 알려져 있으나 잎이 나와 광합성을 할 때에는 이용하지 않으므로 미생물이 주로 이용한다고 볼 수 있다. 또한, 이소시트레이트 리아제 (ICL) 효소가 결손된 세균 및 진균의 돌연변이주 들은 C2 탄소원하에서는 생존하지 못한다(Lorenz MC, Fink GR, Nature, 412, pp83-86, 2001; McKinney JD, Honer Zu Bentrup K, Munoz-Elias EJ, Miczak A, Chen B, Chan WT, Swenson D, Sacchettini JC, Jacobs Jr WR, Russell G, Nature, 406, pp735-738, 2000).
There are two unique enzymes in the glyoxylate cycle: isocitrate lyase (ICL) and malate synthase. The glyoxylate cycle is present in most bacteria and fungi (yeasts, fungi) and plants, but not in vertebrates. Plants are known to be used for germination of lipid-rich seeds, such as peanuts, but microbes are used mainly because they do not use when leaves come out for photosynthesis. In addition, bacterial and fungal mutants lacking isocitrate lyase (ICL) enzymes do not survive under the C2 carbon source (Lorenz MC, Fink GR, Nature, 412, pp83-86, 2001; McKinney JD, Honer Zu Bentrup K , Munoz-Elias EJ, Miczak A, Chen B, Chan WT, Swenson D, Sacchettini JC, Jacobs Jr WR, Russell G, Nature, 406, pp735-738, 2000).
최근, 폐 결핵균인 마이코박테리움 투버쿨로시스(Mycobacterium tuberculosis)는 마크로파지(macrophages) 감염 시에 이소시트레이트 리아제 (ICL)의 발현이 활성화 된다고 보고되었다(McKinney JD, Honer Zu Bentrup K, Munoz-Elias EJ, Miczak A, Chen B, Chan WT, Swenson D, Sacchettini JC, Jacobs Jr WR, Russell G, Nature, 406, pp735-738, 2000; Munoz-Elias EJ, McKinne JD, Nat. Med., 11, pp638-644, 2005). 또한, 인체병원성 진균인 캔디다 알비칸스(Candida albicans) 및 크립토코커스 네오폴만스(Cryptococcus neoformans) 등은 마우스모델 동물실험에서도 병원성 유발에 이소시트레이트 리아제 (ICL)가 매우 중요하다고 보고되었다(Lorenz MC, Fink GR, Nature, 412, pp83-86, 2001; Rude TH, Toffaletti DL, Cox GM, Perfect JR, Infect. Immun., 70, pp5684-5694, 2002). 이러한 보고들은 광범위한 병원성 미생물의 숙주 감염 시에 글리옥실레이트 사이클이 광범위하게 작용하고 있다는 것을 보여준다.
Recently, Mycobacterium tuberculosis, a pulmonary tuberculosis bacterium, has been reported to activate the expression of isocitrate lyase (ICL) during macrophages infections (McKinney JD, Honer Zu Bentrup K, Munoz-Elias). EJ, Miczak A, Chen B, Chan WT, Swenson D, Sacchettini JC, Jacobs Jr WR, Russell G, Nature, 406, pp735-738, 2000; Munoz-Elias EJ, McKinne JD, Nat. Med., 11, pp638 -644, 2005). In addition, Candida albicans and Cryptococcus neoformans, which are human pathogenic fungi, have been reported to be very important for isotogenic lyase (ICL) to induce pathogenicity in mouse model animals (Lorenz MC, Fink GR, Nature, 412, pp83-86, 2001; Rude TH, Toffaletti DL, Cox GM, Perfect JR, Infect. Immun., 70, pp5684-5694, 2002). These reports show that the glyoxylate cycle is at work extensively during host infection of a wide range of pathogenic microorganisms.
벼 도열병균 마그나포르테 그리시 (Magnaporthe grisea)는 전형적인 이주성의 식물 자낭균이며 전세계적으로 재배되는 벼의 가장 심각한 도열병 원인균이다. 마그나포르테 그리시 (M. grisea)는 부착기(appressorium)라 불리는 독특한 둥근 돔 형태의 기관을 형성하여 식물표면에 부착하고, 식물의 세포벽을 뚫고 침입하기 위하여 부착기내에 엄청난 압력(팽압)을 만들어 낸다. 이러한 부착기(appressorium) 내의 높은 압력은 세포내 저장된 지질을 분해하여 글리세롤과 지방산을 만들 때 글리세롤에 의해 형성된다. 이 곰팡이에서 포자 발아와 부착기 형성을 하는 동안, 지질은 포자로부터 부착기 말단으로 이동되는 것으로 알려져 있다. 최근, 도열병균 마그나포르테 그리시(M. grisea)가 벼에 감염될 때, 글리옥실레이트 사이클의 효소인 이소시트레이트 리아제 (ICL)가 균의 세포내에 높은 수준으로 유도 발현되며, 이 효소의 유전자가 결손된 돌연변이주는 야생종 보다 병발력이 감소하고, 병발력과 밀접한 관련성이 있는 부착기 형성 능력이 약화된다고 보고되었다(Wang ZY, Thornton CR, Kershaw MJ, Debao L, Talbot NJ, Mol. Microbiol., 47, pp1601-1612, 2003). 따라서, 이소시트레이트 리아제(ICL)는 벼 도열병 감염억제 및 항진균제 개발의 유용한 표적이라 할 수 있다.
Rice Bacterium Magnaporthe grisea is a typical migratory plant streptococci and the most serious causative agent of rice grown worldwide. M. grisea forms a unique round dome-shaped organ called an appressorium that attaches to the surface of the plant and creates tremendous pressure in the attachment to penetrate and penetrate the cell walls of the plant. The high pressure in these appressorium is formed by glycerol when it breaks down stored intracellular lipids to make glycerol and fatty acids. During this spore germination and adhering formation, lipids are known to migrate from the spores to the end of the adhering group. Recently, when M. grisea is infected with B. aureus, isocitrate lyase (ICL), an enzyme of the glyoxylate cycle, is induced and expressed at a high level in the cells of the bacterium. Deleted mutants have been reported to have fewer incidences and less adherent formation ability, which is closely related to the incidence (Wang ZY, Thornton CR, Kershaw MJ, Debao L, Talbot NJ, Mol. Microbiol., 47, pp1601-1612, 2003). Thus, isocitrate lyase (ICL) is a useful target for rice blight infection suppression and antifungal development.
이에 본 발명자들은 천연물로부터 이소시트레이트 리아제(ICL) 억제 활성물질의 발굴에 관심을 가지고 활성검색 실험을 진행하여, 홍조류인 오돈탈리아 코림비퍼러(Odonthalia corymbifera)의 추출물로부터 다양한 크로마토그래피 방법을 활용해서, 효소 억제물질인 6종의 브로모페놀(Bromophenols)계 화합물을 분리하였고, 이것을 포함하는 조성물을 대한민국 등록특허 제10-0826663호로 특허등록을 받았다. 그러나, 계속된 실험 결과, 상기와 같이 천연의 해조류나 미생물로부터 분리한 화합물은 광범위한 활성을 가지고 이에 따른 독성으로 인해 항균제로 사용하기에는 많은 문제점이 있었다.
Therefore, the present inventors are interested in the discovery of isocitrate lyase (ICL) inhibitory active substances from natural products and conduct an active screening experiment, using various chromatography methods from extracts of red algae Odonthalia corymbifera. , 6 bromophenols (Bromophenols) -based compounds that are enzyme inhibitors were isolated, and the composition comprising the same was registered in Korea Patent No. 10-0826663. However, as a result of continued experiments, the compounds isolated from natural algae or microorganisms as described above have a wide range of activities and due to their toxicity, there are many problems to use as an antimicrobial agent.
상기한 바와 같은 문제점을 해결하기 위한 본 발명은, 천연 브로모페놀계 화합물과는 전혀 다른 구조를 가지면서 우수한 항균 활성을 가지는 신규한 페놀계 화합물(Phenolic compound)과, 그 제조방법 및 이를 유효성분으로 포함하는 항균 조성물을 제공하는 것이 목적이다.
The present invention for solving the above problems, a novel phenolic compound (phenolic compound) having a structure that is completely different from the natural bromophenol-based compound and excellent antimicrobial activity (Phenolic compound), its preparation method and active ingredient It is an object to provide an antimicrobial composition comprising a.
또한, 본 발명은 진균류인 칸디다 알비칸(Candida albicans)의 이소시트래이트 리아제(isocitrate lyase)에 대하여 우수한 저해활성을 가지는 페놀계 화합물을 제공하고, 이를 통하여 유해 진균을 방제하는 살진균용 조성물로 다양하게 활용하고자 하는 것이다.
In addition, the present invention provides a phenolic compound having excellent inhibitory activity against isocitrate lyase of the fungi Candida albicans, as a fungicidal composition for controlling harmful fungi It is intended to be used in various ways.
상기한 목적을 달성하기 위한 본 발명은 신규한 페놀계 화합물, 그 제조방법 및 이를 유효성분으로 함유하는 항균 조성물을 제공한다. 상기 화합물 및 항균 조성물은 다양한 유해 진균 등에 대하여 우수한 항균활성을 나타내고, 특히 칸디다 알비칸(Candida albicans)에 대하여 우수한 항균활성을 나타내며, 바람직하게는 상기 칸디다 알비칸(Candida albicans)의 이소시트래이트 리아제(isocitrate lyase)에 대하여 우수한 저해활성을 가진다. 그래서, 본 발명에 따른 상기 항균 조성물을 유효성분으로 포함하는 의약조성물은 상기 균에 의한 질병의 예방 또는 치료용 조성물로 응용될 수 있다.
The present invention for achieving the above object provides a novel phenolic compound, a preparation method thereof and an antimicrobial composition containing the same as an active ingredient. The compound and the antimicrobial composition exhibit excellent antimicrobial activity against various harmful fungi and the like, and particularly exhibit excellent antimicrobial activity against Candida albicans, preferably isocitrate lyase of Candida albicans. It has excellent inhibitory activity against isocitrate lyase. Thus, the pharmaceutical composition comprising the antimicrobial composition according to the present invention as an active ingredient may be applied as a composition for the prevention or treatment of diseases caused by the bacteria.
본 발명자들은 해조류나 미생물의 대사물질로부터 분리되는 (브로모)페놀계 화합물은 독성이 있는 광범위한 항균 활성을 가지나, 분리될 수 있는 양이 매우 제한되어 있다는 등의 제약으로 인해 항균제로 사용하기에 적합하지 않다는 문제점을 극복하기 위하여, 연구하던 중, 간단한 유기화학 반응을 통하여 효율적으로 대량 생산이 가능한 신규한 페놀계 화합물을 제조하였고, 상기 신규한 모페놀계 화합물이 칸디다 알비칸(Candida albicans)의 이소시트래이트 리아제(isocitrate lyase) 등과 같은 다양한 세균에 대한 우수한 항균 활성을 갖는다는 것을 확인하여 본 발명을 완성하였다.
The inventors have found that (bromo) phenolic compounds isolated from algae and microbial metabolites have a wide range of toxic antimicrobial activities, but are suitable for use as antimicrobial agents due to restrictions such as the limited amount that can be separated. In order to overcome the problem of not being, during the study, a novel phenolic compound capable of mass production was efficiently produced through a simple organic chemical reaction, and the novel parent phenolic compound is isodian of Candida albicans. The present invention was completed by confirming that it has excellent antimicrobial activity against various bacteria such as citrate lyase.
본 발명에 있어서, 항균 조성물이란 항균제, 항생제, 살균제, 방부제, 보존제 또는 제균제와 같은 의미일 수 있으며, 바람직하게는 그람 양성균 및 그람 음성균의 발육과 생활 기능을 저지 또는 억제할 수 있는 물질을 의미한다.
In the present invention, the antimicrobial composition may mean the same as an antimicrobial agent, an antibiotic, a fungicide, a preservative, a preservative or an antimicrobial agent, and preferably means a substance capable of inhibiting or inhibiting the development and life functions of Gram-positive bacteria and Gram-negative bacteria. do.
또한, 본 발명에 있어서, 칸디다 알비칸(Candida albicans)이란 진균류에 속하는 곰팡이로, 칸디다증을 유발시키는 것을 뜻한다. 원래 칸디다는 정상적인 피부?점막?분변?객담?요 등에 존재하며 인체에는 해가 없지만, 항생물질이나 부신피질호르몬을 사용한 경우나, 인체의 감염방어력이 저하된 경우에는 이상증식을 하여 병을 일으킨다. 칸디다증은 점막, 피부, 소화관, 전신성 칸디다증으로 나뉠 수 있으며, 이에 대해 자세히 설명하면 다음과 같다. 첫째, 점막 칸디다증은 구각(口角)?혀?외음부?질 등이 짓무르고 통증이 있다. 때로는 가려우며 흰색의 소반점이 생기기도 한다. 둘째, 피부 칸디다증은 피부의 주름 사이나 손가락 사이, 항문 부근이나 유방 등이 발갛게 짓무른다. 셋째, 소화관 칸디다증은 설사?복통?황달 등을 일으킨다. 마지막으로 전신성 칸디다증은 패혈증과 같은 증세를 띠며, 수막염이나 심내막염을 수반하는 수가 있다.
In addition, in the present invention, Candida albicans is a fungus belonging to a fungus, which means to induce candidiasis. Originally, Candida is present in normal skin, mucous membranes, feces, sputum, urine, etc., but it is harmless to humans, but when antibiotics or corticosteroids are used, or when the body's defense ability for infection is lowered, it causes abnormal growth. Candidiasis can be divided into mucous membranes, skin, digestive tract, and systemic candidiasis. First, mucosal candidiasis is a sore and pain in the mouth (口角), tongue, vulva, vagina. Sometimes itchy and white spots appear. Second, skin candidiasis causes redness between the wrinkles of the skin, between the fingers, near the anus, and the breast. Third, digestive tract candidiasis causes diarrhea, abdominal pain and jaundice. Finally, systemic candidiasis has the same symptoms as sepsis and may involve meningitis or endocarditis.
이하에서는 본 발명의 바람직한 하나의 실시형태를 더욱 상세하게 설명하기로 한다.
Hereinafter, one preferred embodiment of the present invention will be described in more detail.
본 발명의 한 측면에 있어서, 본 발명은 신규한 페놀계 화합물을 제공한다. 상기 페놀계 화합물은 하기의 화학식 A, 화학학 B 또는 화학식 C의 구조를 갖는 화합물일 수 있으며, 이들의 약제학적으로 허용 가능한 염일 수 있다.In one aspect of the invention, the invention provides novel phenolic compounds. The phenolic compound may be a compound having a structure of Formula A, Chemical Formula B, or Formula C below, and may be a pharmaceutically acceptable salt thereof.
(화학식 A)Formula A
(화학식 B)Formula B
(화학식 C)Formula C
상기 식 중, X는 H 또는 Br일 수 있다.
Wherein X may be H or Br.
본 발명에 따라 화학식 A로 표시되는 화합물은 4-(3,4-디하이드록시페녹시)벤젠-1,2-디올(4-(3,4-dihydroxyphenoxy)benzene-1,2-diol),According to the present invention, the compound represented by Formula A is 4- (3,4-dihydroxyphenoxy) benzene-1,2-diol (4- (3,4-dihydroxyphenoxy) benzene-1,2-diol),
2-브로모-4,5-디하이드록시페닐(3,4-디하이드록시페닐) 에테르(2-bromo-4,5-dihydroxyphenyl)(3,4-dihydroxyphenyl) ether),2-bromo-4,5-dihydroxyphenyl (3,4-dihydroxyphenyl) ether (2-bromo-4,5-dihydroxyphenyl) (3,4-dihydroxyphenyl) ether),
비스(2-브로모-4,5-디하이드록시페닐) 에테르(bis(2-bromo-4,5-dihydroxyphenyl) ether) 또는 비스(2,3-디브로모-4,5-디하이드록시페닐) 에테르(bis(2,3-dibromo-4,5-dihydroxyphenyl) ether) 일 수 있고, 화학식 B로 표시되는 화합물은 비스(3,4-디하이드록시페닐)메타논(bis(3,4-dihydroxyphenyl)methanone), 비스(3-브로모-4,5-디하이드록시페닐)메타논(bis(3-bromo-4,5-dihydroxyphenyl)methanone) 또는 (3-브로모-4,5-디하이드록시페닐)(2,3-디브로모-4,5-디하이드록시페닐)메타논((3-bromo-4,5- dihydroxyphenyl)(2,3-dibromo-4,5-dihydroxyphenyl)methanone) 인 것이 가능하며, 화학식 C로 표시되는 화합물은 4-(3,4-디하이드록시페네틸)벤젠-1,2-디올(4-(3,4-dihydroxyphenethyl)benzene-1,2-diol), 2,2'-디브로모-4,4',5,5'-테트라하이드록시비벤질(2,2'-dibromo-4,4',5,5'-tetrahydroxybibenzyl) 또는 2,2’,3-트리브로모-4,4',5,5'-테트라하이드록시비벤질(2,2’,3-tribromo-4,4',5,5'-tetrahydroxybibenzyl) 인 것이 바람직하다.
Bis (2-bromo-4,5-dihydroxyphenyl) ether (bis (2-bromo-4,5-dihydroxyphenyl) ether) or bis (2,3-dibromo-4,5-dihydroxy Phenyl) ether (bis (2,3-dibromo-4,5-dihydroxyphenyl) ether), and the compound represented by Formula B is bis (3,4-dihydroxyphenyl) methanone (bis (3,4 -dihydroxyphenyl) methanone), bis (3-bromo-4,5-dihydroxyphenyl) methanone (bis (3-bromo-4,5-dihydroxyphenyl) methanone) or (3-bromo-4,5- Dihydroxyphenyl) (2,3-dibromo-4,5-dihydroxyphenyl) methanone ((3-bromo-4,5-dihydroxyphenyl) (2,3-dibromo-4,5-dihydroxyphenyl) methanone), and the compound represented by the formula (C) is 4- (3,4-dihydroxyphenethyl) benzene-1,2-diol (4- (3,4-dihydroxyphenethyl) benzene-1,2- diol), 2,2'-dibromo-4,4 ', 5,5'-tetrahydroxybibenzyl (2,2'-dibromo-4,4', 5,5'-tetrahydroxybibenzyl) or 2, 2 ', 3-tribromo-4,4', 5,5'-tetrahydroxybibenzyl (2,2 ', 3-tribromo-4,4', 5,5'-tetrahydroxybibenzyl).
본 발명의 다른 측면에서, 본 발명은 상기 화학식 A, 화학식 B 또는 화학식 C의 구조를 갖는 화합물의 제조방법일 수 있다.
In another aspect of the present invention, the present invention may be a method for preparing a compound having the structure of Formula A, Formula B, or Formula C.
본 발명의 화합물은 하기의 반응식들에 도시된 방법에 의해 제조될 수 있지만, 이들 예로만 한정되는 것은 아니다. 하기의 반응식들은 본 발명의 대표적인 화합물들의 제조방법을 제조 단계별로 나타내는 것으로, 다른 화합물들은 당업자들에 의해 숙지된 시약 및 출발물질의 적당한 변화에 의해 제조될 수 있다.
The compounds of the present invention may be prepared by the method shown in the following schemes, but are not limited to these examples. The following schemes represent the preparation steps of representative compounds of the present invention, and other compounds may be prepared by appropriate changes in reagents and starting materials known to those skilled in the art.
상기 화학식 A의 구조를 갖는 화합물을 제조하는 방법은 하기 반응식 I에 기재된 바에 의할 수 있다.The method for preparing a compound having the structure of Formula A may be as described in Scheme I below.
(반응식 I)Scheme I
예를 들어, 상기 반응식 I의 제조방법은 세사몰(sesamol)과 4-브로모-1,2-(메틸렌다이옥시)벤젠(4-bromo-1,2-(methylenedioxy)benzene)을 반응시켜, 화학식 A의 구조를 갖는 페놀계 화합물을 제조하는 단계;를 포함하는 것을 특징으로 하는 페놀계 화합물의 제조방법일 수 있다.
For example, the preparation method of Scheme I is made by reacting sesamol and 4-bromo-1,2- (methylenedioxy) benzene (4-bromo-1,2- (methylenedioxy) benzene). It may be a method for producing a phenolic compound comprising a; preparing a phenolic compound having a structure of Formula (A).
보다 상세하게는, 상기 세사몰과 4-브로모-1,2-(메틸렌다이옥시)벤젠을 반응시켜서 5-(벤조[d][1,3]다이옥솔-5-와이록시)벤조[d][1,3]다이옥솔(5-(benzo[d][1,3]dioxol-5-yloxy)benzo[d][1,3]dioxole)를 얻고, 상기 얻은 5-(벤조[d][1,3]다이옥솔-5-와이록시)벤조[d][1,3]다이옥솔로부터 상기 화학식 1의 구조를 갖는 페놀계 화합물을 제조하는 것이다.
More specifically, the sesamol and 4-bromo-1,2- (methylenedioxy) benzene are reacted to give 5- (benzo [d] [1,3] dioxol-5-hydroxy) benzo [d ] [1,3] dioxol (5- (benzo [d] [1,3] dioxol-5-yloxy) benzo [d] [1,3] dioxole) was obtained and 5- (benzo [d] obtained above was obtained. A phenolic compound having the structure of
상기 화학식 B의 구조를 갖는 화합물을 제조하는 방법은 하기 반응식 II에 기재된 바에 의할 수 있다.The method for preparing a compound having the structure of Formula B may be as described in Scheme II below.
(반응식 II)Scheme II
예를 들어, 상기 반응식 II의 제조방법은 피페로날(Piperonal)과 4-브로모-1,2-(메틸렌다이옥시)벤젠(4-bromo-1,2-(methylenedioxy)benzene)을 반응시켜, 화학식 B의 구조를 갖는 페놀계 화합물을 제조하는 단계;를 포함하는 것을 특징으로 하는 페놀계 화합물의 제조방법일 수 있다.
For example, the preparation method of Scheme II is obtained by reacting piperonal with 4-bromo-1,2- (methylenedioxy) benzene (4-bromo-1,2- (methylenedioxy) benzene). It may be a method for producing a phenolic compound comprising a; preparing a phenolic compound having a structure of Formula (B).
보다 상세하게는, 상기 피페로날과 4-브로모-1,2-(메틸렌다이옥시)벤젠을 반응시켜서 (벤조[d][1,3]다이옥솔-5-와일)(벤조[d][1,3]다이옥솔-6-와일)메탄올((benzo[d][1,3]dioxol-5-yl)(benzo[d][1,3]dioxol-6-yl)methanol)를 얻고, 상기 (벤조[d][1,3]다이옥솔-5-와일)(벤조[d][1,3]다이옥솔-6-와일)메타놀로부터 (벤조[d][1,3]다이옥솔-5-와일)(벤조[d][1,3]다이옥솔-6-와일)메타논((benzo[d][1,3]dioxol-5-yl)(benzo[d][1,3]dioxol-6-yl)methanone)을 합성하며, 상기 합성한 (벤조[d][1,3]다이옥솔-5-와일)(벤조[d][1,3]다이옥솔-6-와일)메타논으로부터 화학식 B의 구조를 갖는 페놀계 화합물을 제조하는 것이다.
More specifically, the piperonal and 4-bromo-1,2- (methylenedioxy) benzene are reacted to give (benzo [d] [1,3] dioxol-5-yl) (benzo [d] [1,3] dioxol-6-yl) methanol ((benzo [d] [1,3] dioxol-5-yl) (benzo [d] [1,3] dioxol-6-yl) methanol) was obtained. From (benzo [d] [1,3] dioxol) from (benzo [d] [1,3] dioxol-5-yl) (benzo [d] [1,3] dioxol-6-yl) methanol -5-Wyl) (benzo [d] [1,3] dioxol-6-yl) methanone ((benzo [d] [1,3] dioxol-5-yl) (benzo [d] [1,3 ] dioxol-6-yl) methanone), and synthesized (benzo [d] [1,3] dioxol-5-yl) (benzo [d] [1,3] dioxol-6-yl) It is to prepare a phenol compound having a structure of formula (B) from methanone.
상기 화학식 C의 구조를 갖는 화합물을 제조하는 방법은 하기 반응식 III에 기재된 바에 의할 수 있다.The method for preparing a compound having the structure of Formula C may be as described in Scheme III below.
(반응식 III)Scheme III
예를 들어, 상기 반응식 III의 제조방법은 피페로날(Piperonal)을 출발물질로 하여, 화학식 C의 구조를 갖는 페놀계 화합물을 제조하는 단계;를 포함하는 것을 특징으로 하는 페놀계 화합물의 제조방일 수 있다.
For example, the production method of Scheme III includes the step of preparing a phenolic compound having a structure of Formula C, using piperonal (Piperonal) as a starting material. Can be.
보다 상세하게는, 상기 피페로날을 이용하여 (E)-1,2-디(벤조[d][1,3]다이옥솔-5-와일)에텐((E)-1,2-di(benzo[d][1,3]dioxol-5-yl)ethene)를 얻고, 상기 (E)-1,2-디(벤조[d][1,3]다이옥솔-5-와일)에텐로부터 1,2-디(벤조[d][1,3]다이옥솔-5-와일)에탄(1,2-di(benzo[d][1,3]dioxol-5-yl)ethane)을 합성하며, 상기 합성한 1,2-디(벤조[d][1,3]다이옥솔-5-와일)에탄으로부터 화학식 B의 구조를 갖는 페놀계 화합물을 제조하는 것이다.
More specifically, (E) -1,2-di (benzo [d] [1,3] dioxol-5-yl) ethene ((E) -1,2-di ( benzo [d] [1,3] dioxol-5-yl) ethene) and obtained from (E) -1,2-di (benzo [d] [1,3] dioxol-5-yl) ethene.
본 발명의 또 다른 측면에 있어서, 본 발명은 또한 상기 화학식 A의 구조를 갖는 화합물이나 이의 약학적 허용가능한 염, 상기 화학식 B의 구조를 갖는 화합물이나 이의 약학적 허용가능한 염 또는 상기 화학식 C의 구조를 갖는 화합물이나 이의 약학적 허용가능한 염을 유효성분으로 포함하는 항균 조성물을 제공한다.
In another aspect of the present invention, the present invention also provides a compound having the structure of Formula A or a pharmaceutically acceptable salt thereof, a compound having the structure of Formula B or a pharmaceutically acceptable salt thereof or a structure of Formula C. It provides an antimicrobial composition comprising a compound having or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명자들은 다양한 그람 양성균 및 그람 음성균을 대상으로 효소활성 저해능력을 측정한 결과, 상기 항균 조성물은 칸디다 알비칸(Candida albicans)에 대하여 우수한 항균활성을 가지는 것을 확인하였고, 특별히 칸디다 알비칸의 이소시트레이트 리아제(isocitrate lyase)에 대하여 우수한 저해활성을 가지는 것을 확인하였다.
As a result of measuring the enzyme activity inhibiting ability against various Gram-positive and Gram-negative bacteria, the present inventors confirmed that the antimicrobial composition has excellent antimicrobial activity against Candida albicans, and isosheet of Candida albican in particular. It was confirmed to have excellent inhibitory activity against latex lyase.
본 발명의 항균 조성물은, 조성물 총 중량에 대하여 상기 화학식 A의 구조를 갖는 화합물, 상기 화학식 B의 구조를 갖는 화합물 또는 상기 화학식 C의 구조를 갖는 화합물을 0.001 내지 99.99중량%, 바람직하게는 0.1 내지 99 중량%로 포함할 수 있으며, 상기 항균 조성물의 사용방법 및 사용목적에 따라 유효성분의 함량을 적절히 조절할 수 있다.
The antimicrobial composition of the present invention comprises 0.001 to 99.99% by weight of the compound having the structure of Formula A, the compound having the structure of Formula B, or the compound having the structure of Formula C with respect to the total weight of the composition, preferably 0.1 to It may be included in 99% by weight, it can be appropriately adjusted the content of the active ingredient according to the method of use and purpose of use of the antimicrobial composition.
상기 항균 조성물은 병원성 미생물, 구체적으로는 그람 양성균 또는 그람 음성균, 보다 상세하게는 벼 식물 및 그의 종자에 대한 유해 진균, 바람직하게는 벼 도열병균(Magnaporthe grisea), 바이폴라리스(Bipolaris) 종, 드레슬라(Drechslera) 종 또는 리조크토니아 솔라니(Rhizoctonia solani), 더욱 바람직하게는 벼 도열병균(Magnaporthe grisea)에 대하여 항균활성을 가지는 항균 조성물일 수 있다. 또한, 상기 항균 조성물은 칸디다 알비칸(Candida albicans) 균에 대하여 우수한 항균활성을 가지는 항균 조성물일 수 있고, 바람직하게는 칸디다 알비칸의 이소시트레이트 리아제(isocitrate lyase)에 대하여 우수한 저해활성을 가지는 항균 조성물일 수 있다.
The antimicrobial composition is a pathogenic microorganism, specifically Gram-positive bacteria or Gram-negative bacteria, more specifically harmful fungi against rice plants and their seeds, preferably Magnaporthe grisea, Bipolaris species, Dresla (Drechslera) species or Rhizoctonia solani, more preferably, may be an antimicrobial composition having antimicrobial activity against Magnaporthe grisea. In addition, the antimicrobial composition may be an antimicrobial composition having excellent antimicrobial activity against Candida albicans bacteria, preferably an antimicrobial having an excellent inhibitory activity against isocitrate lyase of Candida albicans. It may be a composition.
본 발명의 항균 조성물에는 유효성분인 상기 화학식 A의 구조를 갖는 화합물, 상기 화학식 B의 구조를 갖는 화합물 또는 상기 화학식 C의 구조를 갖는 화합물 외에 당질, 단백질, 지질, 비타민류 및 미네랄류를 포함할 수 있다.
The antimicrobial composition of the present invention may include sugars, proteins, lipids, vitamins and minerals in addition to the compound having the structure of Formula A, the compound having the structure of Formula B, or the compound having the structure of Formula C, which are active ingredients. have.
상기 당질은, 식용 가능한 제한은 없으며, 일예로 벌꿀, 덱스트린, 수크로오스, 팔라티노스, 포도당, 과당, 물엿, 당알콜(sugar alcohol), 소르비톨, 크실리톨, 말티톨일 수 있다. 상기 단백질은 식용 가능한 제한은 없으며, 카제인(casein), 유청 단백질(whey protein) 등의 우유 유래 단백질, 대두 단백질, 이들 단백질의 트립신, 펩신 등의 동물 유래 효소 및 뉴트라아제(neutrase), 알칼라아제(alkilase)에 의한 가수분해물일 수 있다. 상기 지질은 식용가능한 제한은 없으며, 제1가 포화지방산, 다가 불포화지방산을 포함하는 해바라기유, 채종유(rapeseed oil), 올리브유, 홍화유(safflower oil), 옥수수유, 대두유, 팜유(palm oil), 야자유 등의 각종 식물 유래 유지, 중쇄 지방산(middle-chain fatty acid), EPA, DHA, 대두유래 인지질, 우유 유래 인지질 일 수 있다. 상기 비타민류는 특별한 제한은 없으며, 상기 미네랄류는 식용 가능한 제한은 없으며, 일예로 인산칼륨, 탄산칼륨, 염화칼륨, 염화나트륨, 유산칼슘, 글루콘산칼슘, 판토텐산칼슘, 카제인칼슘, 염화마그네슘, 황산제1철, 탄산수소나트륨일 수 있다.
The saccharide is not edible, but may be, for example, honey, dextrin, sucrose, palatinose, glucose, fructose, syrup, sugar alcohol, sorbitol, xylitol, maltitol. The protein is not edible, and there is no limit to edible, milk-derived proteins such as casein and whey protein, soy protein, animal-derived enzymes such as trypsin and pepsin, and neutralases and alkalases of these proteins. hydrolyzate by alkilase. The lipids are not edible, but are not limited to edible saturated fatty acids, sunflower oils including polyunsaturated fatty acids, rapeseed oil, olive oil, safflower oil, corn oil, soybean oil, palm oil, palm oil. Various plant-derived fats and oils, such as middle-chain fatty acids, EPA, DHA, soybean-derived phospholipids, milk-derived phospholipids. The vitamins are not particularly limited, and the minerals are not edible, and examples thereof include potassium phosphate, potassium carbonate, potassium chloride, sodium chloride, calcium lactate, calcium gluconate, calcium pantothenate, calcium casein, magnesium chloride and ferrous sulfate. And sodium hydrogen carbonate.
상기 당질, 단백질, 지질, 비타민류 및 미네랄류 중 어느 것에 대해서도, 조성물의 항균성이 유지되는 한 상기 구체예에 한정되지 않고 다른 성분을 포함할 수 있으며, 각각의 함량은 항균성이 유지되는 한 제한되지 아니하고, 바람직하게는 전체 조성물 대비 0.1 내지 15 중량%, 바람직하게는 0.5 내지 10 중량%일 수 있다.
For any of the above saccharides, proteins, lipids, vitamins and minerals, as long as the antimicrobial properties of the composition are maintained, not limited to the above embodiments and may include other ingredients, each content is not limited as long as the antimicrobial properties are maintained Preferably, it may be 0.1 to 15% by weight, preferably 0.5 to 10% by weight relative to the total composition.
또한, 본 발명은 상기 항균 조성물을 유효성분으로 포함하는 칸디다 알비칸(Candida albicans)에 의한 진균증 또는 칸디다증에 대한 예방 또는 치료용 조성물을 제공한다.
The present invention also provides a composition for preventing or treating fungi or candidiasis caused by Candida albicans including the antimicrobial composition as an active ingredient.
상기 칸디다 알비칸의 감염에 의한 질병은 바람직하게는 점막 칸디다증, 피부 칸디다증, 소화관 칸디다증 및 전신성 칸디다증으로 이루어진 군에서 선택된 1종 이상일 수 있고, 벼 식물 및 그의 종자에 대한 유해 진균, 바람직하게는 벼 도열병균(Magnaporthe grisea), 바이폴라리스(Bipolaris) 종, 드레슬라(Drechslera) 종 또는 리조크토니아 솔라니(Rhizoctonia solani), 더욱 바람직하게는 벼 도열병균(Magnaporthe grisea)에 의해 야기되는 질병을 포함하나, 이에 제한되지는 않는다.
The disease caused by the infection of the Candida albican is preferably at least one selected from the group consisting of mucosal candidiasis, skin candidiasis, digestive tract candidiasis and systemic candidiasis, harmful fungi to rice plants and their seeds, preferably rice blast Includes diseases caused by Magnaporthe grisea, Bipolaris spp., Drechslera spp. Or Rhizoctonia solani, more preferably Magnaporthe grisea, It is not limited to this.
본 발명의 칸디다 알비칸균에 의한 감염에 의한 질병의 예방 또는 치료용 조성물은 상기 항균 조성물 이외에 제형 및 사용방법에 따라 약리학적으로 사용가능한 담체나 부형제를 부가로 포함할 수 있으며, 본 발명의 조성물 단독으로 또는 칸디다 알비칸균에 의한 감염의 치료제로서의 효능 증진을 위해 다른 약학적 활성성분과 조합하여 투여될 수 있다. 이 경우 칸디다 알비칸균에 의한 감염에 의한 질병의 예방 또는 치료용 조성물 내 상기 항균 조성물의 함량은 0.001 내지 99.9 중량%일 수 있다. 조성물 내 유효성분의 함량이 0.001 중량% 미만인 경우 효과적인 효능을 위해선 다량의 투여가 필요할 수 있으며, 99.9 중량% 초과하는 경우 사용량에 비해 효능이 일정할 수 있어 비경제적일 수 있다. 또한, 사용방법 및 사용목적에 따라 칸디다 알비칸균에 의한 감염에 의한 질병의 예방 또는 치료용 조성물은 상기 항균 조성물의 함량을 적절히 조절할 수 있다.
The composition for the prevention or treatment of diseases caused by infection with Candida albicans bacteria of the present invention may further comprise a carrier or excipient which can be used pharmacologically according to the formulation and method of use in addition to the antimicrobial composition, the composition of the present invention alone Or in combination with other pharmaceutically active ingredients for enhanced efficacy as a therapeutic agent for infection by Candida albicans. In this case, the content of the antimicrobial composition in the composition for the prevention or treatment of diseases caused by infection with Candida albicans may be 0.001 to 99.9% by weight. If the amount of the active ingredient in the composition is less than 0.001% by weight may require a large amount of administration for effective efficacy, if the amount exceeds 99.9% by weight may be constant compared to the amount of use may be uneconomical. In addition, according to the method of use and purpose of use, the composition for the prevention or treatment of diseases caused by infection with Candida albicans bacteria can appropriately adjust the content of the antimicrobial composition.
상기 약학적으로 허용되는 담체, 부형제 또는 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐 피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유, 덱스트린, 칼슘카보네이트, 프로필렌글리콜, 리퀴드 파라핀 및 생리시역수로 이루어진 군에서 선택된 1 이상을 들 수 있으나, 이에 한정되는 것은 아니며 통상의 담체, 부형제 또는 희석제 모두 사용가능하다. 또한, 상기 약학 조성물은 통상의 충진제, 증량제, 결합제, 붕해제, 항응집제, 윤활제, 습윤제, 향료, 유화제 또는 방부제 등을 추가로 포함할 수 있다.
Examples of the pharmaceutically acceptable carrier, excipient, or diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, propylhydroxybenzoate, talc, magnesium stearate and mineral oil , Dextrin, calcium carbonate, propylene glycol, liquid paraffin, and at least one selected from the group consisting of physiological function, but is not limited thereto, and any conventional carrier, excipient or diluent may be used. In addition, the pharmaceutical composition may further include conventional fillers, extenders, binders, disintegrants, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers or preservatives.
상기 조성물의 제형은 사용방법에 따라 달라질 수 있으며, 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 잘알려진 방법을 사용하여 제형화될 수 있다. 일반적으로는, 상기 제형은 경고제(PLASTERS), 과립제(GRANULES), 로션제(LOTIONS), 산제(POWDERS), 시럽제(SYRUPS), 액제(LIQUIDSAND SOULTIONS), 에어로솔제(AEROSOLS), 연고제(ONITMENTS), 유동엑스제(FRUIDEXTRACTS), 엘릭서(ELIXIR), 유제(EMULSIONS), 현탁제(SUSTESIONS), 침제(INFUSIONS), 향낭(SACHET), 정제(TABLETS), 알약, 주사제(INJECTIONS), 연질 또는 경질 캅셀제(CAPSULES) 및 환제(PILLS) 등의 형태일 수 있으며, 바람직하게는 과립제, 산제, 시럽제, 액제, 현탁제, 정제, 알약, 주사제 및 연질 또는 경질 캅셀제로 이루어진 군에서 선택된 어느 하나일 수 있다. 더 나아가, 본 발명의 조성물은 당해 기술 분야의 공지된 적절한 방법을 사용하여 또는 레밍턴의 문헌(Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA)에 개시되어 있는 방법을 이용하여 제형화될 수 있다.
The formulation of the composition may vary depending on the method of use and may be formulated using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. Generally, the formulations are PLASTERS, GRANULES, LOTIONS, POWDERS, SYRUPS, LIQUIDSAND SOULTIONS, AEROSOLS, ONITMENTS. , FRUIDEXTRACTS, ELIXIR, EMULSIONS, SUSPENSIONS, INFUSIONS, SACHET, TABLETS, PILLS, INJECTIONS, soft or hard capsules (CAPSULES) and pills (PILLS) and the like, and preferably may be any one selected from the group consisting of granules, powders, syrups, solutions, suspensions, tablets, pills, injections and soft or hard capsules. Furthermore, the compositions of the present invention may be formulated using suitable methods known in the art or using methods disclosed in Remington's Pharmaceutical Science (Recent Edition, Mack Publishing Company, Easton PA). Can be.
상기 조성물이 약제로 사용하는 경우 투여방법은 경구 또는 비경구 모두 가능하며, 일 예로는 경구, 경피, 피하, 정맥 또는 근육을 포함한 여러 경로를 통해 투여될 수 있다.
When the composition is used as a medicament, the administration method may be oral or parenteral, and may be administered through various routes including oral, transdermal, subcutaneous, intravenous or intramuscular.
상기 조성물의 투여량은 여러 가지 조건에 따라 변동가능하기 때문에, 상기 투여량에 가감이 있을 수 있다는 사실은 당업자에게 자명하며, 따라서 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 상기 조성물의 투여량은 투여방법, 복용자의 연령, 성별, 환자의 중증도, 상태, 체내에서 활성 성분의 흡수도, 불활성율 및 병용되는 약물을 고려하여 결정할 수 있으며, 일 예로 1일 유효성분을 기준으로 하였을 때 0.0001mg/kg(체중) 내지 1000 mg/kg(체중), 0.01 mg/kg(체중) 내지 100 mg/kg(체중) 또는 0.5 mg/kg(체중) 내지 50mg/kg(체중)으로 투여할 수 있으며, 1회 또는 수회로 나누어 투여할 수 있다.
Since the dosage of the composition can vary according to various conditions, it will be apparent to those skilled in the art that the dosage may be added or subtracted, and thus the dosage does not limit the scope of the present invention in any aspect. The dosage of the composition may be determined in consideration of the method of administration, age, sex, severity, condition of the patient, absorption of the active ingredient in the body, inactivation rate and the drug used in combination, for example, based on the daily effective ingredient From 0.0001 mg / kg (body weight) to 1000 mg / kg (body weight), 0.01 mg / kg (body weight) to 100 mg / kg (body weight) or 0.5 mg / kg (body weight) to 50 mg / kg body weight It may be administered, and may be administered once or in divided doses.
또한, 상기 조성물의 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 상기 조성물의 투여량은 여러 가지 조건에 따라 변동가능하기 때문에, 상기 투여량에 가감이 있을 수 있다는 사실은 당업자에게 자명하며, 따라서 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 투여횟수는 원하는 범위 내에서 하루에 1회, 또는 수회로 나누어 투여할 수 있으며, 투여 기간도 특별히 한정되지 않는다.
In addition, the dosage amount of the said composition does not limit the scope of the present invention in any aspect. Since the dosage of the composition can vary according to various conditions, it will be apparent to those skilled in the art that the dosage may be added or subtracted, and thus the dosage does not limit the scope of the present invention in any aspect. The frequency of administration can be administered once a day or divided into several times within the desired range, the administration period is not particularly limited.
상기한 본 발명에 의하면, 천연 브로모페놀계 화합물과는 전혀 다른 구조를 가지면서 우수한 항균 활성을 가지는 신규한 페놀계 화합물(Phenolic compound)을 제공할 수 있다. 즉, 본 발명은 진균류인 칸디다 알비칸(Candida albicans)의 이소시트래이트 리아제(isocitrate lyase)에 대하여 우수한 저해활성을 가지는 페놀계 화합물을 제공할 수 있고, 이를 통하여 유해 진균을 방제하는 살진균용 조성물로 다양하게 활용하는 것이 가능하다.
According to the present invention described above, it is possible to provide a novel phenolic compound (Phenolic compound) having a structure completely different from the natural bromophenol-based compound and having excellent antimicrobial activity. That is, the present invention can provide a phenolic compound having an excellent inhibitory activity against isocitrate lyase of the fungi Candida albicans , through which fungi for controlling harmful fungi It is possible to utilize variously as a composition.
또한, 본 발명에 따른 신규한 페놀계 화합물 및 이를 함유하는 항균 조성물은 종래에 보고되지 아니한 신규한 화합물로, 우수한 항균 활성을 가지므로, 기존에 보고된 항생제를 대체할 수 있어 기존 항생제에 대한 내성을 가진 세균에 의한 질병의 치료 또는 예방에 널리 사용될 수 있고, 본 발명의 신규 페놀계 화합물을 제조하는 방법은 간단한 방법으로, 항균 활성을 갖는 신규한 페놀계 화합물을 제조할 수 있으므로, 소량의 화합물만을 수득할 수 있어 생산성이 떨어졌던 홍조류로부터 추출하는 방법과 달리 신규한 화합물을 경제적으로 대량 생산할 수 있는 방법이므로, 본 발명의 신규한 페놀계 화합물의 산업적 이용이 가능하게 되어, 본 발명은 그 산업적 효과가 매우 크다할 것이다.
In addition, the novel phenolic compound and the antimicrobial composition containing the same according to the present invention is a novel compound that has not been reported in the past, and has excellent antimicrobial activity, so that it is possible to replace the previously reported antibiotics and to resist the existing antibiotics. It can be widely used for the treatment or prevention of diseases caused by bacteria, and the method for producing a novel phenolic compound of the present invention can be prepared in a simple way, a novel phenolic compound having an antimicrobial activity, a small amount of the compound Unlike the method of extracting from red algae, which has a low productivity, since only bays can be obtained, it is possible to economically mass-produce new compounds. Therefore, the industrial use of the novel phenolic compounds of the present invention is enabled, and the present invention can be used industrially. The effect will be very big.
도 1은 본 발명의 일 실시예에 따른 페놀 화합물의 핵자기 공명 스펙트럼(NMR)을 나타내는 그래프이다.1 is a graph showing nuclear magnetic resonance spectra (NMR) of phenolic compounds according to an embodiment of the present invention.
본 발명은 하기의 실시예에 의하여 보다 더 잘 이해 될 수 있으며, 하기의 실시예는 본 발명의 예시 목적을 위한 것이며, 첨부된 특허청구범위에 의하여 한정되는 보호범위를 제한하고자 하는 것은 아니다.
The present invention may be better understood by the following examples, which are for the purpose of illustrating the invention and are not intended to limit the scope of protection defined by the appended claims.
실시예 1: 페놀계 화합물의 제조Example 1: Preparation of Phenolic Compound
실시예 1-1: 화학식 A 구조를 가지는 화합물의 제조Example 1-1: Preparation of a Compound Having Formula A Structure
상기한 반응식 I에 따라 화학식 A 구조를 가지는 화합물을 제조하였다.
According to Scheme I, a compound having the structure of Formula A was prepared.
(1) 5-(benzo[d][1,3]dioxol-5-yloxy)benzo[d][1,3]dioxole(화합물 1의 제조)(1) 5- (benzo [d] [1,3] dioxol-5-yloxy) benzo [d] [1,3] dioxole (preparation of compound 1)
Cesium carbonate (3.4 g, 10.4 mmol) 과 copper bromide (70 mg, 0.49 mmol), 2-oxocyclohexane carboxylate (0.158 ml, 0.994 mmol )을 Shlenk tube에 적가한 후 DMSO 2.5ml에 녹이고 Argon gas 상태에서 상온 교반하였다. 30분 후 sesamol 0.82 g (5.96 mmol)과 4-bromo-1,2-(methylenedioxy)benzene (1.0 g, 4.97 mmol )을 DMSO 2.5 ml에 녹인 용액을 syringe를 이용해 천천히 적가한 후에 80℃에서 36시간 교반하였다. 반응을 종료하고 이 혼합물을 cellite 5g으로 충진된 glass filter로 여과한 후 ethyl acetate 60ml 와 Saturated NaHCO3(aq) 60ml로 2회 세척하였다. 유기층을 anhydrous MgSO4로 건조하고 감압증류하였다. 이 혼합물을 실리카겔 칼럼 (ethyl acetate : hexane = 1 : 30)으로 분리하여 화합물 1(62%)을 노란색 액체로 합성하였다.
Cesium carbonate (3.4 g, 10.4 mmol), copper bromide (70 mg, 0.49 mmol) and 2-oxocyclohexane carboxylate (0.158 ml, 0.994 mmol) were added dropwise to a Shlenk tube, dissolved in 2.5 ml of DMSO and stirred at room temperature in Argon gas. . After 30 minutes, a solution of 0.82 g (5.96 mmol) of sesamol and 4-bromo-1,2- (methylenedioxy) benzene (1.0 g, 4.97 mmol) in 2.5 ml of DMSO was slowly added dropwise using a syringe, followed by 36 hours at 80 ° C. Stirred. After completion of the reaction, the mixture was filtered through a glass filter filled with 5 g of cellite, and washed twice with 60 ml of ethyl acetate and 60 ml of saturated NaHCO 3 (aq). The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The mixture was separated by a silica gel column (ethyl acetate: hexane = 1: 30) to synthesize compound 1 (62%) as a yellow liquid.
(2) 4-(3,4-dihydroxyphenoxy)benzene-1,2-diol(화합물 2의 제조)(2) 4- (3,4-dihydroxyphenoxy) benzene-1,2-diol (preparation of compound 2)
상기 화합물 1(0.1 g, 0.387mmol)을 CH2Cl2로 녹여 10분간 교반한 후 0℃에서 플라스크를 호일로 감싼 후에 BBr3 (0.6 g, 2.4mmol)을 천천히 적가하였다. 상온으로 천천히 온도를 올린 후 호일을 벗겨내고 5시간 교반하였다. 이 반응물에 saturated NaHCO3(aq)로 3번 추출한 후 감압여과하여 실리카겔 칼럼(hexane : ethyl acetate = 1:1)로 분리하여 화합물 2(90%)를 합성하였다.Compound 1 (0.1 g, 0.387 mmol) was dissolved in CH 2 Cl 2 , stirred for 10 minutes, and the flask was wrapped with foil at 0 ° C., followed by slowly dropwise addition of BBr 3 (0.6 g, 2.4 mmol). After slowly raising the temperature to room temperature, the foil was peeled off and stirred for 5 hours. The reaction product was extracted three times with saturated NaHCO 3 (aq), filtered under reduced pressure, and separated using a silica gel column (hexane: ethyl acetate = 1: 1) to synthesize Compound 2 (90%).
1H NMR (CD3OD,500MHz)δ6.60 (d, J=8.4 Hz, 2H) 6.33 (d, J=2.4 Hz 2H), 6.19 (dd, J=8.4, 2.4 Hz); 13CNMR(CD3OD, 125MHz)δ152.4, 146.9, 141.8, 116.5, 110.4, 107.5; ESI (-) m/z 233.2 (M-H)-
1 H NMR (CD 3 OD, 500 MHz) δ6.60 (d, J = 8.4 Hz, 2H) 6.33 (d, J = 2.4 Hz 2H), 6.19 (dd, J = 8.4, 2.4 Hz); 13 CNMR (CD 3 OD, 125 MHz) δ 152.4, 146.9, 141.8, 116.5, 110.4, 107.5; ESI (-) m / z 233.2 (MH) -
(3) 화합물 3, 4, 5의 제조(3) Preparation of Compounds 3, 4, and 5
상기 화합물 2 (20 mg, 0.1 mmol)와 bromine (32 mg, 0.21 mmol)의 혼합물을 3 ml의 아세트산과 디클로로메탄 (1:1) 혼합용액에 넣고, 상온에서 두 시간 동안 교반하였다. 반응이 종료된 다음 질소기체를 흘려 여분의 브롬을 제거하고, 감압하에서 반응용매를 제거하였다. 반응 혼합물로부터 칼럼 크로마토그래피하여 화합물 3과 화합물 4를 각각 20%, 56 % 수율로 얻었다. A mixture of Compound 2 (20 mg, 0.1 mmol) and bromine (32 mg, 0.21 mmol) was added to 3 ml of a mixture of acetic acid and dichloromethane (1: 1) and stirred at room temperature for 2 hours. After completion of the reaction, nitrogen gas was flowed to remove excess bromine and the reaction solvent was removed under reduced pressure. Column chromatography from the reaction mixture gave compound 3 and compound 4 in 20% and 56% yield, respectively.
2-bromo-4,5-dihydroxyphenyl)(3,4-dihydroxyphenyl) ether (화합물 3): mp 93-95oC (dec); 1H NMR(CD3OD, 500 MHz) δ 6.21 (1H, dd, J = 8.0, 2.6 Hz), 6.35 (1H, d, J = 2.6 Hz), 6.43 (1H, s), 6.67 (1H, d, J = 8.0 Hz), 6.95 (1H, s);13C NMR(CD3OD, 125 MHz) δ103.5, 106.6, 109.2, 116.4, 119.9, 120.1, 141.9, 143.6, 146.9, 147.1, 148.2, 152.4; ESI(-)m/z311.1(M-H)- 2-bromo-4,5-dihydroxyphenyl) (3,4-dihydroxyphenyl) ether (Compound 3): mp 93-95 o C (dec); 1 H NMR (CD 3 OD, 500 MHz) δ 6.21 (1H, dd, J = 8.0, 2.6 Hz), 6.35 (1H, d, J = 2.6 Hz), 6.43 (1H, s), 6.67 (1H, d , J = 8.0 Hz), 6.95 (1 H, s); 13 C NMR (CD 3 OD, 125 MHz) δ 103.5, 106.6, 109.2, 116.4, 119.9, 120.1, 141.9, 143.6, 146.9, 147.1, 148.2, 152.4; ESI (-) m / z 311.1 (MH) -
bis(2-bromo-4,5-dihydroxyphenyl) ether (화합물 4):mp 146-149oC (dec); 1H NMR(CD3OD, 500 MHz) δ6.31 (1H,s), 6.96(1H, s); 13C NMR (CD3OD, 125 MHz) δ 102.5, 107.9, 120.1, 143.5, 146.9, 148.1; ESI(-) m/z 390.9(M-H)-
bis (2-bromo-4,5-dihydroxyphenyl) ether (Compound 4): mp 146-149 o C (dec); 1 H NMR (CD 3 OD, 500 MHz) δ 6.31 (1 H, s), 6.96 (1 H, s); 13 C NMR (CD 3 OD, 125 MHz) δ 102.5, 107.9, 120.1, 143.5, 146.9, 148.1; ESI (-) m / z 390.9 (MH) -
위와 유사한 방법으로 상기 화합물 2(14 mg)와 3당량의 브롬(40m)l의 반응으로부터 화합물 5인 bis(2,3-dibromo-4,5-dihydroxyphenyl) ether 22mg (67%)을 얻었다. 22 mg (67%) of bis (2,3-dibromo-4,5-dihydroxyphenyl) ether as a compound 5 was obtained from the reaction of Compound 2 (14 mg) with 3 equivalents of bromine (40m) l in the same manner as above.
bis(2,3-dibromo-4,5-dihydroxyphenyl) ether (5): mp 144-146oC (dec); 1H NMR (CD3OD, 500 MHz) δ 6.37 (1H, s); 13C NMR (CD3OD, 125 MHz) δ 106.5, 106.8, 114.6, 142.3, 147.0, 148.5; ESI(-) m/z 548.9(M-H)-
bis (2,3-dibromo-4,5-dihydroxyphenyl) eth er (5): mp 144-146 o C (dec); 1 H NMR (CD 3 OD, 500 MHz) δ 6.37 (1H, s); 13 C NMR (CD 3 OD, 125 MHz) δ 106.5, 106.8, 114.6, 142.3, 147.0, 148.5; ESI (-) m / z 548.9 (MH) -
실시예 1-2: 화학식 B 구조를 가지는 화합물의 제조Example 1-2 Preparation of Compounds Having Formula B Structure
상기한 반응식 II에 따라 화학식 B 구조를 가지는 화합물을 제조하였다.
According to Scheme II, a compound having the structure of Formula B was prepared.
(1) (benzo[d][1,3]dioxol-5-yl)(benzo[d][1,3]dioxol-6-yl)methanol(화합물 6의 제조)(1) (benzo [d] [1,3] dioxol-5-yl) (benzo [d] [1,3] dioxol-6-yl) methanol (preparation of compound 6)
4-bromo-1,2-(methylenedioxy)benzene 1.2 g (5.99 mmol)을 THF 10ml로 5분간 교반하면서 n-butyllithium (1.64 g, 25.6mmol)을 천천히 적가하였다. Piperonal (0.9 g, 5.99 mmol)을 THF 1ml로 녹인 뒤 syringe로 천천히 적가한 뒤 10분 후에 methanol 1ml를 적가 한 후 상온에서 6시간 교반하였다. 이 반응 혼합물을 감압증류한 뒤 CH2Cl2 30ml와 saturated NaHCO3(aq) 30ml로 3회 세척하였다. 유기층을 anhydrous MgSO4로 건조하고 감압증류하였다. 이 혼합물을 실리카겔 칼럼 (ethyl acetate : hexane = 2 : 5)로 분리하여 화합물 6(64%)을 흰색고체로 합성하였다.
N-butyllithium (1.64 g, 25.6 mmol) was slowly added dropwise while stirring 1.2 g (5.99 mmol) of 4-bromo-1,2- (methylenedioxy) benzene with 10 ml of THF for 5 minutes. Piperonal (0.9 g, 5.99 mmol) was dissolved in THF 1ml and slowly added dropwise with a syringe. After 10 minutes, methanol 1ml was added dropwise and stirred at room temperature for 6 hours. The reaction mixture was distilled under reduced pressure and washed three times with 30 ml of CH 2 Cl 2 and 30 ml of saturated NaHCO 3 (aq). The organic layer was dried over anhydrous MgSO 4 and distilled under reduced pressure. The mixture was separated by a silica gel column (ethyl acetate: hexane = 2: 5) to synthesize compound 6 (64%) as a white solid.
(2) (benzo[d][1,3]dioxol-5-yl)(benzo[d][1,3]dioxol-6-yl)methanone(화합물 7의 제조)(2) (benzo [d] [1,3] dioxol-5-yl) (benzo [d] [1,3] dioxol-6-yl) methanone (preparation of compound 7)
상기 화합물 6(0.5 g, 1.836mmol)을 CH2Cl2 20ml로 녹인후 pyridinium dichloronate (2.07 g, 5.5mmol)과 Cellite 2g을 적가 한 후에 3시간 교반하였다. 이 혼합물을 실리카겔 10g으로 충진된 glass filter에 여과하고 감압증류하여 실리카겔 칼럼 (ethyl acetate : hexane = 1 : 2)으로 분리하여 화합물 7(95%)을 흰색고체로 합성하였다.
Compound 6 (0.5 g, 1.836 mmol) was dissolved in 20 ml of CH 2 Cl 2 , and pyridinium dichloronate (2.07 g, 5.5 mmol) and Cellite 2 g were added dropwise, followed by stirring for 3 hours. The mixture was filtered through a glass filter filled with 10 g of silica gel, distilled under reduced pressure, and separated by a silica gel column (ethyl acetate: hexane = 1: 2) to synthesize compound 7 (95%) as a white solid.
(3) bis(3,4-dihydroxyphenyl)methanone(화합물 8의 제조)(3) bis (3,4-dihydroxyphenyl) methanone (preparation of compound 8)
상기 화합물 7(0.1 g, 0.370mmol)을CH2Cl2로 녹여 10분간 교반한 후 0℃에서 플라스크를 호일로 감싼 후에 BBr3 (0.6g, 2.4mmol)을 천천히 적가하였다. 상온으로 천천히 온도를 올린 후 호일을 벗겨내고 5시간 교반하였다. 이 반응물에 saturated NaHCO3(aq)로 3번 추출한 후 감압여과하여 실리카겔 칼럼(hexane : ethyl acetate = 1:1)로 분리하여 화합물 8(90%)을 합성하였다.
Compound 7 (0.1 g, 0.370 mmol) was dissolved in CH 2 Cl 2 , stirred for 10 minutes, and the flask was wrapped with foil at 0 ° C., followed by slowly dropwise addition of BBr 3 (0.6 g, 2.4 mmol). After slowly raising the temperature to room temperature, the foil was peeled off and stirred for 5 hours. The reaction product was extracted three times with saturated NaHCO 3 (aq) and filtered under reduced pressure to separate a silica gel column (hexane: ethyl acetate = 1: 1) to synthesize compound 8 (90%).
(4) 화합물 9, 10의 제조(4) Preparation of
상기 화합물 8의 제조와 유사한 방법으로 화합물 8과 bromine를 반응시켜 화합물 9인 bis(3-bromo-4,5-dihydroxyphenyl)methanone 와 화합물 10인 (3-bromo-4,5- dihydroxyphenyl)(2,3-dibromo-4,5-dihydroxyphenyl)methanone 을 얻었다. In a similar manner to the preparation of
bis(3-bromo-4,5-dihydroxyphenyl)methanone (화합물 9): mp 183-185oC (dec); 1HNMR (CD3OD, 500 MHz) δ 7.18(2H,s), 7.38 (2H,s); 13C NMR(CD3OD, 125MHz) δ 110.1, 116.6, 127.4, 130.9, 146.9, 149.1, 194.4; ESI(-) m/z 401.8(M-H)- bis (3-bromo-4,5-dihydroxyphenyl) methanone (Compound 9): mp 183-185 o C (dec); 1 HNMR (CD 3 OD, 500 MHz) δ 7.18 (2H, s), 7.38 (2H, s); 13 C NMR (CD 3 OD, 125 MHz) δ 110.1, 116.6, 127.4, 130.9, 146.9, 149.1, 194.4; ESI (-) m / z 401.8 (MH) -
(3-bromo-4,5-dihydroxyphenyl)(2,3-dibromo-4,5-dihydroxyphenyl)methanone (화합물 10):1H NMR (CD3OD, 500 MHz) δ 6.99 (1H,s), 7.17(1H,s), 7.36(1H, s); 13C NMR (CD3OD, 125 MHz) δ 109.7, 110.4, 114.7, 116.5, 124.1, 128.1, 130.0, 134.2, 145.8, 146.9, 147.1, 150.4, 194.3; ESI(-) m/z 480.8(M-H)-
(3-bromo-4,5-dihydroxyphenyl) (2,3-dibromo-4,5-dihydroxyphenyl) methanone (Compound 10): 1 H NMR (CD 3 OD, 500 MHz) δ 6.99 (1H, s), 7.17 (1H, s), 7.36 (1H, s); 13 C NMR (CD 3 OD, 125 MHz) δ 109.7, 110.4, 114.7, 116.5, 124.1, 128.1, 130.0, 134.2, 145.8, 146.9, 147.1, 150.4, 194.3; ESI (-) m / z 480.8 (MH) -
실시예 1-3: 화학식 C 구조를 가지는 화합물의 제조Example 1-3 Preparation of Compounds Having Formula C Structure
상기한 반응식 III에 따라 화학식 C 구조를 가지는 화합물을 제조하였다.
According to Scheme III, a compound having the structure of Formula C was prepared.
(1) (E)-1,2-di(benzo[d][1,3]dioxol-5-yl)ethene(화합물 11의 제조)(1) (E) -1,2-di (benzo [d] [1,3] dioxol-5-yl) ethene (Preparation of Compound 11)
Zinc (5.22 g, 70.93mmol)에 THF 50ml을 넣고 10분간 교반한 후 0℃에서 TiCl4 (4.5 g, 39.96mmol)을 천천히 적가하였다. 온도를 70~80℃로 유지하고 piperonal ( 2 g, 13.32mmol)을 THF 50ml에 녹인 용액을 syringe로 적가하였다. 5시간 교반한 후에 이 반응 혼합물을 glass filter에 여과한 후 유기층을 감압증류 한 후 실리카겔 칼럼 (hexane : CH2Cl2= 2 : 1)로 분리하여 화합물 11(53%)을 흰색고체로 합성하였다.50 ml of THF was added to Zinc (5.22 g, 70.93 mmol), stirred for 10 minutes, and slowly added dropwise TiCl 4 (4.5 g, 39.96 mmol) at 0 ° C. The temperature was maintained at 70 ~ 80 ℃ and piperonal (2 g, 13.32 mmol) dissolved in 50ml THF was added dropwise with a syringe. After stirring for 5 hours, the reaction mixture was filtered through a glass filter, and the organic layer was distilled under reduced pressure, and then separated by a silica gel column (hexane: CH 2 Cl 2 = 2: 1) to synthesize compound 11 (53%) as a white solid. .
(2) 1,2-di(benzo[d][1,3]dioxol-5-yl)ethane(화합물 12의 제조) (2) 1,2-di (benzo [d] [1,3] dioxol-5-yl) ethane (Preparation of Compound 12)
상기 화합물 11 (0.3 g, 1.1mmol)에 ethyl acetate 10ml를 넣고 교반하면서 palladium chacohol 100mg(5%)와 ethanol 10ml로 적가한 후 H2 gas로 용기안을 채워주고 6시간동안 교반하였다. Cellite 5g으로 충진된 glass filter로 여과하고 CH2Cl2로 세척한 후 감압여과하였다. 실리카겔 칼럼 (hexane : CH2Cl2= 2 : 1)로 분리하여 화합물 12 (81%)을 흰색고체로 합성하였다.
10 ml of ethyl acetate was added to the compound 11 (0.3 g, 1.1 mmol), and the mixture was added dropwise with 100 mg (5%) of palladium chacohol and 10 ml of ethanol, followed by filling into a container with H 2 gas and stirring for 6 hours. Filtration was performed through a glass filter filled with 5 g of cellite, washed with CH 2 Cl 2, and filtered under reduced pressure. Compound 12 (81%) was synthesized as a white solid by separation with a silica gel column (hexane: CH 2 Cl 2 = 2: 1).
(3) 4-(3,4-dihydroxyphenethyl)benzene-1,2-diol(화합물 13의 제조)(3) 4- (3,4-dihydroxyphenethyl) benzene-1,2-diol (preparation of compound 13)
상기 화합물 12 (0.1 g, 0.370mmol)을 CH2Cl2로 녹여 10분간 교반한 후 0℃에서 플라스크를 호일로 감싼 후에 BBr3 (0.6 g, 2.4mmol)을 천천히 적가하였다.상온으로 천천히 온도를 올린 후 호일을 벗겨내고 5시간 교반하였다. 이 반응물에 saturated NaHCO3(aq)로 3번 추출한 후 감압여과하여 실리카겔 칼럼(hexane : ethyl acetate = 1:1)로 분리하여 화합물 13(90%)을 합성하였다.
Compound 12 (0.1 g, 0.370 mmol) was dissolved in CH 2 Cl 2 , stirred for 10 minutes, and the flask was wrapped with foil at 0 ° C., followed by slowly dropwise addition of BBr 3 (0.6 g, 2.4 mmol) to room temperature. After raising, the foil was peeled off and stirred for 5 hours. The reaction product was extracted three times with saturated NaHCO 3 (aq), filtered under reduced pressure, and separated by silica gel column (hexane: ethyl acetate = 1: 1) to synthesize compound 13 (90%).
(4) 화합물 14, 15의 제조(4) Preparation of the Compound 14, 15
상기 화합물 13의 제조와 유사한 방법을 사용하여 화합물 13으로부터 화합물 14인 2,2'-dibromo-4,4',5,5'- tetrahydroxybibenzyl 과 화합물 15인 2,2’,3-tribromo-4,4',5,5'-tetrahydroxybibenzyl 를 얻었다. 2,2'-dibromo-4,4 ', 5,5'-tetrahydroxybibenzyl, which is compound 14, and 2,2', 3-tribromo-4, which is compound 15, were prepared from compound 13 using a method similar to the preparation of compound 13. 4 ', 5,5'-tetrahydroxybibenzyl was obtained.
2,2'-dibromo-4,4',5,5'-tetrahydroxybibenzyl (화합물 14): mp 205-206oC (dec); 1H NMR(CD3OD, 500 MHz) δ 2.86(4H,m), 6.61(1H,s), 6.91(2H, s); 13C NMR (CD3OD, 125 MHz) δ 146.0, 145.8, 132.8, 120.0, 118.1, 113.3, 37.2; ESI(-) m/z 402.9 (M-H)- 2,2'-dibromo-4,4 ', 5,5'-tetrahydroxybibenzyl (Compound 14): mp 205-206 o C (dec); 1 H NMR (CD 3 OD, 500 MHz) δ 2.86 (4H, m), 6.61 (1H, s), 6.91 (2H, s); 13 C NMR (CD 3 OD, 125 MHz) δ 146.0, 145.8, 132.8, 120.0, 118.1, 113.3, 37.2; ESI (-) m / z 402.9 (MH) -
2,2’,3-tribromo-4,4',5,5'-tetrahydroxybibenzyl (화합물 15):mp 220-225 oC (dec); 1H NMR(CD3OD, 500 MHz) δ 2.86(4H,m), 6.73(1H,s), 6.91 (1H,s), 6.98 (1H,s) ;13C NMR (CD3OD, 125 MHz) δ 35.3, 38.2, 113.4, 113.8, 117.9, 118.9, 120.0, 131.7, 132.8, 145.8, 146.1; ESI(-) m/z 480.9 (M-H)-
2,2 ', 3-tribromo-4,4', 5,5'-tetrahydroxybibenzyl (Compound 15): mp 220-225 o C (dec); 1 H NMR (CD 3 OD, 500 MHz) δ 2.86 (4H, m), 6.73 (1H, s), 6.91 (1H, s), 6.98 (1H, s); 13 C NMR (CD 3 OD, 125 MHz) δ 35.3, 38.2, 113.4, 113.8, 117.9, 118.9, 120.0, 131.7, 132.8, 145.8, 146.1; ESI (-) m / z 480.9 (MH) -
실시예 2; 본 발명에 따른 페놀 화합물의 이소씨트레이트 리아제(isocitrate lyase) 효소저해 활성 측정Example 2; Determination of Isocitrate Lyase Enzyme Inhibitory Activity of Phenolic Compounds According to the Present Invention
먼저, 논문 (Shin, D. S.; Kim, S.; Yang, H. C.; Oh, K. B. J. Microbiol. Biotechnol. 2005, 15, 652.)에 알려진 방법을 따라 칸디다 알비칸스의 DNA로부터 이소씨트래이트 리아제(isocitrate lyase)를 분리하였다.
First, isotate lyase from DNA of Candida albicans following a method known in the paper (Shin, DS; Kim, S .; Yang, HC; Oh, KB J. Microbiol. Biotechnol . 2005, 15 , 652.). isocitrate lyase) was isolated.
그리고, 상기 실시예 1에서 수득한 화합물의 이소시트레이트 리아제 (ICL) 효소 저해활성 측정은 하기와 같이 수행하였다(Hautzel R, Anke H, Sheldrick WS, J. Antibiot., 43, pp1240-1244, 1990).
In addition, the measurement of isocitrate lyase (ICL) enzyme inhibitory activity of the compound obtained in Example 1 was performed as follows (Hautzel R, Anke H, Sheldrick WS, J. Antibiot., 43, pp 1240-1244, 1990 ).
20mM 소듐인산완충액(pH7.0), 1,27mM threo-DL 이소시트레이트, 3.75mM 마그네슘클로라이드, 4.1mM 페닐하이드라진 및 2.5㎍/㎖의 이소시트레이트 리아제 (ICL) 효소로 구성된 혼합 용액을 37℃에서 30분간 반응시킨 후, 이때 생성된 글리옥실레이트페닐하이드라존 화합물의 양을 분광계를 이용하여 324nm에서 측정하고 이때의 효소활성을 100%로 하였다. 이 효소반응을 이용하여 실시예 1에서 수득한 화합물 및 대조 표준물질로서 기존의 저해제로 알려진 3-니트로프로피오네이트(3-nitropropionate; N-5636, Sigma사, 미국)를 각각 첨가하여 효소 활성을 측정하고 효소활성을 50% 저해하는 농도(M)를 IC50으로 표시하였다. 측정 화합물은 디메칠설폭시드(DMSO)에 10㎎/㎖ 농도로 녹여서 효소 반응액에 농도별로 첨가하였고 디메칠설폭시드의 최종농도는 1% 이하가 되도록 조정하였다.
A mixed solution consisting of 20 mM sodium phosphate buffer (pH 7.0), 1,27 mM threo-DL isocitrate, 3.75 mM magnesium chloride, 4.1 mM phenylhydrazine and 2.5 μg / ml isocitrate lyase (ICL) enzyme was prepared at 37 ° C. After reacting for 30 minutes at, the amount of glyoxylate phenylhydrazone compound produced at this time was measured at 324 nm using a spectrometer, and the enzyme activity was 100%. Using this enzyme reaction, 3-nitropropionate (N-5636, Sigma, USA), known as a conventional inhibitor, was added as a compound and a control standard obtained in Example 1, respectively. The concentration (M) that measured and inhibited the enzyme activity by 50% was expressed as IC 50. The measurement compound was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10 mg / ml, and added to the enzyme reaction solution by concentration. The final concentration of dimethyl sulfoxide was adjusted to 1% or less.
실험결과는 하기 표 1에 나타난 바와 같다.Experimental results are shown in Table 1 below.
* NDb : 결정되지 않음(not determined)
* ND b : not determined
상기 표 1에 나타난 바와 같이, 본 발명에 따른 페놀화합물은 전체적으로 우수한 저해활성을 나타내었고, 특히 페놀화합물 4, 5, 8, 9, 10, 14, 15 은 표준 물질인As shown in Table 1, the phenolic compounds according to the present invention showed an excellent inhibitory activity as a whole, in particular
3-니트로프로피오네이트 보다 낮은 IC50(mM) 값을 가지고 있음을 확인할 수 있다.
It can be seen that it has a lower IC 50 (mM) value than 3-nitropropionate.
한편, 상기에서는 본 발명을 특정의 바람직한 실시예에 관련하여 도시하고 설명하였지만, 이하의 특허청구범위에 의해 마련되는 본 발명의 기술적 특징이나 분야를 이탈하지 않는 한도 내에서 본 발명이 다양하게 개조 및 변화될 수 있다는 것은 당업계에서 통상의 지식을 가진 자에게 명백한 것이다.
On the other hand, while the present invention has been shown and described with respect to certain preferred embodiments, the invention is variously modified and modified without departing from the technical features or fields of the invention provided by the claims below It will be apparent to those skilled in the art that such changes can be made.
Claims (16)
(화학식 A)
상기 식 중, X는 H 또는 Br일 수 있다.
Phenolic compounds having the structure of Formula A or a pharmaceutically acceptable salt thereof:
Formula A
Wherein X may be H or Br.
The method of claim 1, wherein the phenolic compound is 4- (3,4-dihydroxyphenoxy) benzene-1,2-diol, 2-bromo-4,5-dihydroxyphenyl (3,4- Phenolic compounds which are dihydroxyphenyl) ether, bis (2-bromo-4,5-dihydroxyphenyl) ether or bis (2,3-dibromo-4,5-dihydroxyphenyl) ether or Its pharmaceutically acceptable salts.
(화학식 B)
(상기 식 중, X는 H 또는 Br일 수 있다.)
상기 페놀계 화합물은 비스(3-브로모-4,5-디하이드록시페닐)메타논 또는 (3-브로모-4,5-디하이드록시페닐)(2,3-디브로모-4,5-디하이드록시페닐)메타논인 페놀계 화합물 또는 그의 약학적으로 허용되는 염.
As a phenolic compound having a structure of formula (B) or a pharmaceutically acceptable salt thereof,
Formula B
(Wherein, X may be H or Br.)
The phenolic compound may be bis (3-bromo-4,5-dihydroxyphenyl) methanone or (3-bromo-4,5-dihydroxyphenyl) (2,3-dibromo-4, Phenolic compound that is 5-dihydroxyphenyl) methanone or a pharmaceutically acceptable salt thereof.
(화학식 C)
(상기 식 중, X는 H 또는 Br일 수 있다.)
상기 페놀계 화합물은 2,2'-디브로모-4,4',5,5'-테트라하이드록시비벤질 또는 2,2’,3-트리브로모-4,4',5,5'-테트라하이드록시비벤질인 페놀계 화합물 또는 그의 약학적으로 허용되는 염.
As a phenolic compound having a structure of formula (C) or a pharmaceutically acceptable salt thereof,
Formula C
(Wherein, X may be H or Br.)
The phenolic compound is 2,2'-dibromo-4,4 ', 5,5'-tetrahydroxybibenzyl or 2,2', 3-tribromo-4,4 ', 5,5' Phenolic compounds which are tetrahydroxybibenzyl or pharmaceutically acceptable salts thereof.
(화학식 A)
상기 식 중, X는 H 또는 Br일 수 있다.
Sesamol and 4-bromo-1,2- (methylenedioxy) benzene are reacted to prepare a phenolic compound having the structure of Formula A. Method of producing a phenolic compound comprising a;
Formula A
Wherein X may be H or Br.
8. The compound of claim 7, wherein the sesamol and 4-bromo-1,2- (methylenedioxy) benzene are reacted to form 5- (benzo [d] [1,3] dioxol-5-hydroxy) benzo [ d] [1,3] dioxol (5- (benzo [d] [1,3] dioxol-5-yloxy) benzo [d] [1,3] dioxole) to obtain 5- (benzo [d] ] [1,3] dioxol-5- hydroxy) benzo [d] [1,3] method for producing a phenolic compound, characterized in that a phenolic compound having the structure of formula (1) is prepared.
(화학식 B)
상기 식 중, X는 H 또는 Br일 수 있다.
Piperonal and 4-bromo-1,2- (methylenedioxy) benzene (4-bromo-1,2- (methylenedioxy) benzene) are reacted to form a phenolic compound having the structure Method of producing a phenolic compound comprising a; step of preparing.
Formula B
Wherein X may be H or Br.
The method according to claim 9, wherein the piperonal and 4-bromo-1,2- (methylenedioxy) benzene are reacted to form (benzo [d] [1,3] dioxol-5-yl) (benzo [d ] [1,3] dioxol-6-yl) methanol ((benzo [d] [1,3] dioxol-5-yl) (benzo [d] [1,3] dioxol-6-yl) methanol) Obtained from (benzo [d] [1,3] dioxol-5-yl) (benzo [d] [1,3] dioxol-6-yl) methanol (benzo [d] [1,3] diox Sol-5-yl) (benzo [d] [1,3] dioxol-6-yl) methanone ((benzo [d] [1,3] dioxol-5-yl) (benzo [d] [1, 3] dioxol-6-yl) methanone) and synthesized (benzo [d] [1,3] dioxol-5-yl) (benzo [d] [1,3] dioxol-6-yl A process for producing a phenolic compound, comprising producing a phenolic compound having the structure of formula B from methanon.
(화학식 C)
상기 식 중, X는 H 또는 Br일 수 있다.
Using a piperonal (Piperonal) as a starting material, to prepare a phenolic compound having a structure of formula (C); a method for producing a phenolic compound comprising a.
Formula C
Wherein X may be H or Br.
The (E) -1,2-di (benzo [d] [1,3] dioxol-5-yl) ethene ((E) -1,2-di according to claim 11 using the piperonal. (benzo [d] [1,3] dioxol-5-yl) ethene), obtained from (E) -1,2-di (benzo [d] [1,3] dioxol-5-yl) ethene 1,2-di (benzo [d] [1,3] dioxol-5-yl) ethane (1,2-di (benzo [d] [1,3] dioxol-5-yl) ethane) And a phenolic compound having a structure of formula (B) from the above synthesized 1,2-di (benzo [d] [1,3] dioxol-5-yl) ethane. .
A phenolic compound or a pharmaceutically acceptable salt thereof according to claim 1, a phenolic compound or a pharmaceutically acceptable salt thereof according to claim 3 or a phenolic compound or a pharmaceutically acceptable salt thereof according to claim 5 is an active ingredient Antimicrobial composition comprising a.
상기 항균 조성물은 칸디다 알비칸(Candida albicans)에 대하여 항균활성을 가지는 것을 특징으로 하는 항균 조성물.
The method of claim 13,
The antimicrobial composition is characterized in that it has an antimicrobial activity against Candida albicans .
상기 항균 조성물은 칸디다 알비칸(Candida albicans)의 이소시트레이트 리아제(isocitrate lyase)에 대하여 저해활성을 가지는 것을 특징으로 하는 항균 조성물.
15. The method of claim 14,
The antimicrobial composition is characterized in that it has an inhibitory activity against isocitrate lyase of Candida albicans .
A composition for preventing or treating fungi or candidiasis caused by Candida albicans comprising the antimicrobial composition according to claim 13 as an active ingredient.
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