CN108078969B - 萘酰肼类化合物在制备抗微生物药物中的用途 - Google Patents
萘酰肼类化合物在制备抗微生物药物中的用途 Download PDFInfo
- Publication number
- CN108078969B CN108078969B CN201711419356.9A CN201711419356A CN108078969B CN 108078969 B CN108078969 B CN 108078969B CN 201711419356 A CN201711419356 A CN 201711419356A CN 108078969 B CN108078969 B CN 108078969B
- Authority
- CN
- China
- Prior art keywords
- compound
- naphthohydrazide
- preparation
- fluoro
- antimicrobial
- 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
Links
- -1 naphthalimide compound Chemical class 0.000 title claims abstract description 30
- 230000000845 anti-microbial effect Effects 0.000 title claims abstract description 13
- 239000003814 drug Substances 0.000 title claims description 18
- 238000002360 preparation method Methods 0.000 title claims description 16
- 229940079593 drug Drugs 0.000 title claims description 4
- 241000191967 Staphylococcus aureus Species 0.000 claims abstract description 10
- 241000222122 Candida albicans Species 0.000 claims abstract description 9
- 229940095731 candida albicans Drugs 0.000 claims abstract description 9
- 241000894006 Bacteria Species 0.000 claims abstract description 7
- 241000233866 Fungi Species 0.000 claims abstract description 7
- 239000004599 antimicrobial Substances 0.000 claims abstract description 7
- 241000228197 Aspergillus flavus Species 0.000 claims abstract description 6
- 244000063299 Bacillus subtilis Species 0.000 claims abstract description 6
- 235000014469 Bacillus subtilis Nutrition 0.000 claims abstract description 6
- 241000235646 Cyberlindnera jadinii Species 0.000 claims abstract description 6
- 241000588724 Escherichia coli Species 0.000 claims abstract description 6
- 241000191938 Micrococcus luteus Species 0.000 claims abstract description 6
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims abstract description 6
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 claims abstract description 6
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims abstract description 5
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims abstract description 4
- 241000588767 Proteus vulgaris Species 0.000 claims abstract description 4
- 229960003085 meticillin Drugs 0.000 claims abstract description 4
- 229940007042 proteus vulgaris Drugs 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 18
- 239000003826 tablet Substances 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 4
- 229940081969 saccharomyces cerevisiae Drugs 0.000 claims description 4
- 239000000443 aerosol Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 244000005700 microbiome Species 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 238000000338 in vitro Methods 0.000 abstract description 3
- 241000192125 Firmicutes Species 0.000 abstract description 2
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 abstract description 2
- 239000003429 antifungal agent Substances 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- VMFUMDXVTKTZQY-UHFFFAOYSA-N naphthalene-1-carbohydrazide Chemical compound C1=CC=C2C(C(=O)NN)=CC=CC2=C1 VMFUMDXVTKTZQY-UHFFFAOYSA-N 0.000 description 7
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000000843 anti-fungal effect Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- LWZFANDGMFTDAV-WYDSMHRWSA-N [2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-WYDSMHRWSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 239000004368 Modified starch Substances 0.000 description 2
- 101100011511 Mus musculus Elovl6 gene Proteins 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 2
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 2
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 2
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 229960005150 glycerol Drugs 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 235000019426 modified starch Nutrition 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 235000010241 potassium sorbate Nutrition 0.000 description 2
- 239000004302 potassium sorbate Substances 0.000 description 2
- 229940069338 potassium sorbate Drugs 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- 239000004328 sodium tetraborate Substances 0.000 description 2
- 239000007779 soft material Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 2
- 229940029284 trichlorofluoromethane Drugs 0.000 description 2
- 229940099259 vaseline Drugs 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- MOBRMRJUKNQBMY-UHFFFAOYSA-N 1-(chloromethyl)-2-fluorobenzene Chemical compound FC1=CC=CC=C1CCl MOBRMRJUKNQBMY-UHFFFAOYSA-N 0.000 description 1
- JJWDELPVPRCLQN-UHFFFAOYSA-N 1-ethyl-6-fluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid;hydrochloride Chemical compound Cl.C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 JJWDELPVPRCLQN-UHFFFAOYSA-N 0.000 description 1
- LEVSFIPVEIPCIQ-UHFFFAOYSA-N 2-amino-6-bromo-4H-benzo[h]isoquinoline-1,3-dione Chemical compound C1C2=C(C3=CC=CC=C3C(=C2)Br)C(=O)N(C1=O)N LEVSFIPVEIPCIQ-UHFFFAOYSA-N 0.000 description 1
- 241000589220 Acetobacter Species 0.000 description 1
- ZQWVFLUAJHYMDO-UHFFFAOYSA-N C1C2=C(C3=CC=CC=C3C(=C2)Br)C(=O)N(C1=O)NCC4=CC=CC=C4F Chemical compound C1C2=C(C3=CC=CC=C3C(=C2)Br)C(=O)N(C1=O)NCC4=CC=CC=C4F ZQWVFLUAJHYMDO-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- XJHABGPPCLHLLV-UHFFFAOYSA-N benzo[de]isoquinoline-1,3-dione Chemical compound C1=CC(C(=O)NC2=O)=C3C2=CC=CC3=C1 XJHABGPPCLHLLV-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229940097572 chloromycetin Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229940093932 potassium hydroxide Drugs 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- 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
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种萘酰肼类化合物在制备抗微生物药物中的用途,萘酰肼类化合物结构如式1所示,其结构简单,具有较强的体外抗微生物活性,尤其是对金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌、枯草杆菌、藤黄微球菌等革兰阳性菌、大肠杆菌、变形杆菌、铜绿假单胞菌、伤寒沙门菌等革兰阴性菌、以及产朊假丝酵母菌、黄曲霉菌、啤酒酵母菌、白色念珠菌、假丝酵母菌等真菌都表现出很高的抑制活性,能够用于制备抗细菌和/或抗真菌药物。
Description
技术领域
本发明属于药物化学领域,涉及萘酰肼类化合物在制备抗微生物药物中的用途。
背景技术
萘酰肼作为苯环与苯环的稠环,具有大的共轭结构和强的分子内电子转移能力,其特殊的结构使其可以与生物体内的酶和受体等形成氢键,与金属离子配位以及发生疏水作用、π-π堆积、静电作用等。因此,萘酰肼类化合物可发生多种非共价键相互作用,表现出某些特殊的性能,在医药、农药、化学、物理等众多领域显示出宽广的应用前景和巨大的开发价值。
近年来,以萘酰肼环构筑的药物分子呈现出广泛的生物活性,如抗病毒、抗癌、消炎镇痛、抗寄生虫等。由于萘酰肼类化合物具有潜在的宽广应用,吸引和鼓励着无数科研工作者从事萘酰肼类化合物的研发,使得含有萘酰肼结构片段的药物的研究已成为当前医药研发十分活跃的领域之一。因此,如何对萘酰肼类化合物进行结构优化以期获得具有不同于传统药物作用机理的新型萘酰肼类衍生物,这对于本领域技术人员而言依然是一个尚未解决的技术难题。
发明内容
有鉴于此,本发明的目的在于提供一种萘酰肼类化合物在制备抗微生物药物中的用途,其抗菌和抗真菌活性强。
为达到上述目的,本发明提供如下技术方案:
1、萘酰肼类化合物在制备抗微生物药物中的用途,所述萘酰肼类化合物结构如式Ⅰ所示:
R为氟、氯或碘。
优选的,R为2-氟、3-氟或4-氟。
更优选的,R为2-氟或3-氟。
作为本发明优选的方案,所述为微生物细菌或真菌。
作为本发明优选的方案,所述细菌为金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌、藤黄微球菌、枯草杆菌、大肠杆菌、铜绿假单胞菌或变形杆菌中的一种或多种;所述真菌为产朊假丝酵母菌、黄曲霉菌、啤酒酵母菌、白色念珠菌或假丝酵母菌中的一种或多种。
作为本发明优选的方案:所述药物为片剂、胶囊剂、气雾剂、软膏剂中的任一种。
本发明的有益效果在于:本发明提供的萘酰肼类化合物的药物应用,该化合物结构简单,具有较强的体外抗微生物活性,尤其是对金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌、枯草杆菌、藤黄微球菌等革兰阳性菌、大肠杆菌、变形杆菌、铜绿假单胞菌、伤寒沙门菌等革兰阴性菌、以及产朊假丝酵母菌、黄曲霉菌、啤酒酵母菌、白色念珠菌、假丝酵母菌等真菌都表现出很高的抑制活性,能够用于制备抗细菌和/或抗真菌药物,从而为临床抗微生物治疗提供更多高效、安全的候选药物,有助于解决日趋严重的耐药性、顽固的致病性微生物以及新出现的有害微生物等临床治疗问题。
具体实施方式
下面将对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。此外,下面所描述的本发明不同实施方式中所涉及的技术特征只要彼此之间未构成冲突就可以相互结合。
本实施例所述的萘酰肼类化合物,具有式I所示的结构:
R表示氟。
实施例1
萘酰胺化合物I-1的制备,反应式如下所示:
具体步骤如下:向100mL圆底烧瓶中加入1.201g的6-溴-2-(2-氟苄胺基)-1H-苯并异喹-1,3(2H)-二酮II-1、氢氧化钠0.144g和N,N-二甲基甲酰胺40mL,控温80℃进行反应,薄层色谱跟踪至反应结束,冷却至室温(18~25℃),减压蒸馏除去N,N-二甲基甲酰胺,残留物用体积比为2:1的二氯甲烷与石油醚的混合液作为洗脱剂进行硅胶柱层析纯化,干燥,即得0.674g黄色固体状的萘酰胺化合物I-1。
本实施例收率为52%;熔点138-140℃;1H NMR(400MHz,CDCl3)δppm:5.27(s,2H,CH2),7.21-7.05(m,4H,2-FPh-3,4,5,6-H),
7.39-7.33(m,2H,naphthalene-7,8-H),7.59-7.50(m,2H,naphthalene-2,3-H),7.88(d,H,J=4.0Hz,naphthalene-4-H),10.54(s,H,CHO)。
其中,原料6-溴-2-(2-氟苄胺基)-1H-苯并异喹-1,3(2H)-二酮II-1是参照文献方法(Lv J.S.;Peng X.M.;Kishore B.;Zhou C.H.1,2,3-Triazole-derivednaphthalimides as a novel type of potential antimicrobial agents:Synthesis,antimicrobial activity,interaction with calf thymus DNA and human serumalbumin.Bioorganic&Medicinal Chemistry Letters,2014,24:308-313),由2-氨基-6-溴-1H-苯并异喹啉-1,3(2H)-二酮和2-氟苄氯发生N-烷基化反应制得。
实施例2
萘酰胺化合物I-2,反应式如下:
具体步骤如下:
向100mL圆底烧瓶中加入1.195g的6-溴-2-(4-氟苄胺基)-1H-苯并异喹-1,3(2H)-二酮II-2、氢氧化钠0.154g和N,N-二甲基甲酰胺40mL,控温80℃进行反应,薄层色谱跟踪至反应结束,冷却至室温(18~25℃),减压蒸馏除去N,N-二甲基甲酰胺,残留物用体积比为2:1的二氯甲烷与石油醚的混合液作为洗脱剂进行硅胶柱层析纯化,干燥,即得0.614g黄色固体状的萘酰胺化合物I-2。
本实施例收率52%;熔点116-118℃;1H NMR(400MHz,CDCl3)δppm:5.11(s,2H,CH2),7.12-7.06(m,4H,4-FPh-2,3,5,6-H),7.43-7.40(m,2H,naphthalene-7,8-H),7.61-7.57(m,2H,naphthalene-2,3-H),7.86(d,H,J=4.0Hz,naphthalene-4-H),9.90(s,H,CHO)。
实施例3
采用符合1993年美国国家委员会制定的临床实验标准(National Committee forClinical Laboratory Standards,NCCLS)的96孔微量稀释法,对实施例1-2制得的萘酰肼化合物进行体外抗微生物活性测试,检测这些化合物对金黄色葡萄球菌、MASR、藤黄微球菌、枯草杆菌、大肠杆菌、铜绿假单胞菌、变形杆菌、产朊假丝酵母菌、黄曲霉菌、啤酒酵母菌、白色念珠菌和假丝酵母菌的最低抑菌浓度(MIC)。
具体测试方法为:将待测化合物用少量二甲亚砜溶解,再加水稀释制成浓度为1.28mg/mL的溶液,再用培养液稀释至1024μg/mL,35℃培养24-72小时,将培养板置于振荡器上充分搅匀后,在波长490nm处测定MIC值,结果见表1和表2。
表1萘酰肼化合物I-1、I-2的抗细菌活性(MIC,μg/mL)
化合物 | 金黄色葡萄球菌 | MASR | 藤黄微球菌 | 枯草杆菌 | 大肠杆菌 | 铜绿假单胞菌 | 变形杆菌 |
I-1 | 8 | 16 | 4 | 16 | 16 | 16 | 8 |
I-2 | 16 | 32 | 8 | 16 | 32 | 32 | 16 |
氯霉素 | 16 | 32 | 8 | 32 | 32 | 32 | 32 |
诺氟沙星 | 1 | 8 | 2 | 4 | 2 | 2 | 4 |
表2萘酰肼化合物I-1、I-2的抗真菌活性(MIC,μg/mL)
化合物 | 产朊假丝酵母菌 | 黄曲霉菌 | 啤酒酵母 | 白色念珠菌 | 假丝酵母菌 |
I-1 | 4 | 16 | 8 | 4 | 4 |
I-2 | 8 | 64 | 8 | 8 | 8 |
氟康唑 | 8 | 256 | 16 | 4 | 8 |
从表1可以看出,萘酰肼化合物对所测试细菌均表现出中等的抑制作用,表2示出了萘酰肼化合物对待测真菌均表现出一定的抑制作用,由此说明本发明所述的萘酰肼化合物具有较强的抗微生物活性,能够用于制备抗细菌和/或抗真菌药物。
实施例4
片剂的制备
处方:萘酰肼化合物I-1 100g,淀粉40g,微晶纤维素80g,硬脂酸镁3.0g,羟丙基甲基纤维素E-30(质量分数为40%的溶液)适量,共制成4000片。
制法:配制质量分数为4%的羟丙基甲基纤维素E-30溶液,备用;称取淀粉20g,105℃干燥5小时,得干淀粉,备用;称取淀粉20g和处方量的萘酰肼化合物I-1、微晶纤维素,混匀,粉碎过80目筛,用质量分数为4%的羟丙基甲基纤维素E-30溶液制软材,20目筛制粒,50-60℃干燥至水份约3%,过20目筛整粒,在干颗粒中加入干淀粉20g和处方量的硬脂酸镁,混匀,压片,即得。
用法和用量:根据患者的病情及个体差异,建议每天服用量为3-6片,相当于0.075-0.15g萘酰肼化合物I-1/60kg体重/天,分3次于饭后服用,服用时饮一满杯水;或遵医嘱。
实施6
胶囊剂的制备
处方:萘酰肼化合物I-2 100g,改性淀粉(120目)50g,微晶纤维素(100目)30g,低取代羟丙纤维素(100目)10g,滑石粉(100目)10g,甜味剂5g,橘子香精1g,色素适量,水适量,制成4000粒。
制法:将处方量的萘酰肼化合物I-2微粉化粉碎成极细粉末后,与处方量的改性淀粉、微晶纤维素、低取代羟丙纤维素、滑石粉、甜味剂、橘子香精和色素混匀,用水制软材,12-14目筛制粒,40-50℃干燥,过筛整粒,装入空胶囊,即得。
用法和用量:根据患者的病情及个体差异,建议每天服用量为3~6粒,相当于0.075-0.15g萘酰肼化合物I-2/60kg体重/天,分3次于饭后服用,服用时饮一满杯水;或遵医嘱。
实施例7
气雾剂的制备
处方:萘酰肼化合物I-1 2.5g,Span20 3g,滑石粉(100目)4g,三氯一氟甲烷加至适量。
制法:将萘酰肼化合物I-1、Span20和滑石粉分别置真空干燥箱内干燥数小时,置干燥器内冷却至室温,用气流粉碎机粉碎成微粉,再按处方量混匀,灌入密闭容器内,加入三氯一氟甲烷至规定量。
用法和用量:根据患者的病情及个体差异,建议每天使用3-4次。
实施例8
软膏的制备
处方:萘酰肼化合物I-2 2g,硬脂酸12g,凡士林3g,单甘油酯3g,尼泊金乙酯0.5g,蒸馏水60mL,硼砂1g,氢氧化钾0.5g,山梨酸钾0.3g,甘油0.5g,液体石蜡0.5g,共制成85g。
制法:取处方量的硬脂酸、凡士林、单甘脂和尼泊金乙酯,加热融化,过100目筛,保温80℃,作为油相,备用;取处方量的蒸馏水、硼砂、氢氧化钾、山梨酸钾、甘油和液体石蜡,加热煮沸,作为水相;将水相降温至85℃,在不断搅拌下加入油相,乳化后,再加入处方量的萘酰肼化合物I-2,冷却搅拌,即得。
用法和用量:涂于患处,反复摩擦至皮肤发热,每日2次。
显然,上述实施例仅仅是为清楚地说明所作的举例,而并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (4)
2.根据权利要求1所述萘酰肼类化合物在制备抗微生物药物中的用途,其特征在于:R为2-氟、3-氟或4-氟。
3.根据权利要求1所述萘酰肼类化合物在制备抗微生物药物中的用途,其特征在于:R为2-氟或3-氟。
4.根据权利要求1所述萘酰肼类化合物在制备抗微生物药物中的用途,其特征在于:所述药物为片剂、胶囊剂、气雾剂、软膏剂中的任一种。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711419356.9A CN108078969B (zh) | 2017-12-25 | 2017-12-25 | 萘酰肼类化合物在制备抗微生物药物中的用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711419356.9A CN108078969B (zh) | 2017-12-25 | 2017-12-25 | 萘酰肼类化合物在制备抗微生物药物中的用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108078969A CN108078969A (zh) | 2018-05-29 |
CN108078969B true CN108078969B (zh) | 2020-06-30 |
Family
ID=62178015
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201711419356.9A Expired - Fee Related CN108078969B (zh) | 2017-12-25 | 2017-12-25 | 萘酰肼类化合物在制备抗微生物药物中的用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108078969B (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109758457A (zh) * | 2019-01-30 | 2019-05-17 | 临沂大学 | 磺胺双苯并咪唑类化合物及其可药用盐在制备抗微生物药物中的应用 |
CN110862374B (zh) * | 2019-12-03 | 2022-11-08 | 临沂大学 | 一种萘酰亚胺苯并咪唑类化合物及其制备方法与应用 |
CN111087388A (zh) * | 2019-12-27 | 2020-05-01 | 西南大学 | 腙基桥连的萘酰亚胺咪唑类化合物及其制备方法和应用 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101489542A (zh) * | 2006-03-09 | 2009-07-22 | 塞尼科斯生物科学股份有限公司 | 清道夫受体类蛋白抑制剂在治疗传染性疾病中的应用 |
WO2009114921A1 (en) * | 2008-03-17 | 2009-09-24 | Dmitrienko Gary I | INHIBITORS OF CLASS B AND CLASS D β-LACTAMASES |
CN103113300A (zh) * | 2013-03-06 | 2013-05-22 | 广西中医药大学 | 一种具有抗肿瘤活性的化合物的制备方法和用途 |
CN103917519A (zh) * | 2011-09-08 | 2014-07-09 | 英特瑞克斯顿股份有限公司 | 结晶状二酰基肼及其用途 |
EP2349983B1 (de) * | 2008-11-26 | 2016-09-14 | Merck Patent GmbH | Difluorphenyl-diacylhydrazid-derivate |
CN108033897A (zh) * | 2017-12-25 | 2018-05-15 | 临沂大学 | 一种萘酰肼类化合物及其制备方法 |
-
2017
- 2017-12-25 CN CN201711419356.9A patent/CN108078969B/zh not_active Expired - Fee Related
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101489542A (zh) * | 2006-03-09 | 2009-07-22 | 塞尼科斯生物科学股份有限公司 | 清道夫受体类蛋白抑制剂在治疗传染性疾病中的应用 |
WO2009114921A1 (en) * | 2008-03-17 | 2009-09-24 | Dmitrienko Gary I | INHIBITORS OF CLASS B AND CLASS D β-LACTAMASES |
EP2349983B1 (de) * | 2008-11-26 | 2016-09-14 | Merck Patent GmbH | Difluorphenyl-diacylhydrazid-derivate |
CN103917519A (zh) * | 2011-09-08 | 2014-07-09 | 英特瑞克斯顿股份有限公司 | 结晶状二酰基肼及其用途 |
CN103113300A (zh) * | 2013-03-06 | 2013-05-22 | 广西中医药大学 | 一种具有抗肿瘤活性的化合物的制备方法和用途 |
CN108033897A (zh) * | 2017-12-25 | 2018-05-15 | 临沂大学 | 一种萘酰肼类化合物及其制备方法 |
Non-Patent Citations (4)
Title |
---|
Hydrazide–hydrazones as potential antimicrobial agents:overview of the literature since 2010;Lukasz Popiolek;《Med Chem Res》;20161125;第287-301页 * |
Hydrazones of 2-aryl-quinoline-4-carboxylic acid hydrazides:Synthesis and preliminary evaluation as antimicrobial agents;Kamel A. Metwally et al.;《Bioorganic & Medicinal Chemistry》;20060901;第8675-8682页 * |
新型磺胺1,2,4-三唑类化合物的设计合成、抗微生物活性及与小牛胸腺DNA 相互作用研究;刘庆龙等;《有机化学》;20170919;第3146-3154页 * |
萘酰肼类化合物的合成设计及其抑制克鲁斯氏锥体虫半胱氨酸蛋白酶的活性;程卯生等;《中国药物化学杂志》;20020831;第12卷(第4期);第187-193页 * |
Also Published As
Publication number | Publication date |
---|---|
CN108078969A (zh) | 2018-05-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108078969B (zh) | 萘酰肼类化合物在制备抗微生物药物中的用途 | |
WO2016145911A1 (zh) | 烟酰胺单核苷酸在制备抗衰老药物或保健品的应用 | |
JPH03505448A (ja) | 遅延放出性製剤 | |
CN101732417B (zh) | 博落回总生物碱离子对混合物的制备方法和用途 | |
CN101849901A (zh) | 一种零级释放棒的控释制剂制备技术及其制剂 | |
CN101890114A (zh) | 一种有抑菌、抗炎和止血作用的黎药提取物及组合物和其制备方法 | |
CN101597272B (zh) | 艾拉莫德的钾盐化合物,其制备方法和药物应用 | |
CN108033897B (zh) | 一种萘酰肼类化合物及其制备方法 | |
CN108640962B (zh) | 化合物三七皂苷st-4的制备方法及应用 | |
CN110862374B (zh) | 一种萘酰亚胺苯并咪唑类化合物及其制备方法与应用 | |
US20050202080A1 (en) | In process conversion method for preparing tannate tablet, capsule or other solid dosage forms | |
CN101602786B (zh) | N6-取代腺苷衍生物、其制法以及药物组合物与用途 | |
CN111875553B (zh) | 一种大黄素唑醇类化合物及其应用 | |
NZ190925A (en) | 3beta-hydroxy-5-ene(or 3beta-hydroxy-5alpha))-spiroketal steroid-3-mono-and-3-disaccharides in antiinflammatory compositions | |
EP2570121B1 (en) | Slow release tablet of elemene anti-tumor plant medicine | |
CN101804054A (zh) | 合成巴马汀的用途、制剂及制备 | |
CN110396090B (zh) | 咪唑醇类四氢黄连肟缀合物及其制备方法和应用 | |
CN104497077B (zh) | 色原酮苷类化合物的提取分离方法及在制备镇痛消炎药物中的应用 | |
CN109422787A (zh) | 苯并卓酚酮类似物及其制备方法与用途 | |
CN102351881B (zh) | 一种稳定的盐酸左氧氟沙星化合物 | |
CN105287522A (zh) | 双苯并咪唑胺类化合物在制备抗微生物药物中的用途 | |
CN105030804B (zh) | 蟾毒灵-3β-N-甲氧基-N-β-D-葡萄糖苷在制备强心药物中的应用 | |
CN110872273A (zh) | 萘酰亚胺苯并咪唑类化合物及其应用 | |
TW401415B (en) | Enantiomerically pure (+)-liarozole | |
CN108570005A (zh) | 地喹氯铵新化合物及其组合物和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200630 |