CN104557743A - Candida albicans-resistant medicines with unsaturated fatty acid structure and preparation method of candida albicans-resistant medicines - Google Patents
Candida albicans-resistant medicines with unsaturated fatty acid structure and preparation method of candida albicans-resistant medicines Download PDFInfo
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- CN104557743A CN104557743A CN201410718613.9A CN201410718613A CN104557743A CN 104557743 A CN104557743 A CN 104557743A CN 201410718613 A CN201410718613 A CN 201410718613A CN 104557743 A CN104557743 A CN 104557743A
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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Abstract
The invention discloses a method for rapidly preparing and screening candida albicans-resistant medicines with an unsaturated fatty acid structure. A structure of an analogue or a derivative of a class of the candida albicans-resistant medicines is represented by a formula (II), wherein R1 represents one of linear alkyl, terminal hydroxyl or sulfydryl-substituted alkyl, oligomeric polyethylene glycol or 1,4-alkyl piperazine; R2 represents one of hydroxyl, amino and methoxyl; and the characters of the medicines are screened by virtue of a bactericidal experiment. The invention discloses a preparation method and a screening method of synthesized medicines. According to the preparation method and the screening method, the development cost of a new medicine can be lowered, and the detection efficiency of the new medicine can be effectively improved.
Description
Technical field
The invention belongs to medicinal design and drug screening field, be specifically related to a class anti-candida albicans pharmaceutical formulating art.
Background technology
Candida albicans (Candida albicans) is the common opportunistic fungus of a kind of mankind, is also one of the main pathogenic fungi of clinical Acquired Infection.Under normal conditions, it is present in the skin of human body, oral cavity, gi tract and mucomembranous surface with the form of fungal component.When human immune system is normal, Candida albicans, as fungal component, keeps balancing with other microorganism species in body, and disease can not be caused to infect.But when immunological competence declines or antibacterials excessively use time, it just may increase rapidly at mucomembranous surface, and causes moniliosis (Candidiasis).Modal is clinically oral candidiasis and monilial vaginitis.In addition, candidiasis also enters endotheliocyte by tissue injury, or forms microbial film field planting indwelling medical devices business, as various conduit, artificial joint, artificial tooth etc., and enters blood thus, causes serious candidemia.
Along with a large amount of uses of clinical antibiotics, cancer therapy drug and immunosuppressor, present oidiomycotic sickness rate presents significantly ascendant trend, day by day increase the threat of human body, especially concerning patient with severe symptoms and bone marrow transplantation receptor, monilial infection probably has life threat.Therefore, oidiomycotic effective treatment is seemed particularly urgent.In more than ten years in the past, the development development of antifungal drug, various medicine sequential use, in clinical, achieves good effect, as the application of the antifungal drugs such as amphotericin B, has saved the life of countless mycosis patient.But simultaneously also create serious problems, life-time service can the mortality problem that strengthens of producing bacterial strain resistance.Therefore, find natural, low toxicity, there is the new antifungal drug that overcomes clinical drug-resistant and propose new control strategy and seem especially urgent and important efficiently, especially.
Triazole antifungal medicine is the class synthesis type antifungal drug that developed recently gets up, its mechanism of action is the Cytochrome P450 by suppressing catalysis lanosterol 14 α-demethyl to generate ergosterol, ergosterol is lacked, thus makes membrane structure and defunctionalization and destruction.In recent years, the researchdevelopment of such medicine is very fast, develop into triazole class medicine by early stage miconazole class medicine such as KETOKONAZOL, econazole etc., as itraconazole, fluconazole etc., but there is long-term taking tolerance and suitable toxic side effect etc. in part triazole class medicine.
In recent years, some natural small molecule compounds having regulation and control or suppress Candida albicans Morphological Transitions activity, receive much concern because being expected to become potential novel antifungal drugs.Oh etc. report morphology control material (ARS)---the method acid of a kind of Candida albicans secretion in calendar year 2001, and this material does not affect the Growth and reproduction of Candida albicans, but can regulate and control candidiasis Morphological Transitions and suppress mycelial growth.A kind of chemical signal molecule of Candida albicans population effect---farnesol also effectively can suppress the growth of Candida albicans mycelia.In addition, from a kind of colony induction signaling molecule---the 3-oxo-dodecanoyl base homoserine cyclic lactone that Pseudomonas aeruginosa produces, the Morphological Transitions of Candida albicans can be disturbed in higher concentrations.Recent years, signaling molecule---the α that successively discovery two kinds is new from Xanthomonas campestris and onion Burkholderia, β-cis unsaturated fatty acid is along 11-methyl 12 carbon-2-olefin(e) acid (DSF) with along 12 carbon-2-olefin(e) acids (BDSF), can regulate and control and suppress the activity of Candida albicans Morphological Transitions, reduce its pathogenicity rate.Although people also understand very few to these micromolecular mechanisms of action at present, the ability of its regulation and control Candida albicans Morphological Transitions, treats fungi infestation to us and brings new enlightenment.Therefore, according to the constructional feature of this type of micromolecular compound and triazole class medicine, a series of analogue of design and synthesis, studies it and seems particularly important to the inhibit activities of Candida albicans.
But the synthesis of DSF class medicine at least needs three steps (as III), and selected raw fatty acid needs industrial production to obtain, and lithium methide is expensive, bromide reagent bromine toxicity is comparatively large, and environmental pollution is serious, and not only cost is high, and complex operation.Selected by the present invention, synthetic method route essence is short, simple to operate, and raw material choose copper sulfate etc. are cheap and easy to get, greatly reduce the cost of development of new drug.
Summary of the invention
Technical problem: the object of the invention is to design and synthesis and go out the new medicine of a class, provide its preparation process, and form one drug screening method fast.
Technical scheme a: class of the present invention comprises the anti-candida albicans medicine of unsaturated fatty acids structure, its structure can be represented by formula (II):
Wherein, R
1represent any one in alkyl, oligomeric ethylene glycol or Isosorbide-5-Nitrae-alkylpiperazine that straight chained alkyl, terminal hydroxyl or sulfydryl replace, R
2any one in hydroxyl, amino, methoxyl group.
Unsaturated fatty acids (ester, acid amides) in formula (II) structure can play antibacterial effect in vivo; Imidazole ring is an effective antibacterial pharmacophore.
Preparation method comprises following synthesis step:
Step I. under nitrogen protection, halides R
1x, catalyzer and sodium azide be 20 ~ 100 DEG C of confined reaction 12 ~ 24h in organic solvent, obtain such as formula the triazo-compound R shown in (I)
1n
3;
Sodium ascorbate is dissolved in solvent by step I i., adds the aqueous solution of hydrated cupric ion salt successively, propioloyl R
2compound and triazo-compound R
1n
3, room temperature confined reaction 5 ~ 10h under nitrogen protection, separating-purifying must such as formula the target compound shown in (II).
R described in step I
1one in alkyl, oligomeric ethylene glycol or Isosorbide-5-Nitrae-alkylpiperazine that representative is straight chained alkyl, terminal hydroxyl or sulfydryl replaces; What described X represented is Cl, Br, I or trifyl, and described catalyzer is potassiumiodide, and described organic solvent is tetrahydrofuran (THF), DMF, the one in methyl-sulphoxide; Hydrated cupric ion salt described in step I i is Salzburg vitriol or Copper dichloride dihydrate; Described R
2for hydroxyl, amino, the one in methoxyl group; Described solvent is the mixture of methyl alcohol, ethanol or the trimethyl carbinol and water volume ratio 1:1 or 2:1.
Beneficial effect
1, medicines structure proposed by the invention both contained disinfection structure, also contains bacteriostatic structure, had certain effect to the treatment of Candida albicans.
2, pharmaceutical synthesis route proposed by the invention is short, cheaper starting materials is easy to get, and can greatly reduce the cost of development of new drug.
3, the inventive method route essence is short, simple to operate, has synthesized the different antifungal drug analogue of a series of structure or derivative, has carried out medicinal property screening by bacteriostatic experiment, defined a kind of method of rapid screening antifungal drug.
Accompanying drawing explanation
Fig. 1. Candida albicans (C.albicans) mycelial growth situation (contrast, mycelia state, shows that Candida albicans is in active state);
Candida albicans (C.albicans) mycelial growth situation (yeast state shows that Candida albicans is in group's silent status) under Fig. 2 .30 μM of antifungal drug effect;
Candida albicans (C.albicans) mycelial growth situation (yeast state shows that Candida albicans is in group's silent status) under Fig. 3 .300 μM of antifungal drug effect.
Fig. 4. Candida albicans (C.albicans) 0-24h growth curve under 100 μMs of antifungal drug effects.
Embodiment
In order to understand content of the present invention better, further illustrate technical scheme of the present invention below by concrete example.But these embodiments do not limit the present invention.
Embodiment 1:
Step 1., in two mouthfuls of round-bottomed flasks (100mL), adds sodiumazide (0.975g, 15mmol), potassiumiodide (0.083g, 0.5mmol), and nitrogen protection adds methyl-sulphoxide 15mL, nitrogen protection, stirs at 50 DEG C.Then, bromooctane (1.92g, 10mmol) is joined in reaction system.After dropwising, continue 50 DEG C and stir 10h.With frozen water cancellation reaction, petroleum ether extraction, organic phase washed with water, saturated nacl aqueous solution wash, anhydrous sodium sulfate drying, concentrated, obtain azide octane 1.3g, productive rate 87%.
Step 2. adds sodium ascorbate (0.17g, 0.85mmol), nitrogen protection in two mouthfuls of round-bottomed flasks (100mL).Then ethanol 3mL is added.Drum nitrogen, then adds the aqueous solution 3mL of copper sulfate (0.1g, 4mmol), instills propynoic acid (0.73g, 10mmol) afterwards and azide octane (1.35g, 8.7mmol) reacts 5h.Add frozen water and extract reaction of going out.Use dilute hydrochloric acid acidifying, extraction into ethyl acetate, concentrated, silica gel chromatography column separating purification.Obtain 1.27g product (1), productive rate 65%.
1HNMR(400MHz,DMSO)δ(ppm):11.0(s,1H),8.67(s,1H),4.37(t,J＝7.1Hz,2H),1.90–1.73(m,2H),1.34–1.10(m,10H),0.83(t,J＝6.9Hz,3H).
Example 2-example 6, method is with example 1, and specific experiment consumption is as following table:
Step 1
| R 1 | R 1Br(g,mmol) | NaN 3(g,mmol) | KI(g,mmol) | DMSO(mL) | R 1N 3(g) | Productive rate (%) | |
| 2 | C 6H 13 | 1.64,10 | 0.975,15 | 0.083,0.5 | 15 | 0.9 | 70 |
| 3 | C 6H 12OH | 1.80,10 | 0.975,15 | 0.083,0.5 | 15 | 0.9 | 63 |
| 4 | C 12H 25 | 2.50,10 | 0.975,15 | 0.083,0.5 | 15 | 1.4 | 70 |
| 5 | C 8H 17 | 1.92,10 | 0.975,15 | 0.083,0.5 | 15 | 1.4 | 90 |
| 6 | C 8H 17 | 1.92,10 | 0.975,15 | 0.083,0.5 | 15 | 1.3 | 84 |
Step 2
Characterization data
Product 2:
1H NMR(400MHz,DMSO)δ(ppm):11.0(s,1H),8.68(s,1H),4.45–4.31(m,2H),1.87–1.73(m,2H),1.22(pd,J＝8.0,5.0Hz,6H),0.82(t,J＝7.0Hz,3H).
Product 3:
1H NMR(400MHz,DMSO)δ(ppm):11.2(s,1H),8.27(s,1H),4.34(t,J＝14.1,7.2Hz,2H),1.80(m,J＝31.2,23.7Hz,2H),1.43(m,J＝45.5,6.9Hz,1H),1.21(d,J＝8.8Hz,13H),0.82(m,J＝ 8.0,5.6Hz,3H).
Product 4:
1H NMR(400MHz,DMSO)δ(ppm):11.3(s,1H),8.27(s,1H),4.34(t,J＝14.1,7.1Hz,2H),1.76(m,J＝14.4,7.1Hz,2H),1.21(d,J＝6.3Hz,18H),0.82(t,J＝6.7Hz,3H).
Product 5:
1H NMR(400MHz,DMSO)δ(ppm):8.67(s,1H),4.37(t,J＝7.1Hz,2H),4.26(m,2H),1.90–1.73(m,2H),1.34–1.10(m,10H),1.09(t,3H)0.83(t,J＝6.9Hz,3H).
Product 6:
1H NMR(400MHz,DMSO)δ(ppm):8.79(s,2H)8.67(s,1H),4.37(t,J＝7.1Hz,2H),1.90–1.73(m,2H),1.34–1.10(m,10H),0.83(t,J＝6.9Hz,3H).
Claims (4)
1. a class comprises the anti-candida albicans medicine of unsaturated fatty acids structure, it is characterized in that such medicine is the compound of following formula (II):
Wherein, wherein, R
1represent any one in alkyl, oligomeric ethylene glycol or Isosorbide-5-Nitrae-alkylpiperazine that straight chained alkyl, terminal hydroxyl or sulfydryl replace, R
2any one in hydroxyl, amino, methoxyl group.
2. the preparation method comprising the anti-candida albicans medicine of unsaturated fatty acids structure according to claim 1, is characterized in that, the preparation method of such medicine comprises following synthesis step:
Step I. under nitrogen protection, halides R
1x, catalyzer and sodium azide be 20 ~ 100 DEG C of confined reaction 12 ~ 24h in organic solvent, obtain such as formula the nitrine R shown in (I)
1n
3compound;
Sodium ascorbate is dissolved in solvent by step I i., adds the aqueous solution of hydrated cupric ion salt successively, propioloyl R
2compound and triazo-compound R
1n
3, room temperature confined reaction 5 ~ 10h under nitrogen protection, separating-purifying must such as formula the target compound shown in (II).
3. a class according to claim 2 comprises the preparation method of the anti-candida albicans medicine of unsaturated fatty acids structure, it is characterized in that the R described in step I
1any one in alkyl, oligomeric ethylene glycol or Isosorbide-5-Nitrae-alkylpiperazine that representative is straight chained alkyl, terminal hydroxyl or sulfydryl replaces; What described X represented is Cl, Br, I or trifyl, and described catalyzer is potassiumiodide, and described organic solvent is tetrahydrofuran (THF), DMF, the one in methyl-sulphoxide.
4. a class according to claim 2 comprises the preparation method of the anti-candida albicans medicine of unsaturated fatty acids structure, it is characterized in that the hydrated cupric ion salt described in step I i is Salzburg vitriol or Copper dichloride dihydrate; Described R
2for the one in hydroxyl, amino, methoxyl group; Described solvent is methyl alcohol or ethanol or the trimethyl carbinol, the mixture of solvent and water volume ratio 1:1 or 2:1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105193808A (en) * | 2015-10-14 | 2015-12-30 | 南京邮电大学 | Synergistic drug effect of combination of BDSF and itraconazole on clinical drug-resistant candida albicans |
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| WO2008046109A2 (en) * | 2006-10-13 | 2008-04-17 | University Of Washington | Conjugates of artemisinin-related endoperoxides and hydrazone derivatives for the treatment of cancer |
| WO2011140202A2 (en) * | 2010-05-04 | 2011-11-10 | Yale University | Mif modulators |
| CN103058942A (en) * | 2012-12-20 | 2013-04-24 | 江苏城市职业学院 | One-pot synthetic method for 1,2,3-triazole compounds |
| CN103421083A (en) * | 2012-05-16 | 2013-12-04 | 南开大学 | Anti-dengue virus heterocycle peptide compounds having 1,2,3-triazole structure, preparation method and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1839150A (en) * | 2003-07-17 | 2006-09-27 | 麦根克斯有限公司 | Compositions of lipopeptide antibiotic derivatives and methods of use thereof |
| WO2008046109A2 (en) * | 2006-10-13 | 2008-04-17 | University Of Washington | Conjugates of artemisinin-related endoperoxides and hydrazone derivatives for the treatment of cancer |
| WO2011140202A2 (en) * | 2010-05-04 | 2011-11-10 | Yale University | Mif modulators |
| CN103421083A (en) * | 2012-05-16 | 2013-12-04 | 南开大学 | Anti-dengue virus heterocycle peptide compounds having 1,2,3-triazole structure, preparation method and use thereof |
| CN103058942A (en) * | 2012-12-20 | 2013-04-24 | 江苏城市职业学院 | One-pot synthetic method for 1,2,3-triazole compounds |
Non-Patent Citations (8)
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105193808A (en) * | 2015-10-14 | 2015-12-30 | 南京邮电大学 | Synergistic drug effect of combination of BDSF and itraconazole on clinical drug-resistant candida albicans |
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Application publication date: 20150429 |