CN113968852B - Thiazole hydrazide derivative and preparation method and application thereof - Google Patents

Thiazole hydrazide derivative and preparation method and application thereof Download PDF

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CN113968852B
CN113968852B CN202010716661.XA CN202010716661A CN113968852B CN 113968852 B CN113968852 B CN 113968852B CN 202010716661 A CN202010716661 A CN 202010716661A CN 113968852 B CN113968852 B CN 113968852B
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CN113968852A (en
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倪廷峻弘
姜远英
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Tongji University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07—ORGANIC CHEMISTRY
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract

The invention provides thiazole hydrazide derivatives, a preparation method and application thereof, and belongs to the field of organic synthesis. The present invention provides a compound represented by the following formula or a pharmacologically acceptable salt thereof,wherein R is 1 Is H or methyl; r is R 2 Is any one of H, alkyl, ester group, tetrahydropyranyl, aryl ring group, substituted aryl ring group, benzyl or substituted benzyl; r is R 3 Is H or alkyl; r is R 4 Is any one of H, alkyl, cyanomethyl or phenyl. The thiazole hydrazide derivative provided by the invention has the advantages of low toxicity, wide antifungal spectrum and the like, has the advantages of simple synthesis, easy product purification and the like, and can be used for preparing novel antifungal medicines.

Description

Thiazole hydrazide derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of medical compounds, in particular to thiazole hydrazide derivatives, a preparation method and application thereof.
Background
In recent years, with the wide-spectrum application of antibiotics, antitumor drugs and immunosuppressants, the widespread progress of radiotherapy and organ transplantation, the widespread development of catheters and cannulas, and the rapid increase of immunodeficiency patients, especially aids patients, have resulted in a great rise in fungal infections, especially deep fungal infections, which have now become the main cause of death from serious diseases such as aids and tumors.
The existing antifungal drugs mainly comprise allylamine acting on squalene epoxidase, azole acting on lanosterol 14a demethylase, lipopeptides acting on cell wall b- (1, 3) -glucan synthase, and the like. However, the existing clinically applied antifungal drugs have the problems of large side effect, narrow antibacterial spectrum, easy drug resistance and the like, and the effective antifungal drugs, particularly the deep antifungal drugs, are very lacking and can not meet the treatment requirements.
Disclosure of Invention
The invention aims to solve the problems, and aims to provide thiazole hydrazide derivatives, and a preparation method and application thereof.
The invention provides thiazole hydrazide derivatives, which have the characteristics that a compound shown as a formula I or pharmaceutically acceptable salts thereof,
in the formula ,R1 Is H or methyl; r is R 2 Is any one of H, alkyl, ester group, tetrahydropyranyl, aryl, substituted aryl, phenylalkyl or substituted phenylalkyl; or R is 1 And R is R 2 Bonding to form an aromatic ring; r is R 3 Is H or alkyl; r is R 4 Is any one of H, alkyl, alkynyl, alkenyl, cyanomethyl or phenyl.
The invention provides a thiazole hydrazide derivative which is characterized in that a substituent in a substituted aryl ring group or a substituted benzyl group is any one of the following substituents: a) Halogen; b) An electron withdrawing group; c) Lower alkyl, lower alkyl is alkyl having 1 to 6 carbon atoms or halogen substituted alkyl having 1 to 6 carbon atoms; d) Lower alkoxy, lower alkoxy containing 1 to 6 carbon atoms, or halogen substituted alkoxy containing 1 to 6 carbon atoms; e) An electron donating group; f) Benzyloxy or benzyloxycarbonylamino.
The invention provides thiazole hydrazide derivatives, which have the characteristics that lower alkyl is methyl or trifluoromethyl.
The invention provides a thiazole hydrazide derivative which has the characteristics that lower alkoxy is any one of methoxy, trifluoromethoxy or difluoromethoxy.
The invention provides a thiazole hydrazide derivative which has the characteristics that the thiazole hydrazide derivative is any one of the following compounds:
the invention provides a preparation method of thiazole hydrazide derivatives, which is used for preparing any thiazole hydrazide derivative, and has the characteristics that the reaction formula is as follows:
wherein ,R1 Is H or methyl; r is R 2 Is any one of H, alkyl, ester group, tetrahydropyranyl, aryl ring group, substituted aryl ring group, benzyl or substituted benzyl; r is R 3 Is H or alkyl; r is R 4 Is any one of H, alkyl, cyanomethyl or phenyl.
The invention provides a preparation method of thiazole hydrazide derivatives, which has the following characteristics: wherein,the preparation method of (2) is as follows:
the invention provides a pharmaceutical composition, which has the characteristics and contains any thiazole hydrazide derivative.
The invention provides a pharmaceutical composition which has the characteristics and also comprises a pharmaceutically acceptable carrier or auxiliary material.
The present invention provides a pharmaceutical composition having such characteristics, further comprising one or more pharmaceutically acceptable adjuvants, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweeteners, flavoring agents, coloring agents, or any combination of the foregoing.
The present invention provides pharmaceutical compositions that can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to a subject by employing procedures well known in the art.
The invention provides application of thiazole hydrazide derivatives in preparing antifungal medicines, which have the characteristics, and the antifungal medicines are used for preventing or treating fungal infection diseases.
The invention provides application of thiazole hydrazide derivatives in preparing antifungal medicines, and has the characteristics that fungi are any one of candida albicans, novel cryptococcus or aspergillus fumigatus.
Effects and effects of the invention
According to the thiazole hydrazide derivatives related to the embodiment, the hydrazide structure is creatively combined with the thiazole ring, so that a series of thiazole hydrazide derivatives are designed and synthesized, and the thiazole hydrazide derivatives have the advantages of low toxicity, wide antifungal spectrum and the like, are simple to synthesize, are easy to purify and the like, so that the thiazole hydrazide derivatives provided by the embodiment can be used for preparing novel antifungal medicines.
Detailed Description
The present invention will be described in detail with reference to the following examples, so that the technical means, the creation characteristics, the achievement of the purpose and the effect achieved by the present invention are easily understood.
Example 1 ]
Preparation of thiazole hydrazide derivative N-1
The preparation method of the thiazole hydrazide derivative N-1 is shown as follows:
step one: dissolving a compound 1 (50 mmol) and a compound 2 (50 mmol) in DMF (50 mL), reacting for 2 hours at room temperature, and adding DMF (50 mL) into a reaction system after the reaction is completed to obtain a mixed solution containing a compound 3, wherein the mixed solution containing the compound 3 is directly used in a second step without further treatment;
step two: compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 4 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-1.
Characterization data for compound N-1 are as follows:
MS(ESI)m/z:366.1[M+H]+.Purity:96％(LC-MS).
example 2 ]
Preparation of thiazole hydrazide derivative N-2
The preparation method of the thiazole hydrazide derivative N-2 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 5 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-2.
Nuclear magnetic data of compound N-2:
1 H NMR(300MHz,DMSO)δ10.55(s,1H),9.56(s,1H),7.65(d,J＝8.8Hz,2H),6.95(s,1H),6.72(d,J＝8.9Hz,2H),3.80(s,2H),2.92(s,6H).
example 3 ]
Preparation of thiazole hydrazide derivative N-3
The preparation method of the thiazole hydrazide derivative N-3 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 6 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-3.
Nuclear magnetic data of compound N-3:
1 H NMR(300MHz,DMSO)δ10.48(s,1H),9.45(s,1H),6.42(s,1H),3.88(m,2H),3.77(s,2H),3.45-3.36(m,2H),2.68(m,1H),1.87-1.72(m,2H),1.57(m,2H).
example 4 ]
Preparation of thiazole hydrazide derivative N-4
The preparation method of the thiazole hydrazide derivative N-4 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 7 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-4.
Nuclear magnetic data of compound N-4:
1 H NMR(300MHz,DMSO)δ10.46(s,1H),9.41(s,1H),6.40(s,1H),3.76(s,2H),1.83(m,1H),0.89–0.60(m,4H).
example 5 ]
Preparation of thiazole hydrazide derivative N-5
The preparation method of the thiazole hydrazide derivative N-5 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 8 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-5.
Nuclear magnetic data of compound N-5:
1 H NMR(300MHz,DMSO)δ10.46(s,1H),9.43(s,1H),6.36(s,1H),3.76(s,2H),1.20(s,9H).
example 6 ]
Preparation of thiazole hydrazide derivative N-6
The preparation method of the thiazole hydrazide derivative N-6 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 9 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-6.
Nuclear magnetic data of compound N-6:
1 H NMR(300MHz,DMSO)δ10.64(s,1H),9.81(s,1H),7.73(s,1H),4.23(q,J＝7.1Hz,2H),3.82(s,2H),1.27(t,J＝7.1Hz,3H).
example 7 ]
Preparation of thiazole hydrazide derivative N-7
The preparation method of the thiazole hydrazide derivative N-7 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 10 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-7.
Nuclear magnetic data of compound N-7:
1 H NMR(300MHz,DMSO)δ10.49(s,1H),9.45(s,1H),7.32–7.06(m,5H),6.41(s,1H),3.78(s,2H),2.94–2.69(m,4H).
example 8 ]
Preparation of thiazole hydrazide derivative N-8
The preparation method of the thiazole hydrazide derivative N-8 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 11 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-8.
Nuclear magnetic data of N-8:
1 H NMR(300MHz,DMSO)δ10.62(s,1H),9.72(s,1H),8.56(d,J＝4.6Hz,1H),7.92–7.77(m,2H),7.50(s,1H),7.36–7.22(m,1H),3.83(s,2H).
example 9 ]
Preparation of thiazole hydrazide derivative N-9
The preparation method of the thiazole hydrazide derivative N-9 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 12 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-9.
Nuclear magnetic data of compound N-9:
1 H NMR(300MHz,DMSO)δ10.47(s,1H),9.43(s,1H),6.36(s,1H),3.76(s,2H),2.77(m,1H),1.16(d,J＝6.8Hz,6H).
example 10 ]
Preparation of thiazole hydrazide derivative N-10
The preparation method of the thiazole hydrazide derivative N-10 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 13 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-10.
Nuclear magnetic data of compound N-10:
1 H NMR(300MHz,DMSO)δ10.64(s,1H),9.80(s,1H),8.58(dd,J＝4.6,1.4Hz,2H),7.76(dd,J＝4.5,1.6Hz,2H),7.67(s,1H),3.83(s,2H).
example 11 ]
Preparation of thiazole hydrazide derivative N-11
The preparation method of the thiazole hydrazide derivative N-11 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 14 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-11.
Nuclear magnetic data of compound N-11:
1 H NMR(300MHz,DMSO)δ10.63(s,1H),9.77(s,1H),9.04(d,J＝1.7Hz,1H),8.49(dd,J＝4.7,1.5Hz,1H),8.16(dt,J＝7.9,1.9Hz,1H),7.52–7.35(m,2H),3.83(s,2H).
example 12 ]
Preparation of thiazole hydrazide derivative N-12
The preparation method of the thiazole hydrazide derivative N-12 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 15 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-12.
Nuclear magnetic data of compound N-12:
1 H NMR(300MHz,DMSO)δ10.58(s,1H),9.86(s,1H),9.63(s,1H),7.74(d,J＝8.7Hz,2H),7.58–7.29(m,7H),7.14(s,1H),5.16(s,2H),3.81(s,2H).
example 13 ]
Preparation of thiazole hydrazide derivative N-13
The preparation method of the thiazole hydrazide derivative N-13 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 16 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-13.
Nuclear magnetic data of compound N-13:
1 H NMR(300MHz,DMSO)δ10.63(s,1H),9.75(s,1H),8.05(d,J＝2.0Hz,1H),7.81(dd,J＝8.4,2.0Hz,1H),7.68-7.63(m,1H),7.51(s,1H),3.83(s,2H).
example 14 ]
Preparation of thiazole hydrazide derivative N-14
The preparation method of the thiazole hydrazide derivative N-14 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 17 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-14.
Nuclear magnetic data of compound N-14:
1 H NMR(300MHz,DMSO)δ10.60(s,1H),9.70(s,1H),7.75(d,J＝8.4Hz,2H),7.63(d,J＝8.4Hz,2H),7.36(s,1H),3.82(s,2H).
example 15 ]
Preparation of thiazole hydrazide derivative N-15
The preparation method of the thiazole hydrazide derivative N-15 is shown as follows:
compound 18 (1 mmol) and compound 19 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, ethanol and water were used to recrystallize the solid once to give compound N-15.
Nuclear magnetic data of compound N-15:
1 H NMR(300MHz,DMSO)δ8.06-7.97(m,2H),7.81(dd,J＝6.2,1.9Hz,3H),7.57-7.40(m,5H),7.34(t,J＝7.3Hz,1H),5.81(s,2H).
example 16 ]
Preparation of thiazole hydrazide derivative N-16
The preparation method of the thiazole hydrazide derivative N-16 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 20 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-16.
Nuclear magnetic data of compound N-16:
1 H NMR(300MHz,DMSO)δ10.57(s,1H),9.63(s,1H),7.42-7.38(m,2H),7.19(s,1H),6.96(d,J＝8.1Hz,1H),4.16-4.10(m,4H),3.81(s,2H),2.19-1.99(m,2H).
< example 17>
Preparation of thiazole hydrazide derivative N-17
The preparation method of the thiazole hydrazide derivative N-17 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 21 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-17.
Nuclear magnetic data of compound N-17:
1 H NMR(300MHz,DMSO)δ10.62(s,1H),9.70(s,1H),7.92(d,J＝8.4Hz,2H),7.71(d,J＝8.0Hz,4H),7.50-7.45(m,3H),7.34(s,1H),3.83(s,2H).
example 18 ]
Preparation of thiazole hydrazide derivative N-18
The preparation method of the thiazole hydrazide derivative N-18 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 22 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-18.
Nuclear magnetic data of compound N-18:
1 H NMR(300MHz,DMSO)δ10.59(s,1H),9.68(s,1H),7.94-7.75(m,2H),7.27-7.19(m,3H),3.82(s,2H).
example 19 ]
Preparation of thiazole hydrazide derivative N-19
The preparation method of the thiazole hydrazide derivative N-19 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 23 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-19.
Nuclear magnetic data of compound N-19:
1 H NMR(300MHz,DMSO)δ10.61(s,1H),9.73(s,1H),8.01(td,J＝8.9,6.9Hz,1H),7.42-7.24(m,1H),7.24-7.10(m,2H),3.83(s,2H).
example 20 ]
Preparation of thiazole hydrazide derivative N-20
The preparation method of the thiazole hydrazide derivative N-20 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 24 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-20.
Nuclear magnetic data of compound N-20:
1 H NMR(300MHz,DMSO)δ10.61(s,1H),9.72(s,1H),7.87(s,1H),7.80(d,J＝7.7Hz,1H),7.51-7.24(m,3H),3.83(s,2H).
example 21 ]
Preparation of thiazole hydrazide derivative N-21
The preparation method of the thiazole hydrazide derivative N-21 is shown as follows:
compound 25 (1 mmol) and compound 26 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, ethanol and water were used to recrystallize the solid once to obtain compound N-21.
Nuclear magnetic data of compound N-21:
1 H NMR(300MHz,DMSO)δ10.20(s,1H),9.52(s,1H),8.04(d,J＝2.0Hz,1H),7.81(dd,J＝8.4,2.0Hz,1H),7.65(d,J＝8.5Hz,1H),7.45(s,1H),1.91(s,3H).
example 22 ]
Preparation of thiazole hydrazide derivative N-22
The preparation method of the thiazole hydrazide derivative N-22 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 277 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, the solid was recrystallized once from ethanol and water to give compound N-22.
Nuclear magnetic data of compound N-22:
1 H NMR(300MHz,DMSO)δ10.57(s,1H),9.62(s,1H),7.75(d,J＝8.8Hz,2H),7.11(s,1H),6.95(dd,J＝9.1,2.3Hz,2H),3.81(s,2H),3.78(s,3H).
example 23 ]
Preparation of thiazole hydrazide derivative N-23
The preparation method of the thiazole hydrazide derivative N-23 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 28 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-23.
Nuclear magnetic data of compound N-23:
1 H NMR(300MHz,DMSO)δ10.50(s,1H),9.37(s,1H),7.59-7.23(m,7H),7.05(d,J＝8.8Hz,2H),5.13(s,3H),3.78(s,2H),2.34(s,3H).
example 24 ]
Preparation of thiazole hydrazide derivative N-24
The preparation method of the thiazole hydrazide derivative N-24 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 29 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-24.
Nuclear magnetic data of compound N-24:
1 H NMR(300MHz,DMSO)δ10.65(s,1H),9.79(s,1H),8.08(d,J＝8.5Hz,2H),7.94(d,J＝8.5Hz,2H),7.59(s,1H),3.83(s,2H),3.23(s,3H).
example 25 ]
Preparation of thiazole hydrazide derivative N-25
The preparation method of the thiazole hydrazide derivative N-25 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 30 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-25.
Nuclear magnetic data of compound N-25:
1 H NMR(300MHz,DMSO)δ10.66(s,1H),9.83(s,1H),8.26(d,J＝8.9Hz,2H),8.09(d,J＝8.9Hz,2H),7.68(s,1H),3.84(s,2H).
example 26 ]
Preparation of thiazole hydrazide derivative N-26
The preparation method of the thiazole hydrazide derivative N-26 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 31 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-26.
Nuclear magnetic data of compound N-26:
1 H NMR(300MHz,DMSO)δ10.64(s,1H),9.72(s,1H),8.37(s,1H),8.05-7.85(m,4H),7.60-7.39(m,3H),3.85(s,2H).
example 27 ]
Preparation of thiazole hydrazide derivative N-27
The preparation method of the thiazole hydrazide derivative N-27 is shown as follows:
compound 32 (1 mmol) and compound 1 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, ethanol and water were used to recrystallize the solid once, to give compound N-27.
Nuclear magnetic data of compound N-27:
1 H NMR(300MHz,DMSO)δ8.03(d,J＝7.7Hz,1H),7.85(d,J＝8.0Hz,1H),7.56-7.44(m,1H),7.37(dd,J＝11.1,4.1Hz,1H),5.78(s,2H),4.45(s,2H).
example 28 ]
Preparation of thiazole hydrazide derivative N-28
The preparation method of the thiazole hydrazide derivative N-28 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 33 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-28.
Nuclear magnetic data for compound N-28:
1 H NMR(300MHz,DMSO)δ10.57(s,1H),9.61(s,1H),7.60(d,J＝3.2Hz,1H),7.39(s,1H),7.02(d,J＝9.0Hz,1H),6.85(dd,J＝8.9,3.3Hz,1H),3.84(s,3H),3.81(s,2H),3.73(s,3H).
< example 29>
Preparation of thiazole hydrazide derivative N-29
The preparation method of the thiazole hydrazide derivative N-29 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 34 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, the solid was recrystallized once from ethanol and water to give compound N-29.
Nuclear magnetic data of compound N-29:
1 H NMR(300MHz,DMSO)δ10.60(s,1H),9.70(s,1H),7.84(d,J＝8.6Hz,2H),7.45(d,J＝8.6Hz,3H),7.36(s,1H),3.82(s,2H).
example 30 ]
Preparation of thiazole hydrazide derivative N-30
The preparation method of the thiazole hydrazide derivative N-30 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 35 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-30.
Nuclear magnetic data of compound N-30:
1 H NMR(300MHz,DMSO)δ10.58(s,1H),9.63(s,1H),7.72(d,J＝8.1Hz,2H),7.21-7.18(m,3H),3.82(s,2H),2.31(s,3H).
example 31 ]
Preparation of thiazole hydrazide derivative N-31
The preparation method of the thiazole hydrazide derivative N-31 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 36 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-31.
Nuclear magnetic data of compound N-31:
1 H NMR(300MHz,DMSO)δ10.58(s,1H),9.63(s,1H),7.43-7.32(m,2H),7.17(s,1H),6.96(d,J＝9.0Hz,1H),3.84-3.75(m,8H).
< example 32>
Preparation of thiazole hydrazide derivative N-32
The preparation method of the thiazole hydrazide derivative N-32 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 37 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-32.
Nuclear magnetic data of compound N-32:
1 H NMR(300MHz,DMSO)δ10.61(s,1H),9.72(s,1H),7.88(d,J＝8.5Hz,1H),7.68(d,J＝2.2Hz,1H),7.49(dd,J＝8.5,2.2Hz,1H),7.39(s,1H),3.82(s,2H).
example 33 ]
Preparation of thiazole hydrazide derivative N-33
The preparation method of the thiazole hydrazide derivative N-33 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 38 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, the solid was recrystallized once from ethanol and water to give compound N-33.
Nuclear magnetic data of compound N-33:
1 H NMR(300MHz,DMSO)δ10.61(s,1H),9.70(s,1H),7.78(d,J＝8.6Hz,2H),7.58(d,J＝8.6Hz,2H),7.37(s,1H),3.82(s,2H).
example 34 ]
Preparation of thiazole hydrazide derivative N-34
The preparation method of the thiazole hydrazide derivative N-34 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 39 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-34.
Nuclear magnetic data for compound N-34:
1 H NMR(300MHz,DMSO)δ10.59(s,1H),9.67(s,1H),7.91-7.76(m,2H),7.51-7.20(m,4H),3.82(s,2H).
example 35 ]
Preparation of thiazole hydrazide derivative N-35
The preparation method of the thiazole hydrazide derivative N-35 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 40 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-35.
Nuclear magnetic data of compound N-35:
1 H NMR(300MHz,DMSO)δ10.64(s,1H),9.77(s,1H),8.04(d,J＝8.1Hz,2H),7.75(d,J＝8.3Hz,3H),7.54(s,1H),3.83(s,2H).
example 36 ]
Preparation of thiazole hydrazide derivative N-36
The preparation method of the thiazole hydrazide derivative N-36 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 41 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-36.
Nuclear magnetic data of compound N-36:
1 H NMR(300MHz,DMSO)δ10.63(s,1H),9.77(s,1H),7.74-7.67(m,1H),7.44-7.27(m,2H),7.27-7.11(m,1H),3.84(s,2H).
example 37 ]
Preparation of thiazole hydrazide derivative N-37
The preparation method of the thiazole hydrazide derivative N-37 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 42 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, the solid was recrystallized once from ethanol and water to give compound N-37.
Nuclear magnetic data of compound N-37:
1 H NMR(300MHz,DMSO)δ10.61(s,1H),9.75(s,1H),7.44(t,J＝4.5Hz,2H),7.12(s,1H),7.07(dd,J＝5.0,3.7Hz,1H),3.81(s,2H).
example 38 ]
Preparation of thiazole hydrazide derivative N-38
The preparation method of the thiazole hydrazide derivative N-38 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 43 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-38.
Nuclear magnetic data for compound N-38:
1 H NMR(300MHz,DMSO)δ10.64(s,1H),9.79(s,1H),8.01(d,J＝8.5Hz,2H),7.85(d,J＝8.5Hz,2H),7.60(s,1H),3.83(s,2H).
example 39 ]
Preparation of thiazole hydrazide derivative N-39
The preparation method of the thiazole hydrazide derivative N-39 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 44 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, the solid was recrystallized once from ethanol and water to give compound N-39.
Nuclear magnetic data of compound N-39:
1 H NMR(300MHz,DMSO)δ10.61(s,1H),9.72(s,1H),7.94(d,J＝8.8Hz,2H),7.40-7.38(m,3H),3.82(s,2H).
example 40 ]
Preparation of thiazole hydrazide derivative N-40
The preparation method of the thiazole hydrazide derivative N-40 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 45 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-40.
Nuclear magnetic data of compound N-40:
1 H NMR(300MHz,DMSO)δ10.55(s,1H),9.57(s,1H),9.52(s,1H),7.63(d,J＝8.6Hz,2H),7.00(s,1H),6.76(d,J＝8.6Hz,2H),3.80(s,2H).
example 41 ]
Preparation of thiazole hydrazide derivative N-41
The preparation method of the thiazole hydrazide derivative N-41 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 46 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-41.
Nuclear magnetic data of compound N-41:
1 H NMR(300MHz,DMSO)δ10.45(s,1H),9.40(s,1H),6.31(s,1H),3.76(s,2H),2.00-1.69(m,15H).
example 42 ]
Preparation of thiazole hydrazide derivative N-42
The preparation method of the thiazole hydrazide derivative N-42 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 47 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-42.
Nuclear magnetic data of compound N-42:
1 H NMR(300MHz,DMSO)δ10.68(s,1H),9.90(s,1H),7.85(d,J＝3.2Hz,1H),7.71(d,J＝3.2Hz,1H),7.45(s,1H),3.83(s,2H).
example 43 ]
Preparation of thiazole hydrazide derivative N-43
The preparation method of the thiazole hydrazide derivative N-43 is shown as follows:
compound 3 (0.5 mmol/mL of DMF solution, 2 mL) and compound 48 (1 mmol) are dissolved in DMF (2 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-43.
Nuclear magnetic data of compound N-43:
1 H NMR(300MHz,DMSO)δ12.91(s,1H),10.63(s,1H),9.75(s,1H),7.95(s,4H),7.49(s,1H),3.83(s,2H).
example 44 ]
Preparation of thiazole hydrazide derivative N-44
The preparation method of the thiazole hydrazide derivative N-44 is shown as follows:
compound 25 (1 mmol) and compound 34 (1 mmol) were dissolved in ethanol (5 mL), and the mixture was refluxed for 1 hour, and after the reaction was completed, the mixture was added to water to precipitate a solid, which was filtered and dried under vacuum to obtain product N-44.
Nuclear magnetic data of compound N-44:
1 H NMR(300MHz,DMSO)δ10.18(s,1H),9.46(s,1H),7.83(d,J＝8.6Hz,3H),7.44(d,J＝8.6Hz,2H),7.30(s,1H),1.91(s,3H).
example 45 ]
Preparation of thiazole hydrazide derivative N-45
The preparation method of the thiazole hydrazide derivative N-45 is shown as follows:
compound 49 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, ethanol and water were used to recrystallize the solid once to obtain compound N-45.
Nuclear magnetic data of compound N-45:
1 H NMR(300MHz,DMSO)δ10.98(s,1H),7.88(d,J＝8.6Hz,2H),7.46(d,J＝8.6Hz,2H),7.39(s,1H),3.85(s,2H),3.32(s,3H).
example 46 ]
Preparation of thiazole hydrazide derivative N-46
The preparation method of the thiazole hydrazide derivative N-46 is shown as follows:
compound 50 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, ethanol and water were used to recrystallize the solid once to obtain compound N-46.
Characterization data for compound N-46 are as follows:
MS(ESI)m/z:280.0[M+H]+.Purity:98％(LC-MS).
example 47 ]
Preparation of thiazole hydrazide derivative N-47
The preparation method of the thiazole hydrazide derivative N-47 is shown as follows:
compound 51 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, ethanol and water were used to recrystallize once to give compound N-47.
Characterization data for compound N-47 are as follows:
MS(ESI)m/z:282.0[M+H]+.Purity:97％(LC-MS).
example 48 ]
Preparation of thiazole hydrazide derivative N-48
The preparation method of the thiazole hydrazide derivative N-48 is shown as follows:
compound 52 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, ethanol and water were used to recrystallize once to give compound N-48.
Characterization data for compound N-48 are as follows:
MS(ESI)m/z:278.0[M+H]+.Purity:96％(LC-MS).
example 49 ]
Preparation of thiazole hydrazide derivative N-49
The preparation method of the thiazole hydrazide derivative N-49 is shown as follows:
compound 53 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, ethanol and water were used to recrystallize the solid once to obtain compound N-49.
Characterization data for compound N-49 are as follows:
MS(ESI)m/z:296.1[M+H]+.Purity:97％(LC-MS).
example 50 ]
Preparation of thiazole hydrazide derivative N-50
The preparation method of the thiazole hydrazide derivative N-50 is shown as follows:
compound 54 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, ethanol and water were used to recrystallize the solid once to obtain compound N-50.
Characterization data for compound N-50 are as follows:
MS(ESI)m/z:310.1[M+H]+.Purity:97％(LC-MS).
example 51 ]
Preparation of thiazole hydrazide derivative N-51
The preparation method of the thiazole hydrazide derivative N-51 is shown as follows:
compound 55 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, ethanol and water were used to recrystallize the solid once to obtain compound N-51.
Characterization data for compound N-51 are as follows:
MS(ESI)m/z:296.0[M+H]+.Purity:96％(LC-MS).
example 52 ]
Preparation of thiazole hydrazide derivative N-52
The preparation method of the thiazole hydrazide derivative N-52 is shown as follows:
compound 56 (1 mmol) and compound 34 (1 mmol) are dissolved in DMF (5 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-52.
Characterization data for compound N-52 are as follows:
MS(ESI)m/z:310.1[M+H]+.Purity:96％(LC-MS).
example 53 ]
Preparation of thiazole hydrazide derivative N-53
The preparation method of the thiazole hydrazide derivative N-53 is shown as follows:
compound 57 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60℃for 2 hours, after the reaction was completed, water was added to precipitate a solid, and after filtration, ethanol and water were used to recrystallize the solid once to give compound N-53.
Characterization data for compound N-53 are as follows:
MS(ESI)m/z:324.1[M+H]+.Purity:95％(LC-MS).
example 54 ]
Preparation of thiazole hydrazide derivative N-54
The preparation method of the thiazole hydrazide derivative N-54 is shown as follows:
compound 58 (1 mmol) and compound 34 (1 mmol) are dissolved in DMF (5 mL) and reacted for 2 hours at 60 ℃, after the reaction is completed, water is added to separate out solid, and the solid is filtered and recrystallized once by ethanol and water to obtain compound N-54.
Characterization data for compound N-54 are as follows:
MS(ESI)m/z:338.1[M+H]+.Purity:97％(LC-MS).
< test example >
Antifungal Activity test
Due to the limitation of experimental conditions, antifungal activity tests are carried out on part of thiazole hydrazide derivatives obtained in the examples. In this test example, antifungal activity was tested on three fungal strains, respectively: candida albicans (SC 5314), cryptococcus neoformans (Cryptococcus neoformans, H99), aspergillus fumigatus (Aspergillus fumigatus, 7544). The fungus strain used in this example was supplied from the fungal house of the Shanghai long-sign hospital or purchased from the department of medicine of the national academy of sciences,
the antifungal activity test experimental procedure were as follows:
1.1 preparation of solution:
1.1.1 preparation of bacterial suspension: the fungi were cultured in YEPD liquid medium at 35℃for 16 hours, twice activated, counted with a hemocytometer, and the concentration of the fungi was adjusted to 1X 104-1X 105/mL with RPM1640 liquid medium.
1.1.2 preparation of liquid medicine: the compound to be tested is taken and dissolved in dimethyl sulfoxide to prepare a drug storage solution with the concentration of 6.4 mg/mL.
1.2 inoculation: 96-well plate No. 1 wells plus RPM1640 100 μl as blank; the bacterial suspension is 100 mu L in each of the 3-12 holes, 200 mu L in the 2 # Kong Jiajun suspension and 2 mu L in the liquid medicine, the drug concentration in each of the 2-11 holes is diluted by 10-level times, the drug concentration in each hole is 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25 and 0.125 mu g/mL, the liquid medicine is not added in the 12 # holes, and the drug control is selected from Fluconazole (fluconazol) and Voriconazole (Voriconazole).
1.3 experimental results
The antifungal activity results are shown in Table 1.
TABLE 1 minimum in vitro antifungal concentration values for the target compounds (MIC 80, μg/mL)
/>
Note that: in the table "-" indicates that no test was performed.
As shown in Table 1, thiazole hydrazide derivatives in the table show certain antifungal activity, wherein the antifungal activity of a part of compounds is even better than that of Fluconazole (Fluconazole) which is an antifungal drug commonly used at present, and particularly has better antifungal activity against Candida albicans (SC 5314) and cryptococcus neoformans (Cryptococcus neoformans, H99).
In addition, toxicity tests are carried out on the thiazole hydrazide derivatives provided in the examples 1-54, and the results of the toxicity tests show that the thiazole hydrazide derivatives provided in the examples 1-54 are low in toxicity and have application prospects in antifungal medicines.
Effects and effects of the examples
According to the thiazole hydrazide derivatives related to the embodiment, the hydrazide structure is creatively combined with the thiazole ring, so that a series of thiazole hydrazide derivatives are designed and synthesized, and the thiazole hydrazide derivatives have the advantages of low toxicity, wide antifungal spectrum and the like, are simple to synthesize, are easy to purify and the like, so that the thiazole hydrazide derivatives provided by the embodiment can be used for preparing novel antifungal medicines.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.

Claims (6)

1. A thiazole hydrazide derivative, which is characterized by being any one of the following compounds:
2. a method for preparing thiazole hydrazide derivatives, which is used for preparing the thiazole hydrazide derivatives according to claim 1, and is characterized in that the reaction formula is as follows:
wherein ,R1 、R 2 、R 3 、R 4 Is shown as a corresponding group in the thiazole hydrazide derivative according to claim 1.
3. The method for preparing thiazole hydrazide derivatives according to claim 2, which is characterized in that:
wherein ,the preparation method of (2) is as follows:
4. a pharmaceutical composition comprising the thiazole hydrazide derivative according to claim 1.
5. The use of thiazole hydrazide derivatives as defined in claim 1 for the preparation of an antifungal drug, wherein the antifungal drug is a disease for preventing or treating fungal infection.
6. The use of thiazole hydrazide derivatives according to claim 5 for the preparation of antifungal drugs, wherein the fungus is any of candida albicans, cryptococcus neoformans or aspergillus fumigatus.
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