CN115260162A - 3-hydroxy-4-pyridone-ciprofloxacin coupling compound and preparation method and application thereof - Google Patents

3-hydroxy-4-pyridone-ciprofloxacin coupling compound and preparation method and application thereof Download PDF

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CN115260162A
CN115260162A CN202211022622.5A CN202211022622A CN115260162A CN 115260162 A CN115260162 A CN 115260162A CN 202211022622 A CN202211022622 A CN 202211022622A CN 115260162 A CN115260162 A CN 115260162A
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ciprofloxacin
hydroxy
pyridone
protecting group
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章国林
何畅
陈俊
俞永平
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Zhejiang University ZJU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • 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
    • A61P31/04—Antibacterial agents
    • 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

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a 3-hydroxy-4-pyridone-ciprofloxacin coupling compound, and a preparation method and application thereof. The invention discloses a 3-hydroxy-4-pyridone-ciprofloxacin coupling compound, which has a structural general formula I:

Description

3-hydroxy-4-pyridone-ciprofloxacin coupling compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a 3-hydroxy-4-pyridone-ciprofloxacin coupling compound, and a preparation method and application thereof.
Background
Bacterial resistance poses a serious threat to human health. As an antibacterial drug frequently used in clinical practice, the problem of bacterial drug resistance of quinolone drugs is particularly serious, and the drug resistance mechanism is generally considered as follows: target enzyme gene mutation, reduced membrane permeability, active efflux systems and plasmid-mediated drug resistance. Among them, the decrease in cell membrane permeability enhances the activity of other resistance mechanisms and can lower the final drug concentration at the target, thus being more important. The phenomenon of the bacteria producing resistance to antibiotics has given police to the medical community and the pharmaceutical industry, and in addition to the correct use of existing effective drugs, new antibacterial drugs need to be developed.
Ciprofloxacin as the fluoroquinolone medicine has broad-spectrum antibacterial activity, excellent pharmacokinetic property and fewer side effects. However, the clinical drug resistance problem to ciprofloxacin is more serious at present, such as escherichia coli, pseudomonas aeruginosa, klebsiella pneumoniae and acinetobacter baumannii, and the drug resistance rate to ciprofloxacin reaches 30% -90%. How to improve the activity of the drug-resistant bacteria and avoid the problem of drug resistance becomes a problem which needs to be researched urgently.
Iron is an important nutrient element essential to microorganisms, and the concentration of free iron ions in blood and tissues is only 10 -24 At least 10 mol/L of iron ion concentration required for bacterial growth -6 mol/L. Microorganism evolved into Fe 3+ Has very high specific affinity (binding constant up to 10) -52 M～10 -20 M) siderophore and a homeomembrane receptor protein.
Due to bacteria on siderophores and Fe 3+ The recognition and the transport of the formed complex are a specific and efficient active process, so that a siderophore and an antibiotic are combined through a connecting chain to form a conjugate, and the antibiotic is transported into a bacterial body while the bacterial actively transports the siderophore by utilizing an iron transport system of a negative bacterium, namely, the Trojan Horse (Trojan Horse), so that the method is an effective way for overcoming the drug resistance caused by the reduction of the permeability of the outer membrane of the negative bacterium and the generation of a drug efflux pump.
To this end, researchers have developed some siderophore-antibacterial conjugates. BAL30072 is a 1,3-dihydroxy-4-pyridone-monocyclic β -lactam conjugate reported by Baselia corporation, is stable to multiple β -lactamases and has good antibacterial activity against multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Cefiderocol (cefiderol) which is developed by Japan salt Yeyi company and takes catechol as siderophore has strong activity on escherichia coli, klebsiella pneumoniae and pseudomonas aeruginosa, and is approved by the United states food and drug administration to be marketed in 11 months in 2019 for treating urinary tract infection.
Figure BDA0003814633590000021
Disclosure of Invention
The invention aims to provide a 3-hydroxy-4-pyridone-ciprofloxacin coupling compound, a preparation method and application thereof, and the 3-hydroxy-4-pyridone-ciprofloxacin coupling compound can solve the drug resistance problem of ciprofloxacin.
In order to solve the technical problems, the invention provides a 3-hydroxy-4-pyridone-ciprofloxacin coupling compound, which has the following structural general formula I:
Figure BDA0003814633590000022
wherein X is
Figure BDA0003814633590000023
The improvement of the 3-hydroxy-4-pyridone-ciprofloxacin coupling compound is shown as a general formula II or a compound I-4:
general formula II:
Figure BDA0003814633590000024
compound I-4:
Figure BDA0003814633590000025
the general formula II is specifically any one of the following: compound I-1, compound I-2, compound I-3;
compound I-1
Figure BDA0003814633590000031
Compound I-2:
Figure BDA0003814633590000032
compound I-3:
Figure BDA0003814633590000033
the invention also provides a tautomer, an optical isomer or a pharmaceutically acceptable salt of the 3-hydroxy-4-pyridone-ciprofloxacin coupling compound.
The invention also provides a preparation method of the 3-hydroxy-4-pyridone-ciprofloxacin coupling compound, which comprises the following steps:
1. the preparation method of the general formula II (namely the compounds I-1, I-2 and I-3) comprises the following steps:
(1.1) carrying out reflux reaction on the compound V and the compound VI for 12 +/-1 hours by using an aprotic polar solvent as a solvent under the condition of inorganic base to obtain a compound VII;
compound V:
Figure BDA0003814633590000034
compound VI:
Figure BDA0003814633590000035
compound VII:
Figure BDA0003814633590000036
the R is 1 Is composed of
Figure BDA0003814633590000041
In the formula 3 Is a hydroxy protecting group; x is
Figure BDA0003814633590000042
The R is 2 Is a carboxyl protecting group;
(1.2) in a mixed solvent, under the catalysis of hydrogen and palladium/carbon, removing a protecting group from a compound VII to obtain a compound (i.e. a compound I-1-a compound I-3) shown in a general formula II;
2. the preparation method of the compound I-4 comprises the following steps:
(2.1) reacting the compound VIII with a condensing agent at room temperature for 12 +/-1 hours by using an aprotic polar solvent as a solvent under the condition of organic base to obtain a compound IX;
compound VIII:
Figure BDA0003814633590000043
compound IX:
Figure BDA0003814633590000044
in the above reaction formula, X is
Figure BDA0003814633590000045
R 1 Is composed of
Figure BDA0003814633590000046
R 2 Is a leaving group which is:
Figure BDA0003814633590000047
(2.2) reacting the compound IX with ciprofloxacin at room temperature for 12 +/-1 hours by using an aprotic polar solvent as a solvent under the condition of organic base to obtain a compound I-4.
As an improvement of the preparation method of the 3-hydroxy-4-pyridone-ciprofloxacin coupling compound of the invention:
R 3 is a hydroxyl protecting group, and the protecting group is benzyl or benzhydryl;
R 2 the protecting group is a carboxyl protecting group, and the protecting group is benzyl or benzhydryl.
As an improvement of the preparation method of the 3-hydroxy-4-pyridone-ciprofloxacin coupling compound of the invention:
in the step (1.1), the inorganic base is potassium carbonate, sodium carbonate or potassium hydroxide; the aprotic polar solvent is acetonitrile or dimethylformamide.
In the step (1.2): the mixed solvent can be dichloromethane/ethanol, dichloromethane/tetrahydrofuran;
in the step (2.1): the organic base is triethylamine and N, N-diisopropylethylamine; the condensing agent is N, N '-succinimide carbonate, 1,1' -carbonyldiimidazole; the aprotic polar solvent is dichloromethane or tetrahydrofuran;
in the step (2.2): the organic base can be triethylamine, N-diisopropylethylamine; the aprotic polar solvent can be dichloromethane or tetrahydrofuran.
The invention also provides the application of the 3-hydroxy-4-pyridone-ciprofloxacin coupling compound in preparing medicines for treating diseases caused by bacteria.
As an improvement of the application of the invention: the bacteria are gram negative bacteria. The method comprises the following specific steps: the bacteria are ciprofloxacin drug-resistant Acinetobacter Baumannii (ABA) and ciprofloxacin drug-resistant Klebsiella Pneumoniae (KP).
In the present invention:
the compounds (I-1), (I-2) and (I-3) of the present invention can be prepared according to the method of the reaction formula (1):
reaction formula (1)
Figure BDA0003814633590000051
In the above reaction formula (1), X is
Figure BDA0003814633590000052
R 1 Is composed of
Figure BDA0003814633590000053
Wherein R is 3 Is a hydroxyl protecting group, which may be selected, for example, from: benzyl, benzhydryl, and the like;
R 2 is a carboxyl protecting group, which may be selected, for exampleFrom: benzyl, benzhydryl, and the like;
(a) Carrying out reflux reaction on the compound V and the compound VI for 12 +/-1 hours by using an aprotic polar solvent as a solvent under the condition of inorganic base to obtain a compound VII;
the inorganic base can be potassium carbonate, sodium carbonate, potassium hydroxide; the aprotic polar solvent may be, for example, acetonitrile, dimethylformamide.
(b) And (3) removing a protecting group from the compound VII in a mixed solvent under the catalysis of hydrogen and palladium/carbon to obtain the compounds I-1-3. The mixed solvent can be dichloromethane/ethanol, dichloromethane/tetrahydrofuran;
the compound (I-4) of the present invention can be prepared according to the process of the reaction formula (2).
Reaction type (2)
Figure BDA0003814633590000061
In the above reaction formula, X is
Figure BDA0003814633590000062
R 1 Is composed of
Figure BDA0003814633590000063
R 2 As a leaving group, the leaving group may for example be selected from:
Figure BDA0003814633590000064
etc.;
(a) Reacting the compound VIII with a condensing agent at room temperature for 12 +/-1 hours by using an aprotic polar solvent as a solvent under the condition of organic base to obtain a compound IX;
the organic base can be triethylamine and N, N-diisopropylethylamine; the condensing agent can be N, N '-succinimide carbonate, 1,1' -carbonyldiimidazole; the aprotic polar solvent may be, for example, dichloromethane or tetrahydrofuran.
(b) IX and ciprofloxacin react for 12 hours at room temperature under the condition of organic base by using an aprotic polar solvent as a solvent to obtain a compound I-4;
the organic base can be triethylamine and N, N-diisopropylethylamine; the aprotic polar solvent can be dichloromethane or tetrahydrofuran.
The invention can be referred to 1,3-dihydroxy-4-pyridone-monocyclic β -lactam conjugates.
In the invention, the general formula (I) connects piperazine N of ciprofloxacin molecule with siderophore 3-hydroxy-4-pyridone, wherein 3-hydroxy-4-pyridone can be used as siderophore to be connected with Fe 3+ Forming a complex, serving as an iron donor, being recognized by a homologous receptor on a cell membrane, and then passing through an extracellular membrane in an active transportation mode, thereby overcoming the drug resistance caused by low permeability of a drug-resistant bacterial membrane and active efflux.
3-hydroxy-4-pyridone as bidentate iron carrier, p-Fe 3+ Has good selectivity and affinity; meanwhile, the 3-hydroxy-4-pyridone-iron compound has better in-vivo stability and safety. Aiming at the drug resistance problem of gram-negative bacteria, the 3-hydroxy-4-pyridone siderophore and the ciprofloxacin antibiotic are combined to form a Trojan horse coupling, so that the ciprofloxacin is actively transported into cells through an iron transportation way mediated by the bacterial siderophore, the antibacterial effect is exerted, and the drug resistance problem of the gram-negative bacteria to the ciprofloxacin is solved.
In conclusion, the invention utilizes a Trojan horse' strategy to design the coupling, namely utilizes the specific recognition of bacteria to siderophore, and connects 3-hydroxy-4-pyridone with ciprofloxacin through a connecting chain to form the siderophore-antibacterial coupling, so that gram-negative bacteria can specifically recognize siderophore and actively transport antibacterial drugs into bacteria to play an antibacterial effect, thereby overcoming the drug resistance of the negative bacteria.
Detailed Description
The present invention will be further illustrated with reference to the following examples, which are not intended to limit the scope of the invention in any way. In all of the embodiments described herein, the first, 1 H-NMR Bruker 500MHz nuclear magnetic resonance instrument of public experimental platform of Zhejiang university college of pharmacyMeasuring, wherein chemical shifts are expressed in delta (ppm), and TMS is used as an internal standard substance; the high resolution mass spectrum is measured by an Agilent1290-HPLC-6224 mass spectrometer; the melting point was determined by a melting point apparatus model Buchi B-540.
Synthesis of compound VI can be referred to in literature (j.med.chem.2013, 56, 2690-2694); ciprofloxacin and maltol (II) as raw materials were purchased from Shanghai Bide pharmaceutical science and technology Co.
Synthesis of target Compound
Example 1: preparation of 1-cyclopropyl-6-fluoro-7- (4- (2- (2- (3-hydroxy-2-methyl-4-pyridonyl) ethyl) amino) -2-carbonylethyl) piperazin-1-yl) -4-carbonyl-1,4-dihydroquinoline-3-carboxylic acid (I-1)
Figure BDA0003814633590000071
Step 1: preparation of benzylmaltol (III)
Maltol (II, 50.4g, 0.40mol) was dissolved in a mixed solvent of 80mL of ethanol and 80mL of water, and sodium hydroxide (17.6 g, 0.44mol) and benzyl chloride (46.8 g, 0.37mol) were added in this order with stirring, and reacted at 60 ℃ overnight (i.e., about 12 hours). After TLC detected that the benzyl chloride reaction was complete, the ethanol was removed by rotary evaporation, the remaining mixture was extracted twice with 80mL dichloromethane, the organic layers were combined, 50mL 5% sodium hydroxide solution, water, and saturated brine were added in order, washed with anhydrous sodium sulfate, and concentrated by rotary evaporation to give a crude product, which was recrystallized from PE and EA (1, v/v) to give brown solid III (62g, 79%).
Melting point is 55-57 ℃; HRMS (ESI) m/z theoretical value of C 13 H 13 O 3 [M+H] + 217.0865, found 217.0863.
Step 2: preparation of 1- (2-aminoethyl) -3-benzyloxy-2-methylpyridin-4-one (IV-1)
III (4.32g, 20mmol), ethylenediamine (1.26g, 218mmol) and sodium hydroxide (0.72g, 18mmol) were dissolved in a mixed solvent of 20mL of water and 20mL of ethanol, and reacted at 80 ℃ for 1.5 hours. After the reaction of TLC detected III was complete, the reaction solution was rotary evaporated to remove ethanol, extracted three times with 50mL of dichloromethane, the organic layers were combined, washed with 30mL of water and saturated brine in order, dried over anhydrous sodium sulfate, and rotary evaporated and concentrated to give a crude product which was purified by silica gel column chromatography (dichloromethane: methanol: triethylamine =10, flow rate 3 mL/min) to give a brown oil IV-1 (2.37g, 45%).
HRMS (ESI) with theoretical m/z value of C 15 H 19 N 2 O 2 [M+H] + 259.1447, found 259.1447.
And step 3: preparation of N- (2- (3- (benzyloxy) -2-methyl-4-pyridonyl) ethyl) -2-chloroacetamide (V-1)
IV-1 (738.7mg, 2.86mmol) and triethylamine (347.1mg, 3.43mmol) are dissolved in 20mL of dichloromethane and subjected to ice bath, after the reaction solution is cooled to 2 ℃, chloroacetyl chloride (451.6 mg, 4.00mmol) is added dropwise, the temperature is kept below 5 ℃ in the dropwise adding process, the ice bath is removed after the dropwise adding process is finished, the temperature is slowly increased to room temperature (the temperature rising speed is about 1.5 ℃/min), and the total time from the dropwise adding process to the completion of the IV-1 reaction is 2 hours. The reaction was quenched with 20mL of water, and the organic layer was washed with 20mL of water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to give a crude product, which was then purified by silica gel column chromatography (dichloromethane: methanol =40, 1,v/V, flow rate 3 mL/min) to give V-1 (802mg, 84%) as a yellow oil.
HRMS (ESI) with theoretical m/z value of C 17 H 2 ClN 2 O 3 [M+H] + 335.1162, found 335.1159.
And 4, step 4: preparation of benzyl 7- (4- (2- (3- (benzyloxy) -2-methyl-4-carbonylpyridine-ethyl) amino) -2-carbonylethyl) piperazin-1-yl) -1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydroquinoline-3-carboxylate (VII-1)
V-1 (67.0mg, 0.2mmol) and VI (105.4mg, 0.25mmol) were dissolved in 10mL of acetonitrile, and potassium carbonate (69.1mg, 0.5mmol) was added thereto to conduct a reflux reaction for 12 hours. After TLC detected that the reaction of the starting material V-1 was completed, the reaction solution was cooled to room temperature, suction-filtered, and the acetonitrile was removed by rotary evaporation of the filtrate, and the residue was dissolved in 50mL of ethyl acetate, washed with 20mL of water and saturated brine in this order, dried over anhydrous sodium sulfate for the organic layer, and concentrated by rotary evaporation to give a crude product, which was then purified by silica gel column chromatography (dichloromethane: methanol =50, 1, V/V, flow rate 3 mL/min) to give a brown oily substance VII-1 (53mg, 37%).
HRMS (ESI) with theoretical m/z value of C 41 H 43 FN 5 O 6 [M+H] + 720.3197, found 720.3196.
And 5: preparation of 1-cyclopropyl-6-fluoro-7- (4- (2- (2- (3-hydroxy-2-methyl-4-pyridonyl) ethyl) amino) -2-carbonylethyl) piperazin-1-yl) -4-carbonyl-1,4-dihydroquinoline-3-carboxylic acid (I-1)
VII-1 (50.4 mg, 0.07mmol) is dissolved in a mixed solvent of 10mL dichloromethane and 10mL ethanol, 5mg palladium/carbon with the mass fraction of 10% is added, vacuum pumping is firstly carried out, then hydrogen is introduced into a hydrogen bag, and the reaction bottle is repeatedly filled with the hydrogen for three times. And the reaction was carried out at room temperature for 3 hours (at this time, excess hydrogen gas was still present in the reaction flask). After the VII-1 reaction is detected to be complete by TLC, the reaction solution is filtered by diatomite, the filtrate obtained by filtering is washed by 20mL of ethanol for three times, and then rotary evaporation and concentration are carried out to obtain a crude product, and then 10mL of ether is used for pulping for three times to obtain a gray solid I-1 (38mg, 95%).
Figure BDA0003814633590000091
Melting point is 158-160 ℃; 1 H NMR(500MHz,DMSO-d 6 )δ8.66(s,1H),8.10(s,1H),7.89(d,J＝13.0Hz,1H),7.54–7.51(m,2H),6.13(d,J＝7.0Hz,1H),4.05(s,2H),3.88–3.85(m,1H),3.38–3.32(m,6H),3.02–3.00(m,2H),2.64–2.60(m,4H),2.31(s,3H),1.36–1.35(m,2H),1.25–1.23(m,2H)； 13 C NMR(125MHz,DMSO-d 6 ) δ 176.77,170.21,169.49,166.40,154.45 (d, J =248.0 Hz), 148.43,145.84,145.63 (d, J =9.0 Hz), 139.64,138.46,129.25,114.04,111.51 (d, J =24.0 Hz), 110.94,107.19,106.70,61.35,52.90,52.23,49.76,38.89,36.35,11.94,8.06; HRMS (ESI) theoretical value of C 27 H 31 FN 5 O 6 [M+H] + =540.2258, found 540.2255.
Example 2: preparation of (R) -1-cyclopropyl-6-fluoro-7- (4- (2- (2- (3-hydroxy-2-methyl-4-carbonylpyridin-1-yl) -3-phenylpropyloxy) -2-carbonylethyl) piperazin-1-yl) -4-carbonyl-1,4-dihydroquinoline-3-carboxylic acid (I-2)
Figure BDA0003814633590000092
Step 1: preparation of benzylmaltol (III)
See example 1, step 1.
Step 2: preparation of (R) -3- (benzyloxy) -1- (1-hydroxy-3-phenylpropan-2-yl) -2-methylpyridin-4-one (IV-2)
Compound III (4.32g, 20mmol) and (R) -2-amino-3-phenylpropanol (4.54g, 30mmol) were subjected to a similar procedure to that of step 2 in example 1 to give IV-2 (2.60g, 65%) as a brown oil.
Namely, specifically: the ethylenediamine in step 2) of example 1 was changed to (R) -2-amino-3-phenylpropanol (4.54g, 30mmol), and the rest was identical to step 2) of example 1, to obtain brown oil IV-2.
HRMS (ESI) with theoretical m/z value of C 22 H 24 NO 3 [M+H] + 350.1756, found 350.1752.
And step 3: preparation of (R) -2- (3- (benzyloxy) -2-methyl-4-carbonylpyridin-1-yl) -3-phenylpropyl 2-chloroacetate (V-2)
Compound IV-2 (1.0g, 2.86mmol) and chloroacetyl chloride (451.6mg, 4.00mmol) were subjected to A brown oil V-2 (2.76g, 65%) was obtained in a similar manner to step 3 of example 1.
Namely, specifically: IV-1 in step 3) of example 1 was changed to compound IV-2 (1.0 g, 2.86mmol), which was identical to step 3) of example 1, brown oil IV-2.
HRMS (ESI) with theoretical m/z value of C 24 H 25 ClNO 4 [M+H] + 426.1472, found 426.1475.
And 4, step 4: preparation of (R) -7- (4- (2- (2- (3- (benzyloxy) -2-methyl-4-carbonylpyridin-1-yl) -3-phenylpropoxy) -2-carbonylethyl) piperazin-1-yl) -1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydroquinoline-3-carboxylic acid benzyl ester (VII-2)
Compound V-2 (85.2mg, 0.2mmol) and VI (105.4mg, 0.25mmol) were used to prepare VII-2 as a brown oil (66mg, 41%) in a similar manner to step 4 of example 1.
Namely, specifically: the V-1 in step 4) of example 1 was changed to the compound V-2 (85.2mg, 0.2mmol), and the remainder was identical to step 4) of example 1, to give VII-2 as a brown oil.
HRMS (ESI) m/z theoretical value of C 48 H 48 FN 4 O 7 [M+H] + 811.3507, found 811.3510.
And 5: preparation of (R) -1-cyclopropyl-6-fluoro-7- (4- (2- (2- (3-hydroxy-2-methyl-4-carbonylpyridin-1-yl) -3-phenylpropyloxy) -carbonyl) piperazin-1-yl) -4-carbonyl-1,4-dihydroquinoline-3-carboxylic acid (I-2)
Compound VII-2 (56.8mg, 0.07mmol) was subjected to a similar procedure as in step 5 of example 1 to give I-2 (41mg, 92%) as a gray solid.
Namely, specifically: the VII-1 in step 5) of example 1 was changed to compound VII-2 (56.8mg, 0.07mmol); the rest was identical to example 1, step 5), giving I-2 as a grey solid.
The melting point is 134-136 ℃; 1 H NMR(500MHz,DMSO-d 6 ) δ 8.67 (s, 1H), 7.85 (d, J =13.0hz, 1h), 7.56 (d, J =7.0hz, 1h), 7.51-7.47 (m, 2H), 7.39-7.35 (m, 3H), 7.34-7.32 (m, 1H), 6.16 (d, J =8.0hz, 1h), 4.84 (d, J = 11.11 hz, 1h), 4.78 (d, J =11.0hz, 2h), 4.56-4.52 (m, 1H), 4.37-4.34 (m, 1H), 3.60-3.58 (m, 1H), 3.17-3.06 (m, 6H), 2.63-2.59 (m, 4H), 1.88 (s, 3H), 1.25-1.19 (m, 2H), 1.15-1.04 (m, 2H); HRMS (ESI) m/z theoretical value of C 34 H 36 FN 4 O 7 [M+H] + =631.2568, found 631.2569.
Example 3: preparation of (S) -1-cyclopropyl-6-fluoro-7- (4- (2- (2- (3-hydroxy-2-methyl-4-carbonylpyridin-1-yl) -3-methylbutoxy) -2-carbonylethyl) piperazin-1-yl) -4-carbonyl-1,4-dihydroquinoline-3-carboxylic acid (I-3)
Figure BDA0003814633590000111
Step 1: preparation of benzylmaltol (III)
See example 1, step 1.
Step 2: preparation of (S) -3- (benzyloxy) -1- (1-hydroxy-3-methylbutan-2-yl) -2-methylpyridin-4-one (IV-3)
Compound III (4.32g, 20mmol) and (S) -2-amino-3-methylbutanol (3.10g, 30mmol) were subjected to a similar manner to that in step 2 of example 1 to obtain brown oil IV-3 (1.99g, 55%).
Namely, specifically: ethylenediamine in step 2) of example 1 was changed to (S) -2-amino-3-methylbutanol (3.10 g, 30mmol), and the remainder was identical to step 2) of example 1, to give a brown oil IV-3.
HRMS (ESI) with theoretical m/z value of C 18 H 24 NO 3 [M+H] + 302.1756, found 302.1756
And step 3: preparation of (S) -2- (3- (benzyloxy) -2-methyl-4-carbonylpyridin-1-yl) -3-methylbutyl 2-chloroacetate (V-3)
Compound IV-3 (862.0 mg, 2.86mmol) and chloroacetyl chloride (451.6 mg, 4.00mmol) were subjected to a similar procedure as in step 3 of example 1 to give V-3 (1.85g, 56%) as a brown oil.
Namely, specifically: IV-1 in step 3) of example 1 was changed to compound IV-3 (862.0 mg, 2.86mmol), which was identical to step 3) of example 1, brown oil V-3.
HRMS (ESI) with theoretical m/z value of C 20 H 25 ClNO 4 [M+H] + 378.1472, found 378.1474
And 4, step 4: preparation of benzyl (S) -7- (4- (2- (2- (3- (benzyloxy) -2-methyl-4-carbonylpyridin-1-yl) -3-methylbutoxy) -2-carbonylethyl) piperazin-1-yl) -1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydroquinoline-3-carboxylate (VII-3)
Compound V-3 (75.6 mg, 0.2mmol) and VI (105.4 mg, 0.25mmol) were subjected to a similar procedure as in step 4 of example 1 to give VII-3 (67mg, 44%) as a brown oil.
Namely, specifically: the V-1 in step 4) of example 1 was changed to the compound V-3 (75.6 mg, 0.2mmol), and the remainder was identical to step 4) of example 1, to give VII-3 as a brown oil.
HRMS (ESI) with theoretical m/z value of C 44 H 48 FN 4 O 7 [M+H] + 763.3507, found 763.3506
And 5: preparation of (S) -1-cyclopropyl-6-fluoro-7- (4- (2- (2- (3-hydroxy-2-methyl-4-carbonylpyridin-1-yl) -3-methylbutoxy) -2-carbonylethyl) piperazin-1-yl) -4-carbonyl-1,4-dihydroquinoline-3-carboxylic acid (I-3)
Compound VII-3 (53.4 mg, 0.07mmol) was subjected to a similar manner to step 5 of example 1 to obtain I-3 (34mg, 84%) as a brown solid.
Namely, specifically: VII-1 in step 5) of example 1 was changed to Compound VII-3 (53.4 mg, 0.07mmol), the remainder being identical to step 5) of example 1, to give I-3 as a brown solid.
The melting point is 143-144 ℃; 1 H NMR(500MHz,DMSO-d 6 )δ8.67(s,1H),7.89(d,J＝13.0Hz,1H),7.73(d,J＝7.5Hz,1H),7.55(d,J＝7.0Hz,1H),6.21(d,J＝7.5Hz,1H),4.53–4.50(m,1H),4.45–4.41(m,2H),3.88–3.83(m,1H),3.29–3.17(m,6H),2.58–2.54(m,4H),2.32(s,3H),1.36–1.31(m,2H),1.26–1.22(m,1H),1.21–1.14(m,2H),1.09–1.03(m,3H),0.70–0.67(m,3H)； 13 C NMR(125MHz,DMSO-d 6 ) δ 171.75,171.59,169.55,164.56,153.56 (d, J =245.0 Hz), 148.37,144.37,143.82 (d, J =10.0 Hz), 138.02,137.49,136.69,135.34,121.92,111.73 (d, J =23.0 Hz), 108.82,106.28,71.73,65.22,63.97,51.64,49.42,34.82,29.94,19.23,18.79,7.49; HRMS (ESI) m/z theoretical value of C 30 H 36 FN 4 O 7 [M+H] + ＝583.2568,found583.2565.
Example 4: preparation of (S) -1-cyclopropyl-6-fluoro-7- (4- ((2- (3-hydroxy-2-methyl-4-carbonylpyridin-1-yl) -3-phenylpropoxy) carbonyl) piperazin-1-yl) -4-carbonyl-1,4-dihydroquinoline-3-carboxylic acid (I-4)
Figure BDA0003814633590000121
Step 1: preparation of (S) -3-hydroxy-1- (1-hydroxy-3-phenyl-2-propyl) -2-methylpyridin-4-one hydrochloride (VIII) maltol (II, 189.2mg,1.5 mmol), (R) -2-amino-3-phenylpropanol (251.0mg, 1.66mmol) and boric acid (92.7mg, 1.5 mmol) were added to 50mL of water, and the mixture was refluxed. After the TLC detects that maltol completely reacts, the reaction liquid is cooled to room temperature, the pH value of the reaction liquid is adjusted to 8.5 by 40% sodium hydroxide solution, 100mL of dichloromethane is added for extraction twice, an organic layer is dried by anhydrous sodium sulfate, rotary evaporation and concentration are carried out, the residue is adjusted to pH =1 by 6M hydrochloric acid solution, heating and dissolution are carried out at 40 ℃, then the mixture is slowly cooled to an ice bath, and stirring is carried out until solid is separated out. Suction filtration and cake washing with 10mL of water, drying and recrystallization with n-butanol and acetonitrile (3, 1, v/v) gave yellow solid VIII (154mg, 61%).
Melting point 186-187 deg.C; HRMS (ESI) with theoretical m/z value of C 8 H 12 NO 3 [M+H] + 169.0739, found 169.0736.
Step 2: preparation of (S) -2,5-dioxopyrrolidin-1-yl (2- (3-hydroxy-2-methyl-4-oxopyridin-1 (4H) -yl) -3-phenylpropyl) carbonate (IX)
VIII (346.7mg, 1mmol) was dissolved in 30mL of tetrahydrofuran, triethylamine (556.6mg, 5.5mmol) and N, N' -succinimidyl carbonate (384.3mg, 1.5mmol) were added, the mixture was stirred at room temperature for 2 hours, and after completion of the VIII reaction by TLC, the mixture was concentrated by rotary evaporation to give the crude product of IX which was directly used in the next step.
And step 3: preparation of (S) -1-cyclopropyl-6-fluoro-7- (4- ((2- (3-hydroxy-2-methyl-4-carbonylpyridin-1-yl) -3-phenylpropoxy) carbonyl) piperazin-1-yl) -4-carbonyl-1,4-dihydroquinoline-3-carboxylic acid (I-4)
The crude IX was dissolved in 10mL of dichloromethane, followed by addition of ciprofloxacin (397.7mg, 1.2mmol) and triethylamine (404.8mg, 4mmol), stirring at room temperature for two hours (in which TLC disappearance of IX was detected), and quenching with 20mL of water. The layers were separated and the aqueous layer was extracted twice with 50mL dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol =30, flow rate 3 mL/min) to give a pink solid (400mg, 65%).
Melting point is 136-138 ℃;1H NMR (500MHz, DMSO-d) 6 )δ8.66(s,1H),7.96(d,J＝7.5Hz,1H),7.89(d,J＝13.0Hz,1H),7.52(d,J＝7.5Hz,1H),7.28–7.22(m,2H),7.20–7.17(m,3H),6.21(d,J＝7.5Hz,1H),4.86–4.82(m,1H),4.54–4.45(m,1H),4.42–4.38(m,1H),3.87–3.84(m,1H),3.51–3.47(m,4H),3.27–3.06(m,6H),2.01(s,3H),1.35–1.30(m,2H),1.20–1.15(m,2H)；13C NMR(125MHz,DMSO-d 6 )δ176.78,169.34,166.40,154.41(d,J＝249.0Hz),154.17,148.47,145.38(d,J＝10.0Hz),145.04,139.55,137.05,134.42,130.05,129.44,128.94,127.27,119.43 (d, J =8.0 Hz), 111.72,111.47 (d, J =24.0 Hz), 107.32,107.20,66.52,60.22,43.62,43.59,36.56,36.36,12.03,8.05; HRMS (ESI) m/z theoretical value of C 33 H 34 FN 4 O 7 [M+H] + =617.2412, found 617.2410.
Test example 1 in vitro test for the Activity of the Compound against drug-resistant negative bacteria
1.1 test strains
The tested clinical isolated strains selected for in vitro antibacterial activity test were: ciprofloxacin-resistant Acinetobacter Baumannii (ABA), ciprofloxacin-resistant Klebsiella Pneumoniae (KP), see: the method comprises the steps of carrying out drug-resistant phenotype and molecular typing analysis on carbapenems-resistant Klebsiella pneumoniae in Yongkang areas, and carrying out 2022,44 (10), 1063-1066 in Zhejiang medical science; molecular typing research of multiple drug-resistant Acinetobacter baumannii in Yongkang areas of Zhejiang province, china journal of preventive medicine 2015,16 (5), 379-383.
The strain source is as follows: the strain used in the experiment is clinical isolated pathogenic bacteria collected in Zhejiang area at 2021 months 05. Each strain of bacteria was subjected to single colony streaking on an agar plate before the experiment, and the freshly cultured cells at 37 ℃ overnight were appropriately diluted for the experiment.
1.2 in vitro antibacterial test method
Each test sample was assayed using the micro broth dilution method recommended by the american society for Clinical and Laboratory Standards (CLSI) antibacterial drug susceptibility test protocol, and MIC values were determined for the tested strains in normal MHB medium and iron-deficient MHB medium.
1.3 Experimental procedures
1.3.1 MIC values in Normal Medium
1.3.1.1MHB liquid medium configuration
Weighing 11g of MHB dry powder in 500ml of ultrapure water, stirring for dissolving, putting into a high-pressure steam sterilization pot (121 ℃,20 min), taking out after sterilization is finished, cooling, and placing in a constant-temperature incubator at 37 ℃ for later use.
1.3.1.2 preparation of drug stock solutions
3 mu mol of the target compound or the positive control drug is weighed and dissolved in 3ml of DMSO to prepare a 1mM compound solution. Add 2mLpH8.0 Tris-HCl buffer, then 1mLFeCl3 solution (1 mM), shake to make drug stock solution (0.5 mM).
1.3.1.3 preparation of bacterial suspension
Taking out the strain frozen at-70 deg.C, inoculating on blood agar plate (BA) in different regions, culturing in incubator at 35 deg.C for 16-24 hr, and standing after single strain grows out. Before the experiment, a single colony is picked up by using a sterile inoculating loop and is put into 0.45 percent of physiological saline, and the concentration of the bacterial liquid is adjusted to be 0.5 McLeod turbidity (1.0 multiplied by 10) 8 CFU/ml)。
1.3.1.4 minibouillon dilution method drug sensitivity test
Draw 512 μ L of drug stock solution, dilute to 1mL with MHB culture solution, and prepare broth working solution with concentration of 256 μ M. In the clean bench, the cleaning liquid is introduced into the clean bench,
(1) 200 mul of diluted liquid medicine is respectively added into the first hole of a 96-hole plate, 100 mul of MHB broth is respectively added into the second hole to the ten holes, 200 mul of bacterial liquid is added into the eleventh hole to serve as a bacterial liquid negative control, and 200 mul of MHB broth is added into the twelfth hole to serve as a positive control.
(2) Draw 100 μ L of the antimicrobial from the first row to the second row using an eight-channel pipette and mix, and then draw 100 μ L from the second row to the third row and mix. This two-fold gradient dilution was performed until the tenth column was mixed, 100. Mu.L of the mixture was aspirated and discarded.
(3) Then 100. Mu.L of bacterial suspension is added to the first to the tenth rows respectively, and the final concentrations of the compounds in the first to the tenth rows are 128, 64, 32, 16, 8, 4, 2,1, 0.5 and 0.25. Mu.M respectively.
(4) And (4) marking the 96-well plate, placing the 96-well plate in an incubator at 35 ℃ for culturing for 16-24h, and observing the result. The bacteria liquid negative control hole shows turbidity, the positive control hole shows clearness, the quality is controlled in a specified range, and the Minimum Inhibitory Concentration (MIC) of the compound is obtained by observing the minimum Concentration without bacterial growth by naked eyes.
1.3.2 MIC values in iron-deficient Medium
The compound sequesters iron in the medium by adding 2,2' -bipyridine to normal medium. Under the condition of iron deficiency, the bacteria secrete a large amount of siderophores and 2,2' -bipyridine to compete for iron in the culture medium, the unique iron uptake way of the bacteria is excited, and the siderophores-antibacterial drug conjugates are favorable for playing an antibacterial role. In addition, in human and animal bodies, iron elements are complexed by various proteins, so that the concentration of free iron which can be utilized by bacteria is extremely low, the iron-deficiency culture medium added with 2,2' -bipyridine is just the simulation of the iron-deficiency environment in the bodies, and the condition of the iron-deficiency culture medium can more effectively reflect the antibacterial effect of the compound.
1.3.2.1MHB iron-deficiency culture medium configuration
Weighing 11g of MHB dry powder in 500ml of ultrapure water, stirring for dissolving, putting into a high-pressure steam sterilization pot (121 ℃,20 min), taking out after sterilization is finished, cooling, and placing in a constant-temperature incubator at 37 ℃ for later use.
1.3.2.2 preparation of drug stock solutions
3 mu mol of the target compound or the positive control drug is weighed and dissolved in 3ml of DMSO to prepare a 1mM compound solution. Add 2mM of Tris-HCl buffer (pH8.0), then add 1mM of LFeCl3 solution (1 mM), shake up, and prepare the drug stock solution (0.5 mM).
1.3.2.3 preparation of bacterial suspension
Taking out the strain frozen at-70 deg.C, inoculating on blood agar plate (BA) in different regions, culturing in incubator at 35 deg.C for 16-24 hr, and standing after single strain grows out. Before the experiment, a single colony is picked up by using a sterile inoculating loop and is put into 0.45 percent of physiological saline, and the concentration of the bacterial liquid is adjusted to be 0.5 McLeod turbidity (1.0 multiplied by 10) 8 CFU/ml)。
1.3.2.4 minim broth dilution method drug sensitivity test
Draw 512 μ L of drug stock solution, dilute to 1mL with MHB culture solution, and prepare broth working solution with concentration of 256 μ M. In the clean bench, the cleaning liquid is introduced into the clean bench,
(1) 200 mul of diluted liquid medicine is respectively added into the first hole of a 96-hole plate, 100 mul of iron-deficiency MHB broth is respectively added into the second hole to the ten holes, 200 mul of bacterial liquid is added into the eleventh hole to serve as bacterial liquid negative control, and 200 mul of iron-deficiency MHB broth is added into the twelfth hole to serve as positive control.
(2) Draw 100 μ L of the antimicrobial from the first column to the second column using an eight channel pipette and mix, and then draw 100 μ L from the second column to the third column and mix. The two-fold gradient dilution method is adopted until the tenth row is mixed evenly, 100 mu L of the mixture is sucked out and discarded.
(3) Then 100. Mu.L of the bacterial suspension is added into the first to the tenth rows respectively, and the final concentration of the compounds in the first to the tenth rows is 128, 64, 32, 16, 8, 4, 2,1, 0.5 and 0.25. Mu.M respectively.
(4) And (4) marking the 96-well plate, placing the 96-well plate in an incubator at 35 ℃ for culturing for 16-24h, and observing the result. The bacteria liquid negative control hole shows turbidity, the positive control hole shows clearness, the quality is controlled in a specified range, and the Minimum Inhibitory Concentration (MIC) of the compound is obtained by observing the minimum Concentration without bacterial growth by naked eyes.
1.4 in vitro test results for drug-resistant negative bacteria
TABLE 1 MIC values (unit: μ M) of the compounds against drug-resistant negative bacteria
Figure BDA0003814633590000161
The data in the table show that under normal conditions, the compounds of the present invention have moderate antibacterial activity against drug-resistant klebsiella pneumoniae and acinetobacter baumannii, which is equivalent to or slightly weaker than that of ciprofloxacin. The iron-deficient culture medium simulates the in-vivo infection iron-deficient environment and can more effectively react the antibacterial activity of the compound. Under the condition of iron deficiency, the antibacterial activity of the compound I-1 to drug-resistant Klebsiella pneumoniae is doubled compared with that of ciprofloxacin, and the antibacterial activity of the compounds I-2,I-3 and I-4 to drug-resistant Acinetobacter baumannii is doubled compared with that of ciprofloxacin.
In conclusion, the compound has a novel chemical structure, improves the antibacterial activity of ciprofloxacin drug-resistant bacteria under the condition of iron deficiency, and is expected to be developed into a medicament for treating infectious diseases caused by drug-resistant gram-negative bacteria.
Finally, it is also noted that the above-mentioned lists merely illustrate a few specific embodiments of the invention. It is obvious that the invention is not limited to the above embodiments, but that many variations are possible. All modifications which can be derived or suggested by the person skilled in the art from the present disclosure are to be considered within the scope of the present invention.

Claims (10)

  1. The 3-hydroxy-4-pyridone-ciprofloxacin coupling compound is characterized by having the following structural general formula I:
    Figure FDA0003814633580000011
    wherein X is
    Figure FDA0003814633580000012
  2. 2. The 3-hydroxy-4-pyridone-ciprofloxacin coupling compound of claim 1, characterized by the general formula ii or the compound I-4:
    general formula II:
    Figure FDA0003814633580000013
    compound I-4:
    Figure FDA0003814633580000014
  3. 3. the 3-hydroxy-4-pyridone-ciprofloxacin couple of claim 2, characterized in that formula ii is any one of the following: compound I-1, compound I-2, compound I-3;
    compound I-1
    Figure FDA0003814633580000015
    Compound I-2:
    Figure FDA0003814633580000021
    compound I-3:
    Figure FDA0003814633580000022
  4. 4. a tautomer, optical isomer or a pharmaceutically acceptable salt of the 3-hydroxy-4-pyridone-ciprofloxacin couple according to any one of claims 1 to 3.
  5. A method for preparing a 3-hydroxy-4-pyridone-ciprofloxacin coupling compound is characterized by comprising the following steps:
    1. the preparation method of the general formula II comprises the following steps:
    (1.1) carrying out reflux reaction on the compound V and the compound VI for 12 +/-1 hours by using an aprotic polar solvent as a solvent under the condition of inorganic base to obtain a compound VII;
    compound V:
    Figure FDA0003814633580000023
    compound VI:
    Figure FDA0003814633580000024
    compound VII:
    Figure FDA0003814633580000025
    the R is 1 Is composed of
    Figure FDA0003814633580000026
    In the formula 3 Is a hydroxy protecting group; x is
    Figure FDA0003814633580000027
    The R is 2 Is a carboxyl protecting group;
    (1.2) in a mixed solvent, under the catalysis of hydrogen and palladium/carbon, removing a protecting group from a compound VII to obtain a compound shown in a general formula II;
    2. the preparation method of the compound I-4 comprises the following steps:
    (2.1) reacting the compound VIII with a condensing agent at room temperature for 12 +/-1 hours by using an aprotic polar solvent as a solvent under the condition of organic base to obtain a compound IX;
    compound VIII:
    Figure FDA0003814633580000031
    compound IX:
    Figure FDA0003814633580000032
    R 1 is composed of
    Figure FDA0003814633580000033
    R 2 Is a leaving group which is:
    Figure FDA0003814633580000034
    (2.2) reacting the compound IX with ciprofloxacin at room temperature for 12 +/-1 hours by using an aprotic polar solvent as a solvent under the condition of organic base to obtain a compound I-4.
  6. 6. The method for producing a 3-hydroxy-4-pyridone-ciprofloxacin coupling compound according to claim 5, wherein:
    R 3 is a hydroxyl protecting group, and the protecting group is benzyl or benzhydryl;
    R 2 the protecting group is a carboxyl protecting group, and the protecting group is benzyl or benzhydryl.
  7. 7. The method for producing a 3-hydroxy-4-pyridone-ciprofloxacin coupling compound according to claim 5 or 6, characterized in that:
    in the step (1.1), the inorganic base is potassium carbonate, sodium carbonate or potassium hydroxide; the aprotic polar solvent is acetonitrile or dimethylformamide;
    in the step (1.2): the mixed solvent is dichloromethane/ethanol, dichloromethane/tetrahydrofuran;
    in the step (2.1): the organic base is triethylamine and N, N-diisopropylethylamine; the condensing agent is N, N '-succinimide carbonate, 1,1' -carbonyldiimidazole; the aprotic polar solvent is dichloromethane or tetrahydrofuran;
    in the step (2.2): the organic base is triethylamine and N, N-diisopropylethylamine; the aprotic polar solvent is dichloromethane or tetrahydrofuran.
  8. 8. Use of a 3-hydroxy-4-pyridone-ciprofloxacin conjugate according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of a disease caused by bacteria.
  9. 9. Use according to claim 8, characterized in that: the bacteria are gram negative bacteria.
  10. 10. Use according to claim 8 or 9, characterized in that: the bacteria are ciprofloxacin drug-resistant Acinetobacter Baumannii (ABA) and ciprofloxacin drug-resistant Klebsiella Pneumoniae (KP).
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Publication number Priority date Publication date Assignee Title
CN113149990A (en) * 2020-01-23 2021-07-23 嘉圣生物医药(嘉兴)有限公司 Siderophore-dihydrofolate reductase inhibitor conjugate and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113149990A (en) * 2020-01-23 2021-07-23 嘉圣生物医药(嘉兴)有限公司 Siderophore-dihydrofolate reductase inhibitor conjugate and application thereof

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* Cited by examiner, † Cited by third party
Title
刘君 等: "铁载体分子偶联抗生素药物研究进展", 《有机化学》, vol. 40, no. 10, pages 3026 - 3043 *
竺越: "3-羟基吡啶酮铁载体—环丙沙星耦合物的设计、合成和体外抗菌活性评价及2-氨基（胺基）噻唑类化合物库的构建", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》, no. 5, pages 079 - 44 *

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