CN108084075A - Proline derivative with beta-lactam enzyme inhibition - Google Patents
Proline derivative with beta-lactam enzyme inhibition Download PDFInfo
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- CN108084075A CN108084075A CN201611043205.3A CN201611043205A CN108084075A CN 108084075 A CN108084075 A CN 108084075A CN 201611043205 A CN201611043205 A CN 201611043205A CN 108084075 A CN108084075 A CN 108084075A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention discloses the proline derivative with beta-lactam enzyme inhibition, with formula (I) Suo Shi：Wherein, amido bond includes the cis or trans rotational isomer of its naturally occurring in formula (I)；R1For OH or NH2；R2For ortho-sulfonic acid base phenyl, adjacent sulfoamido phenyl, sulfonic group phenyl, sulfoamido phenyl, p-sulfonic acid base phenyl, to sulfoamido phenyl or adjacent carboxyl benzyl.Through the proline derivative shown in active testing proof formula (I) to beta lactamase, particularly there is good inhibiting effect to NDM 1.By inhibiting beta lactamase, particularly 1 activity of NDM, decreases or even eliminates hydrolysis of the NDM 1 to beta-lactam class antibiotic, alleviates drug resistance caused by NDM 1, recover the effect of antibiotic is to bacterium, infected so as to treat the drug-resistant bacteria as caused by NDM 1.
Description
Technical field
The present invention relates to the proline derivatives with beta-lactam enzyme inhibition.
Background technology
From antibiotic medicine since nineteen forties are applied to clinic, the incidence of the infectious diseases of the mankind
It has obtained significantly improving with the death rate.But with abuse of the mankind to antibiotic and misuse, most disease
The effect of opportunistic pathogen is converted to as antibiotic resistant bacteria, therefore the drug resistance for inhibiting pathogen recovers antibacterials becomes when business
It is anxious.
On August 11st, 2010, famous medical journal《Lancet》It publishes the article and has reported a kind of special enterobacteriaceae lactobacteriaceae, it is right
All beta-lactam antibacterials have the case of drug resistance.This report causes global extensive concern, further investigation
It was found that such bacterium carries a kind of novel metal beta-lactam that Klebsiella Pneumoniae (Klebsiellapne μM of oniae) encodes
Enzyme is combined with zinc ion in its active site, can hydrolyze the nearly all antibiotic clinically applied.Because first case case
It is found in India New Delhi, so it is defined as 1 (NDM-1 of New Delhi metallo-β-lactamase by researchers：New Delhi
metallo-β-1actamase 1).NDM-1 belongs to a member in B class beta-lactamase superfamilies, has multiple drug resistance, removes
It is to remaining all antibiotic all apparent altitude resistance to beyond polymyxins (Colistin) and tigecycline (Tigecycline)
Pharmacological property, and most of beta-lactamase inhibitors are resistant to, such as Sulbactam, Tazobactam Sodium, clavulanic acid.More merit attention
Be, carry blaNDM-1 genes be located on plasmid, can the horizontal transfer between different strain, other strains is caused also to have
Antibiotic resistance.Therefore, the drug for finding the activity that can inhibit production NDM-1 drug-resistant bacterias has very important significance.
Nankai University in 2014, which reports to have as the captopril of blood-pressure drug and its a variety of derivative, to be inhibited
Metallo-β-lactamase NDM-1 effect (Bioorganic＆Medicinal Chemistry Letters 24 (2014) 386-
389), research further discloses method of evaluating drug effect of the evaluation for NDM-1.The play-by-play such as Proschak in 2015 are not as
The a variety of compounds inhibited to NDM-1 found in the clinical medicine listed with indication
(J.Med.Chem.2015,58,3626-3630).But the marketed drug inhibited to NDM-1 disclosed above or
Person's compound, most of all containing thiol molecule structure in molecular structure, it is displeased that the presence of sulfydryl not only can generate drug
Fast smell, and since the strong coordination ability of sulfydryl and metal causes compounds containing thiol groups can be to human body when being used as drug
The enzyme of interior a variety of metal ions generates the inhibitory action without selection so as to cause poisonous side effect of medicine.For example, as shown in Figure 1 by
The majority drug containing sulfydryl that Proschak concludes report is all considered to be not suitable as clinical medicine for inhibiting super drug-fast bacteria
Metallo-β-lactamase NDM-1 (J.Med.Chem.2015,58,3626-3630).
The content of the invention
The purpose of the present invention is overcome the deficiencies of the prior art and provide the proline with beta-lactam enzyme inhibition to spread out
Biology.
Second object of the present invention is to provide a kind of doctor of the proline derivative with beta-lactam enzyme inhibition
The salt allowed on.
Third object of the present invention is to provide a kind of proline derivative with beta-lactam enzyme inhibition
Solvate.
Fourth object of the present invention be to provide a kind of proline derivative with beta-lactam enzyme inhibition with
The composition for the carrier composition medically allowed.
Technical scheme is summarized as follows：
Proline derivative with beta-lactam enzyme inhibition, shown in Formulas I：
Wherein, amido bond includes the cis or trans rotational isomer of its naturally occurring in formula (I)；
R1For OH or NH2；
R2For ortho-sulfonic acid base phenyl, adjacent sulfoamido phenyl, sulfonic group phenyl, sulfoamido phenyl, p-sulfonic acid base
Phenyl, to sulfoamido phenyl or adjacent carboxyl benzyl.
Preferably, Formulas I structure is：
The salt medically allowed of the above-mentioned proline derivative with beta-lactam enzyme inhibition.
The solvate of the above-mentioned proline derivative with beta-lactam enzyme inhibition.
The group formed with the carrier medically allowed of the above-mentioned proline derivative with beta-lactam enzyme inhibition
Close object.
Advantages of the present invention：
Through active testing prove the present invention the proline derivative with beta-lactam enzyme inhibition to NDM-1 with
Good inhibiting effect.The present invention has the proline derivative of beta-lactam enzyme inhibition can be by inhibiting β-interior
Amidase, particularly NDM-1 activity, decrease or even eliminate hydrolysis of the NDM-1 to beta-lactam antibiotic, alleviate NDM-1 and draw
The drug resistance risen recovers the effect of antibiotic is to bacterium, infects, has so as to treat the drug-resistant bacteria as caused by NDM-1
Good medicinal application prospect.
Description of the drawings
Fig. 1 is majority medicines structure containing the sulfydryl formula that Proschak concludes report.
Specific embodiment
The present invention, as starting point, is found that by Science Explorations with formula using existing natural amino acid L-PROLINE in human body
(I) sulfydryl is not contained in the proline derivative with beta-lactam enzyme inhibition represented, is new NDM-1 metals β-interior
Lactamase inhibitor.
The present invention is first using the crystal structure of NDM-1 in Protein Data Bank as model (PDB：1Q6X), appliance computer
Aided drug design software SYBYL 2.0 is evaluated the proline shown in the formula (I) being pre-designed by the way of the molecular docking and spread out
The nucleophilic energy of biology and NDM-1 ligand binding sites.R in the formula (I) being pre-designed1It is defined as NH2Or OH, R2It is defined as energy
Enough from the commercially available all chloride compounds of SIGMA-ALDRICH and all carboxylic acid compounds.
Concrete operations are as follows：
【The design and screening of reactive compound】
By the NDM-1 (PDB containing ampicillin hydrolysate ligands：Work station 1Q6X) is downloaded to, is utilized
Surflex-dock programs in SYBYL2.0 and the method for following software defined carry out molecular docking preparation to protein.
These preparations include removing hydrone, correct and define unreasonable amino acid, assign metal zinc atom to divalent charge, right
Protein assigns the AMBER field of forces, and the TRIPOS field of forces are assigned to all ligand compounds.Follow the molecular docking operation journey of software
Sequence implements molecular docking and marking for each evaluated molecular structure.Marking includes total mark (Total Score), D-
Score, PMF-Score, G-Score and CHEM-Score, the present invention are used Total-Score and CHEM-Score two
Compared with the marking of native ligand ampicillin hydrolysate, marking is commented better than ampicillin hydrolysate for marking
Valency compound is considered as the candidate compound with potential NDM-1 inhibitory action.What these were selected out has lateral reactivity
Compound is synthesized and prepared by laboratory, is eventually used for the screening of NDM-1 metallo-β-lactamase inhibitory activity.
【The expression separation and purifying of NDM-1 metallo-β-lactamases】
According to the literature procedures method (foundation of Li Huiru, superbacteria NDM-1 gene tester, antibacterial evaluation model
And the research of the antibacterial exploratory experiment of the coptis, Traditional Chinese Medicine University Of Guangzhou Ph.D. Dissertation, 2011；Xie Nannan, " superbacteria "
NDM-1 inhibitor screenings are measured with antibacterial activity in vitro, Nankai University's master thesis, and 2013), the present invention utilizes large intestine
Bacillus BL21 competent cells, implement the conversion of NDM-1 plasmids first, and the single bacterium colony cell that will be singled out is inoculated into 5mL LB
Then fluid nutrient medium, 37 DEG C of 220rpm shaken overnights add 10% glycerine fungi preservation is for use in -80 DEG C.Take above-mentioned guarantor
The 50 μ L of expression bacterium deposited are inoculated in LB fluid nutrient mediums of the 50mL containing kanamycins (working concentration 50ug/mL), 37 DEG C
220rpm shaken overnight cultures, obtain seed liquor；With 1:2mL seed liquors are transferred to LBs of the 200mL containing kanamycins by 100 ratio
In fluid nutrient medium, 37 DEG C of shaken cultivations；When the OD600 values of bacterium solution are about 0.8,1mL bacterium solutions are taken, 4 DEG C, 12000rpm is centrifuged
2 minutes, bacterial sediment is collected, the 1M IPTG storing solutions (working concentration 1mM) of 200 μ L are added in 20 DEG C, is lured in 180rpm vibrations
Lead 8 it is small when；1mL is taken to induce bacterium solution, 4 DEG C, 12000rpm is centrifuged 2 minutes, is collected bacterial sediment, is stored in -80 DEG C；Go bail for what is deposited
Thalline adds in Binding-Buffer (pH7.4) according to the ratio of 10mL/g, and addition protease inhibitors PMSF to concentration is
1mM.Bacterium solution is then placed in glass beaker, 400W ultrasounds intermittently 3 seconds 3 seconds, are ultrasonically treated 15 minutes, every time until bacterium under ice bath
Liquid is transparent.After bacterial cell disruption, at 4 DEG C, 12000rpm is centrifuged 30 minutes, collects supernatant precipitation respectively.The bodies such as precipitation supernatant
Long-pending PBS solution is resuspended.The purifying of albumen uses Ni-NTA columns, bed volume 2mL, with Binding-Buffer with 2mL/
The flow velocity of min balances 5 bed volumes, and supernatant is crossed 0.45 μM of filter membrane, after be loaded into Ni affinity columns, flow velocity 1mL/min.With
Contain Binding-Buffer (pH7.4) the progress gradient elutions of 50,100,200 and 400mM imidazoles respectively, collect each gradient and wash
De- sample with the purification result of SDS-PAGE electrophoresis detection NDM-1 albumen, obtains the NDM-1 recombinant proteins that purity is more than 90%.
The present invention is further described with specific embodiment below, but does not limit the present invention.
Embodiment 1：The synthesis of compound Ia：
(1) o-carboxyl phenylacetic acid (360mg, 2mmol) is dissolved in dry dimethyl formamide solution at ambient temperature
Among (10ml), ethyl [3- (dimethylamino) propyl] carbodiimide (384mg, 2mmol) and 1- hydroxy benzos three are successively added in
Azoles (270mg, 2mmol) stirs 15 minutes, then adds in L-PROLINE benzyl ester hydrochloride (532mg, 2.2mmol) and 4- diformazans
Aminopyridine (805mg, 6.6mmol), reaction solution react at room temperature 12 it is small when.After the completion of reaction, revolving removes solvent, with two
Chloromethanes diluting reaction object is washed with saturated sodium bicarbonate, 3M hydrochloric acid solutions and saturated nacl aqueous solution, obtains organic mix respectively
Agent is dried with anhydrous sodium sulfate, and decompression is spin-dried for, with HPLC (methanol: water=7: 3) to reaction product implement purify, obtain white solid
Body intermediate (404mg), yield 55%.1H NMR(600MHz,CDCl3) δ 7.96 (d, J=7.6Hz, 0.8H), 7.92 (d, J
=7.5Hz, 0.2H, rotamer), 7.37 (m, 7.8H), 7.02 (d, J=7.6Hz, 0.2H, rotamer), 5.28-5.21 (m,
0.4H, rotamer), 5.12 (dd, J=40.4,12.3Hz, 1.6H), 4.73 (dd, J=8.6,2.5Hz, 0.2H,
), rotamer 4.60 (dd, J=8.6,3.7Hz, 0.8H), 4.02 (m, 1.6H), 3.94 (m, 0.4H, rotamer), 3.87-
3.80(m,0.8H),3.73(m,0.8H),3.68–3.64(m,0.2H,rotamer),3.59(m,0.2H,rotamer),
2.40–2.31(m,0.3H,rotamer),2.27–1.99(m,3.2H),1.98–1.84(m,0.5H,rotamer).13C NMR
(150MHz,CDCl3)δ172.25,172.15(rotamer),179.12–171.20,136.29,135.69,135.30
(rotamer),132.59–132.15,132.15–132.06,131.73,131.35,130.60,128.82–128.35,
128.20,128.05,127.19,67.38(rotamer), 66.86,59.91(rotamer),59.05,47.43,46.86
(rotamer),40.26,31.41(rotamer),29.28,24.80,22.72(rotamer).IR(KBr):3422.62,
1359.72,1159.57,1075.22,948.86,860.35,546.18,525.85,463.77.
(2) at room temperature, by midbody compound obtained above (300mg, 0.82mmol), it is dissolved in methanol (5ml),
Then 5% Pd/carbon catalyst of catalytic amount is added in, with air in hydrogen displacement flask, reacts 4h at room temperature.Reaction is completed
Afterwards, filtered with diatomite, revolving remove solvent, with HPLC (methanol: water=4: 6) to reaction product implement purify, obtain light green
Color solid product Ia (164mg), yield 72%.Nuclear-magnetism detection shows that product is amido bond rotamer mixture.1H
NMR(400MHz,D2O)δ8.03–7.95(m,1H),7.58(m,1H),7.45(m,1H),7.34(m,1H),4.67(m,0.3H,
), rotamer 4.45-4.37 (m, 0.7H), 4.21 (d, J=16.7Hz, 0.7H), 4.14 (d, J=7.9Hz, 0.4H,
rotamer),3.99(m,0.8H),3.93(m,0.3H,rotamer),3.79–3.67(m,1.5H),3.36(m,0.8H,
rotamer),2.39–2.27(m,1.1H,rotamer),2.13–1.96(m,3.2H).13C NMR(150MHz,D2O)δ
176.59(rotamer),176.34,173.05(rotamer),172.72,170.54,135.91,133.56–133.25,
133.03,132.82–132.43,131.15–130.82,127.87(rotamer),127.62,60.51(rotamer),
59.22,47.67,46.97(rotamer),40.11,29.12,28.74(rotamer),24.29,23.60(rotamer).IR
(KBr):3422.96,2434.13,1397.00,1360.13,1159.64,1075.02,948.67,860.31,546.16,
525.69,464.07.MS,m/z:276.10[M-H]-
Embodiment 2：The synthesis of compound Ib
(1) adjacent carboxyl benzene sulfonic acid (360mg) is dissolved in dry dimethyl formamide solution (10ml) at ambient temperature
In the middle, ethyl [3- (dimethylamino) propyl] carbodiimide (384mg) and I-hydroxybenzotriazole (270mg) are successively added in, is stirred
It mixes 15 minutes, then adds in L-PROLINE benzyl ester hydrochloride (532mg) and 4-dimethylaminopyridine (805mg), reaction solution is in room
When the lower reaction 12 of temperature is small.After the completion of reaction, revolving removes solvent, with dichloromethane diluting reaction object, respectively with saturated brine, 3M
Hydrochloric acid solution and saturated nacl aqueous solution washing, obtain organic phase solvent and are dried with anhydrous sodium sulfate, decompression is spin-dried for, with HPLC (first
Alcohol: water=5: 5) reaction product is implemented to purify, obtains white solid product (404mg), be directly used in next step reduction reaction.
(2) at room temperature, by compound obtained above (300mg), it is dissolved in methanol (5ml), then adds in catalytic amount
5% Pd/carbon catalyst, with hydrogen displacement flask in air, react 4h at room temperature.After the completion of reaction, filtered with diatomite,
Revolving remove solvent, with HPLC (methanol: water=4: 6) to reaction product implement purify, obtain white solid product I b
(164mg), yield 72%.Nuclear-magnetism detection shows that product is amido bond rotamer mixture.1H NMR(600MHz,
MeOD) δ 7.93 (d, J=6.9Hz, 0.7H), 7.87 (d, J=7.8Hz, 0.3H, rotamer), 7.86-7.81 (m, 1H),
7.79–7.70(m, 0.5H,rotamer),5.16(m,0.3H,rotamer),4.87(m,0.7H),4.30–4.26(m,
0.6H),4.13(m,0.6H),4.04–3.95(m,0.4H,rotamer),3.89(m,0.4H,rotamer),2.495(m,
0.4H,rotamer),2.40–2.10(m,2.7H),2.00–1.95(m,0.8H,rotamer).MS,m/z:298.06[M-H]-
Embodiment 3：The synthesis of compound Ic, Id
(1) under room temperature, adjacent sulfonamide benzoic acid (50mg, 0.25mmol) is added in reaction bulb in thionyl chloride
In (3ml), system is warming up to reflux, when reaction 2 is small, residue is dissolved in dry methylene chloride by low pressure removal thionyl chloride
In, under the conditions of 0 DEG C, it is added into the dry methylene chloride solution of L-PROLINE benzyl ester hydrochloride (60mg, 0.25mmol),
Then add in triethylamine (56mg, 0.55mmol), reaction solution react at room temperature 2 it is small when.It is dilute with dichloromethane after the completion of reaction
Reactant is released, is washed respectively with saturated sodium bicarbonate and saturated nacl aqueous solution, organic phase solvent is obtained and is dried with anhydrous sodium sulfate,
Decompression is spin-dried for, using silica gel column chromatography (petroleum ether: ethyl acetate=2: 1) to reaction product implement purify, obtain target product
Intermediate (55mg), yield 57%.Nuclear-magnetism detection shows that product is amido bond rotamer mixture.1H NMR
(600MHz, CDCl3) δ 7.95 (d, J=7.5Hz, 0.7H), 7.90 (d, J=7.5Hz, 0.3H, rotamer), 7.85 (d, J=
7.8Hz, 0.7H), 7.73 (t, J=7.5Hz, 0.9H), 7.67 (t, J=7.6Hz, 0.8H), 7.61 (t, J=7.0Hz, 0.3H,
), rotamer 7.41-7.27 (m, 5H), 5.23 (dd, J=36.9,12.2Hz, 1.6H), 5.11 (d, J=11.8Hz, 0.4H,
rotamer),5.03–4.96(m,1H),4.30–4.23(m,0.7H),4.07(m,1H),3.97(m,0.3H,rotamer),
2.47–2.11(m,3.2H),2.07(m,0.8H,rotamer).13C NMR(150MHz,CDCl3)δ170.48,159.03,
144.66,144.20(rotamer),135.36,134.54(rotamer),133.06,132.64,129.52–128.75,
128.65,128.36,128.18,127.95(rotamer),125.03,123.81(rotamer),122.75,67.97
(rotamer),67.46,63.89,61.24(rotamer),52.45(rotamer),49.70,32.41(rotamer),
28.59,25.16,21.82(rotamer).IR(KBr):3422.10,1359.38,1158.96,1075.29,947.86,
859.97,545.76,463.30.
(2) at room temperature, by compound intermediate obtained above (55mg, 0.14mmol), it is dissolved in methanol (5ml),
Then 5% Pd/carbon catalyst of catalytic amount is added in, with air in hydrogen displacement flask, reacts 4h at room temperature.Reaction is completed
Afterwards, filtered with diatomite, revolving remove solvent, with HPLC (methanol: water=7: 13) to reaction product implement purify, obtain white
Solid product (Ic) (34mg), yield 82%.Nuclear-magnetism detection shows that product is amido bond rotamer mixture.1H
NMR (600MHz, MeOD) δ 8.15 (d, J=6.9Hz, 0.5H), 7.93 (d, J=6.9Hz, 0.7H), 7.89 (d, J=7.8Hz,
0.3H,rotamer),7.86–7.79(m,1H),7.79–7.72(m,0.5H,rotamer),5.11(m,0.3H,rotamer),
4.81(m,0.7H),4.35–4.26(m,0.6H),4.19(m,0.6H),4.04–3.98(m,0.4H,rotamer),3.89(m,
0.4H,rotamer),2.49(m,0.4H,rotamer),2.44–2.14(m,2.7H),2.10–1.97(m,0.8H,
rotamer).13C NMR(100MHz,MeOD)δ159.19,143.82,143.58(rotamer),132.90,127.98,
126.13,125.32(rotamer),121.69,53.44(rotamer),52.37,49.87,31.96(rotamer),
28.49,24.72,21.60(rotamer).IR(KBr):3424.69,2429.39,1795.93,1396.80,1359.91,
1159.17,1075.32,948.66,860.32,546.11,463.62.MS,m/z:297.08[M-H]-
(3) compound obtained above (Ic) (60mg) is dissolved in dry tetrahydrofuran solution at ambient temperature
Among (10ml), ethyl [3- (dimethylamino) propyl] carbodiimide (48mg) and I-hydroxybenzotriazole are successively added in
(33mg), stir 15 minutes, then add in ammonium hydroxide (148 μ L), reaction solution react at room temperature 12 it is small when.After the completion of reaction, rotation
Solvent is evaporated off, with silica gel column chromatography (dichloromethane: methanol=25: 1) implement purifying to reaction product, obtain white solid production
Product (Id) (40mg), yield 65%.Nuclear-magnetism detection shows that product is amido bond rotamer mixture.1H NMR
(400MHz,D2O)δ8.07(m,0.8H),8.02–7.99(m,0.2H,rotamer),7.94–7.75(m,1H),7.75–7.65
(m,1H),4.63–4.42(m,0.6H),4.50–4.34(m,0.3H,rotamer),3.73(m,0.5H,rotamer),3.70–
3.49(m,1.5H),2.49–2.27(m,1.3H,rotamer),2.09–1.79(m,2.7H).MS,m/z:298.10[M+H]+
Embodiment 4：The synthesis of compound Ie
Using method same as Example 1, change starting material into a carboxyl benzene sulfonic acid, finally obtain compound Ie.
White solid, 200mg, yield 85%.Nuclear-magnetism detection shows that product is amido bond rotamer mixture.1H NMR
(400MHz,D2O) δ 8.07 (m, 0.7H), 8.00 (dd, J=18.7,5.7Hz, 1H), 7.91 (m, 0.3H, rotamer), 7.81
(d, J=7.8Hz, 0.7H, rotamer), 7.71 (m, 1.3H), 4.59 (m, 0.7H), 4.40 (m, 0.3H), 3.72 (m, 0.6H,
rotamer),3.65–3.50(m,1.4H),2.54–2.30(m,1H,rotamer),2.16–1.85(m,3H).MS,m/z:
298.05[M-H]-
Embodiment 5：The synthesis of compound If, Ig
(1) under room temperature, carboxybenzenesulfonamide (365mg, 1.93mmol) is in thionyl chloride between being added in reaction bulb
In (5ml), system is warming up to reflux, when reaction 2 is small, residue is dissolved in dry methylene chloride by low pressure removal thionyl chloride
In, under the conditions of 0 DEG C, it is added into the dry methylene chloride solution of L-PROLINE benzyl ester hydrochloride (483mg, 2mmol), so
Afterwards add in triethylamine (487mg, 4.83mmol), reaction solution react at room temperature 2 it is small when.It is dilute with dichloromethane after the completion of reaction
Reactant is released, is washed respectively with saturated sodium bicarbonate and saturated nacl aqueous solution, organic phase solvent is obtained and is dried with anhydrous sodium sulfate,
Decompression is spin-dried for, using silica gel column chromatography (petroleum ether: ethyl acetate=2: 1) to reaction product implement purify, obtain white solid
Intermediate (402mg), yield 54%.Nuclear-magnetism detection shows that product is amido bond rotamer mixture.1H NMR
(600MHz,CDCl3) δ 8.06 (s, 1H), 7.94 (d, J=7.8Hz, 0.7H), 7.89-7.84 (m, 0.4H, rotamer),
7.68 (d, J=7.6Hz, 1H), 7.52 (q, J=8.0Hz, 0.8H), 7.42 (m, 0.3H, rotamer), 7.40-7.28 (m,
5H), 5.20 (dd, J=32.0,12.3Hz, 1.6H), 5.02 (dd, J=37.8,12.1Hz, 0.4H, rotamer), 4.69
(dd, J=8.4,5.1Hz, 0.8H), 4.29 (d, J=6.4Hz, 0.2H, rotamer), 3.83-3.73 (m, 0.4H,
rotamer),3.61(m,0.8H),3.55–3.42(m,0.8H),2.37–2.26(m,0.9H,rotamer),2.07–1.84
(m,3.3H).13C NMR(150MHz,CDCl3)δ170.91(rotamer),170.77,167.96(rotamer),167.17,
141.81,136.34(rotamer),135.76,134.58,133.93(rotamer),129.92,129.35(rotamer),
128.27,127.64,127.38,127.14,126.93,126.49(rotamer),124.24,123.54(rotamer),
66.36(rotamer),66.02,60.49(rotamer),58.43,48.99,45.92(rotamer),28.66
(rotamer),28.29,24.27,23.94(rotamer).IR(KBr):3422.57,1358.56,1159.60,1075.08,
948.72,860.31,546.24,525.62,463.86.
(2) at room temperature, by intermediate obtained above (300mg, 1.01mmol), it is dissolved in methanol (5ml), Ran Houjia
Enter 5% Pd/carbon catalyst of catalytic amount, with air in hydrogen displacement flask, react 4h at room temperature.After the completion of reaction, silicon is used
Diatomaceous earth filters, and revolving removes solvent, with HPLC (methanol: water=7: 13) implement purifying to reaction product, obtain white solid production
Product If (228mg), yield 76%.Nuclear-magnetism detection shows that product is amido bond rotamer mixture.1H NMR
(400MHz,D2O) δ 8.07 (m, 0.7H), 8.03 (dd, J=18.7,5.7Hz, 1H), 7.91 (m, 0.3H, rotamer), 7.84
(d, J=7.8Hz, 0.7H, rotamer), 7.72 (m, 1.3H), 4.59 (m, 0.7H), 4.40 (m, 0.3H), 3.72 (m, 0.6H,
rotamer),3.65–3.50(m,1.4H),2.54–2.30(m,1H,rotamer),2.16–1.85(m,3H).13C NMR
(100MHz,D2O)δ176.35(rotamer),175.94,170.76(rotamer),169.85,141.85,136.45
(rotamer),135.95,131.36,130.83(rotamer),130.23(rotamer),130.03,128.01,127.60
(rotamer),124.32,123.74(rotamer),62.36 (rotamer),59.86,50.48,47.41(rotamer),
31.08(rotamer),29.31,24.83,22.53(rotamer).IR(KBr):3423.72,1619.63,1397.74,
1357.46,1159.68,1074.99,948.72,860.46,546.37,525.19,464.29.MS,m/z:297.08[M-
H]-
(3) compound If (64mg, 0.22mmol) obtained above is dissolved in dry tetrahydrofuran at ambient temperature
Among solution (10ml), ethyl [3- (dimethylamino) propyl] carbodiimide (45mg, 0.23mmol) and 1- hydroxyls are successively added in
Benzotriazole (31mg, 0.23mmol) stirs 15 minutes, then adds in ammonium hydroxide (148 μ L), it is small that reaction solution reacts 12 at room temperature
When.After the completion of reaction, revolving removes solvent, with silica gel column chromatography (dichloromethane: methanol=25: 1) to reaction product implementation
Purifying, obtains white solid product I g (40mg), yield 63%.Nuclear-magnetism detection shows that product mixes for amido bond rotational isomer
Object.1H NMR(400MHz,D2O)δ8.07(m,0.8H),8.02–7.99(m,0.2H,rotamer),7.94–7.75(m,1H),
7.75–7.65(m,1H),4.63–4.42(m,0.6H),4.50–4.34(m,0.3H,rotamer),3.73(m,0.5H,
rotamer),3.70–3.49(m,1.5H),2.49–2.27(m,1.3H,rotamer),2.09–1.79(m,2.7H).13C NMR
(100MHz,D2O)δ176.84,176.62(rotamer),170.83(rotamer),170.05,141.81,136.30
(rotamer),136.01,131.45,130.87(rotamer),130.24,129.98,129.71(rotamer),128.00,
127.59,126.56(rotamer),124.42,123.68(rotamer),62.37(rotamer),60.75,50.80,
47.84(rotamer),31.58(rotamer),30.12,24.87,22.67(rotamer).IR(KBr):3423.05,
1397.86,1360.21,1158.84,1075.50,948.21,860.07,545.76,463.62.MS,m/z:298.10[M+
H]+
Embodiment 6：The synthesis of compound Ih
Using method same as Example 1, starting material is changed into carboxyl benzene sulfonic acid, finally obtains compound Ih.
White solid, 180mg, yield 78%.Nuclear-magnetism detection shows that product is amido bond rotamer mixture.1H NMR
(400MHz,D2O) δ 8.07 (m, 0.7H), 8.00 (dd, J=18.7,5.7Hz, 1H), 7.91 (m, 0.3H, rotamer), 7.81
(d, J=7.8Hz, 0.7H, rotamer), 7.71 (m, 1.3H), 4.59 (m, 0.7H), 4.40 (m, 0.3H), 3.72 (m, 0.6H,
rotamer),3.65–3.50(m,1.4H),2.54–2.30(m,1H,rotamer),2.16–1.85(m,3H).MS,m/z:
298.06[M-H]-
Embodiment 7：The synthesis of compound Ii
(1) dry dimethylformamide will be dissolved in sulfonamide benzoic acid (274mg, 1.36mmol) at ambient temperature
Among solution (10ml), ethyl [3- (dimethylamino) propyl] carbodiimide (384mg, 2mmol) and 1- hydroxy benzenes are successively added in
And triazole (270mg, 2mmol), it stirs 15 minutes, then adds in L-PROLINE benzyl ester hydrochloride (362mg, 1.5mmol) and 4-
Dimethylamino naphthyridine (580mg, 4.75mmol), reaction solution react at room temperature 12 it is small when.After the completion of reaction, add in 150ml and steam
Distilled water is stood overnight under the conditions of 4 DEG C.Then filter, gained white solid is target product intermediate (412mg), yield
For 78%.Nuclear-magnetism detection shows that product is amido bond rotamer mixture.1H NMR (400MHz, dimethyl sulfoxide (DMSO)) δ
7.89 (d, J=8.1Hz, 1.6H), 7.80 (d, J=8.0Hz, 0.4H, rotamer), 7.68 (d, J=8.0Hz, 1.5H),
7.49 (d, J=5.8Hz, 1.8H, rotamer), 7.37 (dd, J=13.4,3.5Hz, 3.2H), 7.17 (d, J=6.8Hz,
0.4H,rotamer),5.29–5.06(m,1.6H),5.01–4.90(m,0.4H,rotamer),4.55(m,0.8H),4.49
(m,0.2H,rotamer),3.59(m,0.4H,rotamer),3.49(m,1.6H),2.32(m,1H,rotamer),2.08–
1.67(m,3H).13C NMR (100MHz, dimethyl sulfoxide (DMSO)) δ 172.31 (rotamer), 171.99,168.57 (rotamer),
167.71,145.79,145.37(rotamer),140.33(rotamer),139.58,136.47,135.81(rotamer),
130.47,129.51–128.11,128.11–128.10,128.10–127.90,127.61,126.61(rotamer),
126.25,66.90(rotamer),66.39,61.04(rotamer),59.50,49.87,47.03(rotamer),31.49
(rotamer),29.36,25.41,22.73(rotamer).IR(KBr):3422.89,1357.72,1160.04,1074.90,
948.95,860.32,545.94,525.77,463.97.
(2) at room temperature, by compound obtained above (311mg, 0.8mmol), it is dissolved in methanol (5ml), Ran Houjia
Enter 5% Pd/carbon catalyst of catalytic amount, with air in hydrogen displacement flask, react 4h at room temperature.After the completion of reaction, silicon is used
Diatomaceous earth filter, revolving remove solvent, with HPLC (methanol: water=1: 3) to reaction product implement purify, obtain white solid product
It is deprotected benzoic acid (191mg), yield 80%.Nuclear-magnetism detection shows that product is amido bond rotamer mixture.1H
NMR(400MHz,CD3OD) δ 7.99 (d, J=8.1Hz, 1.5H), 7.94 (d, J=8.0Hz, 0.5H, rotamer), 7.72 (d,
J=8.1Hz, 1.5H), 7.58 (d, J=8.1Hz, 0.5H, rotamer), 4.65-4.54 (m, 0.8H), 4.40 (m, 0.2H,
rotamer),3.72(m,0.4H,rotamer),3.65–3.45(m,1.6H),2.50–2.31(m,1H),2.17–1.86(m,
3H).13C NMR(100MHz,CD3OD)δ173.97,172.74(rotamer)170.12(rotamer),169.08,145.35,
144.94(rotamer),140.09(rotamer),139.46,127.41,127.08(rotamer),126.02,61.30
(rotamer),59.34,51.52(rotamer),49.80,30.94(rotamer),29.18,24.81,22.20
(rotamer).IR(KBr):3422.84,1396.70,1358.80,1160.01,1074.94,948.67,860.29,
546.02,525.68,464.17.
(3) that compound obtained above (50mg, 0.16mmol) is dissolved in dry tetrahydrofuran at ambient temperature is molten
Among liquid (10ml), ethyl [3- (dimethylamino) propyl] carbodiimide (34mg, 0.18mmol) and 1- hydroxy benzenes are successively added in
And triazole (24mg, 0.18mmol), it stirs 15 minutes, then adds in ammonium hydroxide (110 μ L), it is small that reaction solution reacts 12 at room temperature
When.After the completion of reaction, revolving removes solvent, with silica gel column chromatography (dichloromethane: methanol=25: 1) to reaction product implementation
Purifying, obtains white solid product I i (25mg), yield 53%.Nuclear-magnetism detection shows that product mixes for amido bond rotational isomer
Object.1H NMR(400MHz,D2O) δ 8.02 (d, J=8.5Hz, 1.4H), 7.99 (d, J=8.5Hz, 0.6H, rotamer),
7.78 (d, J=8.5Hz, 1.4H), 7.61 (d, J=8.5Hz, 0.6H, rotamer), 4.57 (dd, J=8.2,6.1Hz,
0.7H), 4.41 (dd, J=8.0,3.8Hz, 0.3H, rotamer), 3.75 (m, 0.6H, rotamer), 3.65-3.51 (m,
1.4H),2.49–2.33(m,1H),2.08–1.89(m,3H).13C NMR(100MHz,D2O)δ176.84,176.64
(rotamer),171.11(rotamer),170.37,143.09,142.83(rotamer),139.47(rotamer),
139.20,127.91,127.40(rotamer),126.38(rotamer),126.25,62.28(rotamer),60.60,
50.71,47.79(rotamer),31.85(rotamer),30.11,24.81,22.66(rotamer).IR(KBr):
3422.47,1397.63,1360.08,1158.76,1075.44,947.92,859.90,545.28,463.66.MS,m/z:
298.10[M+H]+
Embodiment 8：Enzyme inhibition activity is tested
Degradation substrate using Imipenem monohydrate as NDM-1 carries out Activity determination, the compound contain there are one β-
The structure of lactam nucleus simultaneously containing O=C-N-C=C conjugated structures, shows that substrate can generate UV absorption.NDM-1 can be with water
Solve Imipenem beta-lactam nucleus, cause to grip altogether it is destructurized so that UV absorption dies down.By compare NDM-1 with
Full wavelength scanner uv absorption spectra before and after substrate reactions if tested compound has inhibitory action to NDM-1, makes
NDM-1 can not hydrolyze Imipenem substrate, and so as to prevent the reduction of the ultraviolet absorption value of substrate, compound is may determine that with this
Whether there is inhibition to NDM-1, so as to carry out the screening of NDM-1 inhibitor medicaments.
NDM-1 Stock concentrations be 50nM, system buffer solution be 30mM 4- hydroxyethyl piperazineethanesulfonic acids (pH7.3), 10 μ
The 10 μ L of tested compound of various concentration using 500 μM of Imipenem, are made an addition to survey by the ZnCl2 of M, 10ug/mL BSA
In examination system, 37 DEG C are incubated 15 minutes, in 300nM wavelength measurement UV absorptions.
Positive control is 1mM ethylenediamine tetra-acetic acids-dimethyl sulphoxide solution of 10 μ L；
The Imipenem dimethyl sulphoxide solution that negative control group is added for no albumen and any inhibitor.
NDM-1 maximum inhibitions=(A300nmExperimental group-A300nmNegative control group)/(A300nmPositive controls-A300nmIt is cloudy
Property control group) X100%.In formula, A300nmFor the ultraviolet absorption value of test solution at 300 nm wavelength.
(1) preparation of degradation Substrate stock liquid
Imipenem monohydrate control substrate is dissolved in 30mM 4- hydroxyethyl piperazineethanesulfonic acid (4- hydroxyethyl piperazines
Ethanesulfonic acid) in, 500 μM of stock solution is configured to for testing.
(2) preparation of testing compound solution
Testing compound is dissolved in 95% dimethyl sulfoxide (DMSO) and 5% distilled water in the mixed solvent, is configured to 100mM concentration
Solution, prepared solution is then diluted to 1mM respectively, 500 μM, 250 μM, 100 μM, 10 μM, 1 μM, 0.1 μM, is preserved
With spare in 4 DEG C of refrigerator.
(3) preparation of metallo-β-lactamase NDM-1 albumen buffer solution
NDM-1 is dissolved in albumen buffer solution (pH=6.8), is configured to the NDM-1 albumen buffer solutions of 50nM.Buffer solution
Ingredient include 30mM 4- hydroxyethyl piperazineethanesulfonic acids, 10 μM of ZnCl2With the Bovine serum albumin (BSA) of 10 μ g/mL.
(4) NDM-1 inhibitory activity
96 microwell plates are taken,
500 μM of substrate Imipenem solution (50 μ L) is added in 15 multiple holes,
5 multiple holes are as positive control：1mM ethylenediamine tetra-acetic acids-dimethyl sulphoxide solution of 10 μ L,
5 multiple holes are that negative control group is no albumen and Imipenem (50 μ L, 500 μM) diformazan of any inhibitor addition
Base sulfoxide solution,
The testing compound solution (10 μ L) of above-mentioned prepared various concentration is added in, each 5 multiple holes of concentration vibrate,
Incubation at room temperature 1 minute.Finally, heliotropism control group and test group add in 500 μM of substrate Imipenem solution (50 μ L) per hole
It is reacted.Vibration is incubated at room temperature 15 minutes.Detect 300nm UV absorptions.Draw NDM-1 maximum inhibitions and sample concentration
Curve calculates test compound and inhibits half-strength IC50 values to NDM-1.
Table -1：Test compound is to the half-inhibition concentration of NDM-1
Embodiment 9：Clinical drug-resistant bacterium inhibitory activity is tested
For various clinical antibody-resistant bacterium, by proline derivative of the present invention respectively with clinical antibacterials：Cefotaxime
With weight ratio 1:2 are used in mixed way, and compared with these clinical antibacterials exclusive uses, evaluation proline derivative is recovering anti-
Bacterium drug is to the fungistatic effect of drug-fast bacteria.
1, bacterial species：Preceding four measure bacterial strain is isolated from clinical patients below, through microorganism and molecular biology side
Method confirms that latter two bacterium part is purchased from ATCC, and all bacterial strains are all from infectious disease diagnosis and treatment National Key Laboratory of Zhejiang University.
A) ESBL escherichia coli 2251 (CTX-M-14), escherichia coli 3947 (CTX-M-55) are produced；
B) ESBL Klebsiella Pneumoniaes 2661 (CTX-M-15), Klebsiella Pneumoniae 2837 (CTX-M-14) are produced；
C) ESBL, KPC enzyme reference culture (Klebsiella Pneumoniae) ATCC70063 (production ESBL) is produced；
D) escherichia coli ATCC25922.
2, antibacterial activity in vitro method
Antibacterial activity in vitro is measured to be carried out according to U.S. clinical Laboratory Standard research institute (CLSI) agar dilution.
1) dissolved dilution of drug
Cefotaxime sterilizing water dissolution, enzyme inhibitor (proline derivative of the present invention, hereinafter referred to as enzyme inhibitor) is with two
Methyl sulfoxide dissolves.
Cefotaxime and enzyme inhibitor Ia-Ii are configured to 10mg/mL storage liquid respectively first.Prepare single medicine cephalo he
Pyridine takes 0.512mL antibacterials to be configured to 1mL solution, 0.5mL is taken to be added in the culture medium that 20mL mixes up cation concn, i.e.,
Initial concentration is 128mg/L, then adds mixing taking-up 0.5mL solution after 0.5mL water, and so on, it is diluted to the last one concentration
0.06mg/L.Prepare inhibitor compound and single medicine 1:2 compound preparation, i.e. inhibitor compound Ia-Ii and they point
Not with three kinds of single medicine initial concentrations than being respectively 64:128mg/L first prepares single medicine according to above method, then by enzyme inhibitor
Compound takes 0.256mL to be configured to 1mL solution, and 0.5mL is taken to be added in first piece of culture medium, i.e., initial concentration is 64mg/L, is pressed
According to single prescription method doubling dilution.It is spare after mixing cooling.
2) inoculation, the incubation of bacterium
Monoclonal bacterium colony prepares the bacteria suspension of 0.5 Maxwell concentration, then carries out 1: 10 dilution, is added in 96 orifice plates, uses multiple spot
Inoculation instrument is inoculated in agar plate surface.35 DEG C of incubation 16-20h of postposition have been inoculated with, have observed result.
3) result is observed
Using on agar plate bacterium start non-growing tablet drug concentration as minimum inhibitory concentration i.e. MIC.
Table -2：Test compound and cefotaxime (caz) Combination test result
It is demonstrated experimentally that embodiment 1-7 has medically allowing for the proline derivative of beta-lactam enzyme inhibition
Salt has beta-lactam enzyme inhibition.
The solvate of proline derivatives of the embodiment 1-7 with beta-lactam enzyme inhibition is with beta-lactamase
Inhibitory action.
Embodiment 1-7 has the proline derivative of beta-lactam enzyme inhibition and the carrier medically allowed composition
Composition has beta-lactam enzyme inhibition.
It is proved through active testing, the proline derivatives of various embodiments of the present invention is to beta-lactamase, particularly pair
NDM-1 has good inhibiting effect.L-PROLINE derivative of the present invention can be by inhibiting, to beta-lactamase, to be particularly
NDM-1 activity, decreases or even eliminates hydrolysis of the NDM-1 to beta-lactam antibiotic, alleviates drug resistance caused by NDM-1, extensive
The effect of multiple antibiotic is to bacterium infects so as to treat the drug-resistant bacteria as caused by NDM-1, has good medicinal application
Prospect.
Claims (5)
1. the proline derivative with beta-lactam enzyme inhibition, with formula (I) Suo Shi：
Wherein, amido bond includes the cis or trans rotational isomer of its naturally occurring in formula (I)；R1For OH or NH2；
R2For ortho-sulfonic acid base phenyl, adjacent sulfoamido phenyl, sulfonic group phenyl, sulfoamido phenyl, p-sulfonic acid base phenyl,
To sulfoamido phenyl or adjacent carboxyl benzyl.
2. the proline derivative according to claim 1 with beta-lactam enzyme inhibition, it is characterized in that formula (I) is tied
Structure is：
3. claim 1 or 2 has the salt medically allowed of the proline derivative of beta-lactam enzyme inhibition.
4. claim 1 or 2 has the solvate of the proline derivative of beta-lactam enzyme inhibition.
5. claim 1 or 2 there is the proline derivative of beta-lactam enzyme inhibition with the vehicle group medically allowed
Into composition.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997010225A1 (en) * | 1995-09-15 | 1997-03-20 | Smithkline Beecham Plc | Pyrrolidine and thiazole derivatives with antibacterial and metallo-beta-lactamase inhibitory properties |
| CN105636592A (en) * | 2013-07-11 | 2016-06-01 | 伊万斯彻有限公司 | Pro-drug forming compounds |
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2016
- 2016-11-21 CN CN201611043205.3A patent/CN108084075A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997010225A1 (en) * | 1995-09-15 | 1997-03-20 | Smithkline Beecham Plc | Pyrrolidine and thiazole derivatives with antibacterial and metallo-beta-lactamase inhibitory properties |
| CN105636592A (en) * | 2013-07-11 | 2016-06-01 | 伊万斯彻有限公司 | Pro-drug forming compounds |
Non-Patent Citations (1)
| Title |
|---|
| AFSHIN MALEKI ET AL.,: "Comparison of QSAR Models Based on Combinations of Genetic Algorithm, Stepwise Multiple Linear Regression, and Artificial Neural Network Methods to Predict Kd of Some Derivatives of Aromatic Sulfonamides as Carbonic Anhydrase II Inhibitors", 《RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY》 * |
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