CC BY
109
ISSN 2522-1841 (Online) ISSN 0005-2531 (Print)
UDC547. 541.572.54
SYNTHESIS OF NANOSTRUCTURES ON THE BASIS OF DIAZACROWN ETHER AND MAGNETITE NANOPARTICLES LOADED BY CEPHALOSPORIN ANTIBIOTICS
U-A-Hasanova1, L.Z.Vezirova2, Z.O.Gakhramanova2
'Baku State University SRI "Geotechnological problems of oil, gas and Chemistry "
vazirova. leyla@gmail. com
Received 05.02.2018
Synthesis of hydroxyl containing azacrown macrocycles (MC) that is able to mimic the properties of natural siderophores has been perfomed. On the basis of synthesized MC the supramolecular ensembles with magnetite nanoparticles, loaded by cephalosporin antibiotics were prepared. The synthesized MC was investigated by NMR, mass-, FTIR spectroscopy methods. The morphology of prepared nanoen-sembles was analyzed by scanning electron microscopy SEM, FTIR, X-ray diffraction XRD analysis methods. The quantitative analysis of nanostructures was made by atom absorbance spectroscopy (AAS) as well as on the basis of Lambert-Beer law by UV spectroscopy method. Prepared nanostructures were tested on gramnegative Escherichia Coli and gram -positive Staphylococcus aureus, having multi drug resistance propertie it has been found that the nanostructures significantly increase the antimicrobial effect of cephalsporins and decrease their minimum inhibitory concentration (MIC).
Keywords: macrocycles, crown ether, supramolecular chemistry, siderophores, magnetite nanoparticles.
Introduction
Today's great problem, faced to clinicians, been is the problem of antibiotic resistance. Synthesis and application of new drugs, for which have not been worked out yet as it is rather prolonged and hard that requires significant investment. As the samples of resistance can be provided the fact revealed, that the quantity of the ESBLs producing strains of the Escherichia Coli, causing nosocomial and community-acquired infections, is increasing rapidly day by day [1]. Staphylococcus Aureus also show the rise of the number of resistant strains to antibiotics especially to betta-lactames particularly in developing countries [2].
As a result, there is an urgent requirement of new modified drugs that are effective against antibiotic-resistant bacteria. The one of the possible ways is nanostructuring of already used drugs that will enhance and improve their activity. In particular, attention is paid to the application of magnetite nanoparticles in targeted drug delivery, not only due to their biocompati-bility, but also because of the possible targeting of these nanoparticles, loaded with drug, directly to the infected sites and organs of organism by means of the applied external magnetic field [3]. And, in case with nanoantibiotics, magnetite nanoparticles can reduce the toxicity and side effects of antimicrobial agents. It is known that the
development and functioning of most pathogenic microorganisms require a great concentration of iron ions, and as a result they have developed a special system of binding and transport of iron ions that are necessary for the functioning of their life cycle. This system is based on a shuttle mechanism that uses small-molecule compounds, called siderophores, that selectively bind to the iron ions. Many scientists point, that antibiotics, coupled with siderophore-mimic compounds, can easily penetrate through the membrane of gramnegative bacteria [4, 5].
In accordance to above mentioned, it was interesting to synthesize the hydroxyl containing azacrown ether that is able to mimic the properties of natural siderophores and prepare the supramolecular ensembles of synthesized MC with magnetite nanoparticles, loaded by cephalosporin antibiotics. The investigation of their biological activity against grampositive and gramnegative microorganisms is a matter of interest in terms of finding the synergistic effect of siderophore-mimic MC and magnetite NPs, loaded with cephalosporin antibiotics.
Experemental part
All chemicals, used in the synthesis, were of analytical grade and used as received. Eth-ylenediamine, l,3-dichloro-2-propanol, salysilal-dehyde were purified by distillation under re-
duced pressure, created by water pump. FeCl3 6H20, FeS04 7H20, NH4OH (25%) were purchased from Sigma-Aldrich (Taufkirchen, Germany); Nutrient Broth was purchased from Biolife (Mlano, Italia). Synthesis of MC 1,13-Diaza-5,9-dioxa-7-hydroxy-3,4,10,1 -dibenzocyc-lopentadecan with further purification by recrys-tallization from benzene, yield - 0.70 g (65%), Tmeit. - 148-149°C. Found, %: C 69.5, H 7.4, N 8.7. C19H24N2O3. Calculated, %: C 69.5, H 7.4, N 8.5. IR (KBr): 3350 (OH); 3330, 1455 (NH); 1604, 1590, 1492 (Ar); 1251, 1035 (Ar-0-CH2); 754 (1,2-Ar) cm"1. JH NMR: 2.64 (s, 4H, NCH2CH, N), 3.24 (m, 3H, NH and OH), 3.65 (s, 4H, ArCH2), 4.14 (5H, CH2CHCH2), 6.74-7.25 (m, 8H, ArH) ppm. Synthesis of nanostructures, based on Fe304, coated by MC and cephalosporin antibiotics (cefotaxime and ceftriaxone): MC@Fe304@cefotaxime (MC@Fe304@CTAX) and MC@Fe304@cefhiaxone
(MC@Fe304@CTRIX) NPs. Magnetic iron oxide nanoparticles are usually prepared by wet chemical precipitation from aqueous iron salt solutions in alkaline milieu, created by using NH4OH, in the atmosphere of gaseous nitrogen. The formed Fe304 nanoparticles (NPs) were separated by strong NdFeB permanent magnet, repeatedly washed with distilled water and dispersed in ethanol [6]. The ethanol solution of MC, taken in excess, was added to ethanol solution of Fe304 nanoparticles and vigorously stirred 45 minutes. Then nanoparticles were stabilized by cefotaxime and ceftriaxone molecules, by adding the water solution of corresponded antibiotics into reaction mixture. After stirring during 8 hours in ambient, the prepared nanostructures were separated by strong NdFeB permanent magnet and repeatedly were washed with distilled water [7, 8]. The obtained NPs were dried at ambient conditions, and the iron content in the samples was analyzed by atom absorption spectroscopy and performed on Var-ian SpectrAA 220FS Atomic absorption spectrometer. Samples were prepared by Milestone ETHOS 1 Microwave extraction unit. The UV spectra have been recorded on Spectrophotometer Specord 250 Plus. UV spectra were recorded at 238 nm for standard solutions of ceftriaxone with different concentrations in the range and 275 nm for standard solutions of MC.
Characterization of structure
XRD - X-ray diffraction analysis was performed on Rigaku Mini Flex 600 XRD dif-fractometer in ambient. In all the cases, CuK,,-radiation from a Cu X-ray tube (run at 15 raA and 30 kV) was used. The samples were scanned in the Bragg angle 2 h range of 20-70°.
FTIR The functional groups, present in the powder samples of MC@Fe304@CTRIX and MC@Fe304@CTAXNPs, were identified by Fourier Transform Infrared (FTIR) spectroscopy. FTIR spectra were recorded on a Varian 3600 FTIR spectrophotometer in KBr tablets. The spectrum was taken in the range of 4000 -400 cm"1 at room temperature.
Scanning Electron Microscope (SEM) and Energy-Dispersive Spectrum (EDS) analysis SEM and EDS analysis of prepared samples of MC@Fe304@CTRIX and MC@Fe304@CTAX nanoparticles were taken on Field Emission Scanning Electron Microscope [9, 10].
Antibacterial activity of pristine antibiotics and the prepared nanostructures were tested by diffusion method on Staphylococcus aureus and Escherichia coli. Cephalosporinswere taken in amount 30|ig (indicator disks were purchased by Research-and-Development Center of Pharmacotherapy, 192236 St. Petersburg). The synthesized substances were also taken in amount equal to 30 |ig. Escherichia coli was cultivated on Endo's medium and Staphylococcus aureus on Baird-Parker agar (cultures were kindly provided by one of the clinical laboratories of Baku). Microbiological tests were performed on Petri dishes. Due to the fact that this method provides only quality data, microdilution method was also performed [11]. By this method the MICs of the prepared nanostructures and usual antibiotics were identified and further compared to each other. To perform microdilution method the stock solutions with different concentrations of the substances were prepared in distilled sterile water and were distributed in 96 multi-well plates. Each well was inoculated with 0.1 mL of microbial suspensions of 0.5 Mc Farland turbidity, prepared from 24 h fresh culture. Sterility control wells (nutrient broth) and microbial growth controls (inoculated nutrient broth) were used. The plates were incubated for 24 h at 37 C [12].
Results and discussions
Synthesis of MCl,13-Diaza-5,9-dioxa-7- is shown on the Scheme 1. hydroxy-3,4, 10,1-dibenzocyclopentadecan (II)
C
OC0
I
o
H
A
/C
HO
NH2+
."c
(I)
II
NaOH/cl T ci 7 OH
IV
OH
+NaBH/i
+NaBH4
/-\
^-NH H . CH CH
o
III
H
CH Hi
x>
ii
Scheme 1. The synthesis of MC l,13-Diaza-5,9-dioxa-7-hydroxy-3,4,10,l-dibenzocyclopentadecan.
N,N'ethylenebis(salysilimine) (II) were prepared by condensation of salysilaldehide (I) with ethylenediamine. The reduction of (II) was carried out by sodium borhydride. The ring closure step was carried out by reaction of corresponding saturated derivative (III) with 1,3-dichloro-2-propanol as in Scheme 1.
The purity and crystalline properties of the MC@Fe304@CTAX and MC@Fe304@CTRIX were investigated by powder X-ray diffraction (XRD). The XRD patterns are shown in Figures 1 and 2 correspondingly. All the XRD peaks were well defined and corresponded to Fe304 nanoparticles with cubic structure. In XRD peak broadening testifies for the formation of nano-crystals. In both patterns all lines relate to magnetite and can be indexed, using the ICDD
(PDF-2/Release 2011 RDB) DB card number 00-001-1 111, for prepared nanostructures. The patterns of MC@Fe304@CTAX and MC@Fe304@CTRIXNPs have characteristic
3
as
à m d H
Ml hzAfO* ......
29, degree
Fig. 1. a - XRD pattern for the na no structured MC@Fe304@CTAX, b - XRD pattern for the nano-structured MC@Fc304@CTRIX.
0s
H
1000
2000
Wave length, cm
3000
4000
1000
2000
Wave length, cm
3000
-1
4000
Fig. 2a- FTIR spectra (3) MC@Fe304'@CTAX; (2) pristine cefatixime, (/) pristine Fe304; b - FTIR spectra (3) MC(@Fe304@CTRX, (2) pristine ceftriaxone, (/) pristine Fc;0|.
peaks at 30.44° (220), 35.64° (311), 43.16° (400), 57.31° (511), 62.76° (440) Figure 1(a) and 30.58° (220), 35.66° (311), 43.30° (400), 57.30° (511), 62.89 (440) Figure 1(6) correspondingly, which correlate with the standard pattern of Fe304 well. The intensity of the diffraction peak of (311) plane of both samples is stronger than other peaks. The average crystal size, estimated from (311) peak, using the Scherrer formula, is 11.8 nm for MC@Fe304@CTAX and 8.5 nm for MC@Fe304@CTRIX pattern nanoparticles. Figure 2 a and b present the FTIR spectra of MC@Fe304@CTAX and MC@Fe304@CTRIX correspondingly. The spectra of prepared nanostructures were compared with spectra of pristine MC on spectra of pristine cephalosporins Figure 2 a and b\ and spectra of pristine Fe304 in order to determine the coordination sites that may be involved in chelation with surface of magnetite nanoparticles. The spectra of both nanostructures Figure 2 a and b exhibit a characteristic peak of Fe3C>4 at about 574-580 cm"1 (Fe-0 stretching). The IR spectra of cephalosporins, exhibit the strong absorption band at 1730-1740 cm"1, corresponding to betta-lactam (C=0) stretching vibrations. This band is not shifted in the prepared nanostructures compared to the pure cephalosporins indicating that this group is not involved in coordination. In the both samples the band at 1600-1610 cm"1, corresponding to the (COO)
group of the free cephalosporins, is shifted (20-50 cm"1) to lower wave numbers in the spectra of prepared nanostructures, indicating coordination through that group. The band at around 1370-1380 cm"1, which corresponds to symmetrical carboxylate group (COO), also changes that points to chelation via this group with the magnetite surface. The bands in the wave number regions 3250-3100 cm"1 and 3050-2810 cm"1, corresponding to the (NH) and (CONH) groups of pure cephalosporins, disappear in the spectra of nanostructures that provides the strong evidence that these groups are involved in chelation process [9]. The absence of band in the wave region 3445-3500 cm"1, corresponding to OH group of free ceftriaxone in the spectra of MC@Fe304@CTRIX, may indicate the ionization of this group during coordination. At the same time the comparison of spectra of pure MC Figure 2 a and b with spectra of prepared nanostructures shows the shifting of strong band at 1455 cm"1, corresponding to the NH groups of MC, to 1399 cm"1 region in the nanostructures. The wide band at 3330-3350 cm"1, corresponding to (OH) and (NH) in pristine MC, disappears in the spectra of nanostructures and that is strong evidence of coordination of MC molecules with magnetite surface via OH and NH groups of MC. The intense band at 1251 cm"' (Ar-0-CH2) of MC) is shifted to 1180 cm"1 region in the spectra of MC@Fe304@CTAX and disappears in the
spectra ofMC@Fe304@CTRIX These indicate the involving of macrocycle's oxygen atoms in coordination process. As is seen from FTIR spectra the absorption occurs through carb-oxylic, amine, CONH, hydroxyl groups of ceftriaxone and cefotaxime and NH, OH and cyclic oxygen atoms of MC by self-assembling via non-covalent interaction with surface of magnetic NPs. Thus, the LR spectra results provide strong evidences for the multiple chelation sites of MC and drugs molecules with surface of magnetite NPs.
The surface morphology of the MC@Fe304@CTAX and MC@Fe304@CTRIX NPs, determined by SEM, are shown in Figure 3 and 4 correspondingly.
Л
\a *
• io<a аои/лмм. i/n/ioi» _« jjMjj lS.OfcV Ml_gjj MP « S— »:»:«!
Fig. 3. SEM image of MC@Fe304@.CTAX NPs.
X2
.3333
4
I One JIOL/WU 14-JU-H
I «1И lijjg » » »
Fig. 4. SEM image of \lCc/I;e;O c/CTRIX NPs.
As is shown the prepared nanostructures are monoclisperse with almost uniform size approximately 6-13 nm. The average sizes of formed nanoparticles correlate well with data, obtained from XRD analysis.
Quantitative analysis of cephalosporins molecules, contained in MC@Fe304@CTAX and MC@Fe304@CTRIX NPs, was carried out by UV spectroscopy methods on the basis of Lambert-Beer law and the iron content in NPs samples was determined by AAS method. In accordance with results and following calculation of both methods, they correlate with each other very well and reveal very close value of loaded cephalosporins' molecules in NPs that makes 0.18 and 0.21 g of ceftriaxone and cefotaxime in 1 gr of MC@Fe304@CTAX and MC@Fe304@CTRIX NPs correspondingly. The microbiological assay was performed on two different strains of bacteria: Staphylococcus aureus and Escherichia coli. The choice was based on the results of our previous research, showing that gramnegative and grampositive bacteria react differently to nanostructures, containing magnetite nanoparticles. We assumed that the presence of siderophoric system, which is responsible for iron uptake in the most of gramnegative bacteria, overcomes the destroying of betta-lactam ring of cephalosporins via dragging drug loaded magnetite through the siderophoric channels in outer membrane of the bacteria [15] On the basis of this suppose we synthesized MC that is able to mimic the natural siderophores, in order to get the synergistic effect with antibiotics, coupled with magnetite NPs. As it is known from our previous study, the Fe304@CTAX and Fe304@CTRJX have no antimicrobial effect on S. aureus. However, the results of agar diffusion test on Staphylococcus aureus show that the inhibition zones of pure cefotaxime and MC@Fe304@CTAX were almost the same, equal to 13 and 11 mm correspondingly; MC@Fe304@CTRIX and pure ceftriaxone have absolutely the same inhibition zone, as shown on the Table 1. Thus, the binding of MC to the Fe304@CTAX and Fe304@CTRIX NPs restores the antimicrobial properties of initial drugs in the MC@Fe304@CTAX and MC @F e304@C TRIX NPs correspondingly. However, the effect of the MC@Fe304@CTAX on E.coli was significant [16]. From the Table 2, is seen that the diameter of inhibition zone of MC@F©304@CTAX was 29 mm, whereas pristine cefotaxime produced 9 mm of inhibition zone's diameter.
la И
•t'.та
\
Table 1. The diameter of inhibition zones, produced by synthesized nanostractures and pristine antibiotics, and their MICs 011 Staphylococcus aureus_
Cefatoxime Ceftroaxone Fe304@CTAX Fe304#CTRIX MC(0Fe3O4@CTAX MC@Fe304(®CTRIX
Diameter, mm 13 11 0 0 11 11
MIC, Hg/mL 6 6 0 0 6 6
Table 2. The diameter of inhibition zones, produced by synthesized nanostractures and pristine antibiotics, and their MICs on Escherichia coli
Cefatoxime Ceftroaxone Fe304i®CTAX Fe304i®CTRIX MC@Fe3O4(0,CTAX MC(®Fe304@CTRIX
Diameter, mm 9 7 22 34 29 34
MIC, Hg/mL 6 6 1 0.5 0.5 0.25
The Fe304@CTAX NPs' inhibition zone diameter is 22 mm, that is also noticeably greater than that made by pure cefotaxime. MC@Fe304@CTRIX and Fe304@CTRIX produced the same inhibition zone with diameter 34 mm; however, pure ceftriaxone produced the zone with diameter equal only to 7 mm. According to obtained results, we can suggest that MC mimics the properties of natural side-rophores, bound with iron, helps antibiotic to avoid the mechanism of the resistance, elaborated by bacteria. The microdilution method provided us information about MICs of the studied substances. As is shown from the Table 1 MICs of cefotaxime, ceftriaxone, MC@Fe304@CTAX and MC@Fe304@CTRIX on S.aureus were the same and equal to 6 (Ag/mL. In turn, as is shown from the Table 2, MIC of Fe304@CTAX on E.coli was 6 times and MC@Fe304@CTAX 12 times lower than MIC of pristine cefotaxime. The results of ceftri-
axone's nanostructures are even better. The MIC of Fe304@CTRIX was 12 times and MC@Fe304@CTREX 24 times lower than MIC of pure ceftriaxone. The improvement of MIC on Escherichia coli correlates well with the increase of the antimicrobial effect, seen from diffusion method and also evidences that MC mimics side-rophore and significantly improves the effectiveness of antibiotics [17]. At the same time, it was of interest to investigate the biological activity of the obtained samples with respect to bio-films. According to the spectrophotometric analysis of the spectra measured with the Specord 250 plus spectrometer in relation to Klebsiella, the Fe304@CTAX nanostructure exhibits an inhibitory effect on the development of biofilms at concentrations of 0.5 ug/rn L. The Fe304@CTRIX nanostructures inhibit the growth and development of the biofilm at a concentration of 0.25 (j,g/mL, as shown in Figure 5.
0,18
-Q 0.12 <X
4 2 1
Consentration, (ig/mL
0,5
Fig. 5. Effect of Fe304@.CTAX and Fe304@CTRIX on Klebsiella varieties, biofilm development after 24 hours incubation.
However, it should be noted that, firstly, since cephalosporins are concentration-independent antibiotics [18], the amount of nanostructured cephalosporins should not be very large; and secondly, since nanoparticles in large numbers can aggregate, this can significantly affect the effectiveness of their action and they become inactive.
Conclusion
We reported on successful synthesis of hydroxyl containing diazacrown ether (MC) that is able to mimic the properties of natural side-rophores. The binding of MC to Fe304@CTAX and Fe3O4@CTR.IX NPs overcomes the destroying of betta-lactam ring of cephalosporins, due to their synergetic effect. It was shown that nanostructuring of cefotaxime and ceftriaxone significantly improves the antimicrobial effect of abovementioned drugs, even on the resistant strains of Escherichia coli. We can also conclude that the impressive synergistic effect of synthesized MC and cephalosporin antibiotics, united in magnetite based nano-structures, impressively decreases the MIC of antimicrobial agents. As consequence, the na-notechnological approach creates a possibility to reduce the dosage of taken medicines with keeping therapeutic effect is high and side effects is low.
References
1. Steed J.W., Atwoo J.L. Supramolecular chemistry. 2nd edition. John Wiley & Sons, Ltd. 2009. Chapter 1.7. P. 27-38.
2. Peter J. Cragg. Supramolecular Chem. // Biol. Inspiration to Biomedical Appl. 2010. V. 4. P. 109-156.
3. Lili Liu and Shimou Chen. Theoretical Study on Cyclopeptides as the Nanocarriers for Li+, Na+, K+ and F . CI*, Br // Journal of Nanomater. 2015. V. 2. P. 18-26.
4. Marcel H. Tempelaars, Susana Rodrigues, Tjakko Abee. Comparative Analysis of Antimicrobial Activities of Valinomycin and Cereulide, the Bacillus cereus Emetic Toxin // Appl. and environmental microbiology. 2011. V. 77. P. 2755-2762
5. Kenneth N. Raymond. Recognition and transport of natural andsyntheticsiderophores by microbes // Pure and Applied Chemistty. 1994. V. 66. No 4. P. 773-778.
6. Saravanan Periasamy, Hwang-SooJoo, Anthony C. Duong, Thanh-Huy L. Bach, Vee Y. Tan, Som S. Chatteijee,Gordon Y.C. Cheung. Michael Otto. How Staphylococcus aureus biofilms develop theircharacteristicstructure // Proceedings of the National Academy of Sciences (PNAS). 2012. V. 109. No 4. P. 1281-1286.
7. Chris J. Jones and John R. Thomback. Medicinal Applications of Coordination Chemistry. The Royal Society of Chemistry. Chapter 4. P. 203-205.
8. Tatsuya Nabeshima. Ag+ Selective Macrocycles Containing Soft Ligating Moieties and Regulation of Ag+ Binding // J. Incl. Phenom. Mol. Recognit. Chem. 1998. V. 32. Issue 2-3. P. 331-345.
9. Vuk Uskokovic. Nanostructured Platforms for the Sustained and Local Delivery of Antibiotics in the Treatment of Osteomyelitis // Critical Rev. Therapeutic Drug Carrier Systems. 2015. V. 32(1). P. 1-59.
10.Dena Domiani, MolidZobir bin Hussein Aminu Umar Kura, Sharida Fakurazi. Abdul HalimShaari, Zalinah Ahmad. Preparation and characterization of 6-mercaptopurine-coated magnetite nanoparticles as a drug delivery system // Drug Design Development and Therapy. 2013. V. 7. P. 1015-1026.
11. Grumezescu Jorgensen J.H., Lee J.C. Microdilution Technique for Antimicrobial Susceptibility Testing of Haemofilus influenza // Antimicrobial Agents and Chemotherapy. 1975. V. 8. P. 610-611.
12. Emu M„ Genta G„ Tuveri E„ Qrru G„ Barbato G... Levi R. Microliter Spectrophotometric Biofilm Production Assay Analyzed with Metrological Methods and Uncertainty Evaluation // Measurement. 2012. V. 45. P. 1083-1088.
13.Gestal M.C., Holban A.M., Grumezescu V., Vasile B S., Mogoanta L., lordache F„ Bleotu C., Mogosanu G.D. Biocompatible Fe304 Increases the Efficacy of Amoxicillin Delivery against Gram-Positive and Gram-Negative Bacteria // Molecules. 2014. V. 19. P. 5013-5027.
14.Magda Latorre, Carlos Rinaldi. Applications of Magnetic Nanoparticles in Medicine: Magnetic Fluid Hyperthermia // Puerto Rico Health Sciences Journal"(PRHSJ). 2009. V. 28. No 3. P. 227-238.
15. Massart R. Preparation of Aqueous Magnetic Liquids in Alkaline and Acidic Media // IEEE Transactions 011 Magnetics. 1981. V. 17. P. 1247-1248.
16. Mayrliofer S., Domig K.J., Mair C., Zitz U„ Huys G., Kneifel W. Comparison of Broth Mcrodilution Etest and Agar Disk Diffusion Methods for Antimicrobial Susceptibility Testing of Lactobacillus Acidophilus Group Members // Applied and Environmental Microbiology. 2008. V. 12. P. 3745-3748.
17. Grumezescu A.M., Cotar A.I., Andronescu E., Ficai A., Gliitulica C D.. Grumezescu V., Vasile B.S., Cliifiriuc M.C. In Vitro Activity of the New Water-Dispersible Fe304 a Usitc Acid Nanostruc-
ture against Planktonic and Sessile Bacterial Cells //J. Nanoparticle Research. V. 15. 2013. P. 1-10(10). 18.Hasanova U.A., Ramazanov M.A., Maharramov A.M., Eyvazova Q.M., Agamaliyev Z.A., Parfyo-nova Y.V., Hajiyeva S.F., Hajiyeva F.V., Veliyeva
S.B. Nano-Coupling of Cephalosporin Antibiotic with Fe304 Nanoparticles: Trojan Horse Approach in Antimicrobial Chemotherapy of Infections Caused by Klebsiella spp. // J. Biomaterials and Nanobiotechnology. 2015. V. 6. P. 225-235.
DiAZAKRAUNEFiRLORi, MAQNETiT NANOHiSSOCiKLORi УЭ SEFALOSPORlN ANTiBiOTibCLORlNDON iBAROT NANOSTRUKTURLARIN SiNTEZi
и.Э.Нэ«эпоуа, L.Z.Vazirova, ZO.Qahramanova
Tobii sideroforlann xususivvotlorini toqlid cdon azakraun makrotsikllar (MT) sintez edildi. Sintez cdilmis МТ-1эг asefalosporin antibiotiklori viiklonmis vo maqnetit nanohissociklorindon ibarot supra molekulyar ansambllar ha/irlanmisdir. Sintez cdilmis makrotsikllar NMR, kiitlo. iQ spektroskopiya usullan ib bdqiq cdilmisdir. Ha/irlanmis nano ansambllann morfologiyasi skanedici elektron mikroskopiya SEM, FTIR, rentgen diffraksiyasi, XRD analiz usullan ib bhlil cdilmisdir. Nanostrukturlarin komivvot analizi atom adsorbsion spektroskopiyasi (AAS) vo Lambert-Beer qanunu osasinda UB spektroskopiya tisulu ib bdqiq cdilmisdir. Hazirlanan nanostrukturlar yuksak dor man rezistentliyi xususivvotino malik olan qram-monfi Escherichia Coliva qram-miisbot Staphylococcusaureus ii/orindo test cdilmisdir. Nanostrukturlarin scfalosporinlorin antimikrob aktivliyini ohomivvotli dorocodo artirdigi vo MiK-ni azaltdiqlan тиэууэп olundu.
Agar sozfor: makrotsiklhr, kraun efir, supramolekulyar kimya, siderofor, maqnetit nanohiss3cikhri.
СИНТЕЗ НАНОСТРУКТУР НА ОСНОВЕ ДИАЗАКРАУН ЭФИРОВ (МС) И НАНОЧАСТИЦ МАГНИТИТА ЗАГРУЖЕННЫХ ЦЕФАЛОСПОРННОВЫМИ АНТИБИОТИКАМИ
У.А.Гасанова, Л.З.Везирова, З.О.Гахраманова
Синтезированны макроциклы (МЦ), которые способны имитировать свойства природных сидерофоров. На основе синтезированных МЦ были получены супрамолекульярные ансамбли с наночастицами магнетита, нагруженные антибиотиками цефалоспорина. Синтезированные МС исследовали методами ЯМР, масс-, ИК-спектроскопии. Морфологию подготовленных наноансамблей анализировали методами сканирующей электронной микроскопии СЭМ, ИК, рентгеноструктурного анализа. Количественный анализ наноструктур осуществляли методами спектроскопии поглощения атомов (ААС), УФ-спектроскопии, а также на основе закона Ламберта-Бера. Подготовленные наноструктуры тестировали на грамотрицательные Escherichia Coli и грамположительные Staphylococcusaureus, обладающие свойствами резистентности к лекарственным средствам. Обнаружено, что наноструктуры значительно увеличивают антимикробный эффект цефальспоринов и уменьшают их МИК минимальную ингибигорную концентрацию.
Ключевые слова: макроцикл, краун-эфир, супрамолекулярная химия, сидерофор, наночастицы магнетита.
