Ph.d Thessis

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Synthesis, Spectroscopic Characterization , and study biological Activities of Some mixed ligand with certain cephalosporin antibiotics complexes with some metals IonsDr. Taghreed Hashim Manhel Reemon Aziz & Dr. Ahmed Thabit Cephalosporin Cephalosporin is a -lactam antibiotic, which was first introduced in 1945. Such drugs are among the most widely prescribed antimicrobial classes because of their broad spectrum of activity, low toxicity, ease of administration, and favorable pharmacokinetic profile. The safety profile of cephalosporins is generally good although a wide range of allergic reactions have been caused by -lactamantibiotics. It is possible to classify these reactions by the Levine's classification system, which is based on the time of the onset of the reactions. The frequency of hypersensitivity reactions to cephalosporins is less than to penicillins. It has been estimated that nearly 75% of fatal anaphylactic reactions result from the administration of penicillin.Cephalexin

6R,7R)-7-{[(2R)-2-amino-2-phenylacetyl]amino}- 3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylic acidAmoxicillin

2S,5R,6R)- 6-{[(2R)-2-amino- 2-(4-hydroxyphenyl)- acetyl]amino}- 3,3-dimethyl- 7-oxo- 4-thia- 1-azabicyclo[3.2.0]heptane- 2-carboxylic acid acid Ampicillin

(2S,5R,6R)-6-([(2R)-2-amino-2-phenylacetyl]amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acidAim of the present work In this study, we have selected -lactam antibiotics (cephalexin, Amoxcilline and Ampicillin trihydrate) as: First ) A starting material for synthesis and characterization of the six tridentate Schiff bases ligands (HL1-HL6) and Preparation of their mixed ligand complexes. Synthesis and characterization of the six tridentate Schiff bases ligands (HL1- HL6 ) derives from selected -lactam antibiotics (cephalexin, Amoxcilline and Ampicillin trihydrate with 4(dimethylamino)benzaldehyde) and Vanillin containing (N ,O and O) as donor atoms type (O N O).Schiff bases ligands (HL1-HL6) uses as primary ligand with nicotinamide (NA), as a secondary ligands with M(II) , where M(II) = Fe(II), Co(II), Ni(II), Cu(II), and Zn(II).of the composition [M(L1)(NA)2Cl], [M(L2)(NA)2]Cl, [M(L3)(NA)2Cl], [M(L4)(NA)3]Cl, [M(L5)(NA)2Cl] and [M(L6)(NA)2Cl] in 1:1:2 ,[M:L:2NA] molar ratio. Second ) Mixed ligands complexes: A primary ligands with nicotinamide [NA] as a secondary ligands with M(II) where M(II) = Fe(II), Co(II), Ni(II), Cu(II), and Zn(II).of the composition [M(Ceph)(NA)3] Cl, [M(Amox)(NA)3] Cl and [M(Ampi)(NA)3] Cl, in 1:1:3 , [M:L:3NA] molar ratio.Synthesis and characterization of the ligands (HL1- HL6): In the present study six new Class of Schiff bases ligands(HL1- HL6) were prepared according to the general method shown in table and Schemes . SymbolChemical formulaSchiff bases derives formHL1C25H26N4O4SCephalexine + 4(dimethylamino)benzaldehydeHL2C25H28N4O5SAmoxcilline + 4(dimethylamino)benzaldehydeHL3C25H28N4O4SAmpicillin trihydrate + 4(dimethylamino)benzaldehydeHL4C24H23N3O6SCephalexine + VanillinHL5C24H25N3O7SAmoxcilline + VanillinHL6C24H25N3O6SAmpicillin trihydrate + Vanillin

The Experimental

1- Melting point measurements2-Conductivity measurements3- Infrared spectra (I.R) 4- Electronic (U.V- Vis) spectra5- Chloride contents 6- Metal determination (AAS)7- Elemental micro analysis (C.H.N) for ligands8- Nuclear magnetic resonance spectra 1H 13C NMR for ligands9- Magnetic susceptibility for complexes SolubilityCompoundH2ODMFDMSOMeOHEtOHC3H6OC6H6CCl4CHCl32-propanol Petroleum etherCeph.+++-----NA-+++++---+-Amox+++-----Ampi+++-----4DMAB-+++++---+-Vanillin+++++------HL1-+++++- ---+-HL2-+++++---+-HL3-+++++---+-HL4-+++++---+-HL5-+++++---+-HL6-+++++---+-CompoundsCompound formulaMolecular weightM .p CColourFound (Calc.)CHNOSCeph.C16H17N3O4S365.39176-182Cream55.324.9312.1018.429.23NicotinamideC6H6N2O122.12128-131White59.014.9522.9413.10-------AmoxC16H19N3O5S419.10198-206White55.005.4812.0318.329.18AmpiC16H19N3O4S403.11128-131White59.014.9522.9413.10-------4DMABC9H11NO149.1972-7572.46 7.43 9.3910.72-------VanillinC8H8O3152.1581-83White63.155.3031.5563.15-------HL1C25H26N4O4S478.1776-80Orange62.74(61.1) 5.48 (6.11)11.71 (11.90)13.37- 6.70 (7.10)HL2C25H28N4O5S496.58146-152Orange60.47(59.3) 5.68 (6.37)11.28 (10.4)16.11- 6.46 (6.32)HL3C25H28N4O4S480.5888-93Orange62.48(62.0) 5.87 (6.12)11.66 (11.86)13.32 6.67 (5.89)HL4C24H23N3O6S481.5276-80yellow59.86(60.37) 4.81 (5.02)8.73 (8.85)19.9- 6.66 (7.12)HL5C24H25N3O7S499.54100-106Orange57.70(56.70) 5.04 (5.16)8.41 (9.13)22.42 - 6.42 (6.54)HL6C24H25N3O6S483.54156-162Orange59.61(54.17) 5.21 ( (6.11)8.69 ( 9.13)19.85- 6.63 (6.54)The microanalysis results and some physical properties for the starting materials and prepared ligandsFTIR spectrum of the ligand (HL1):

FT-IR spectrum of (HL2)

FT-IR spectrum of (HL6)Table : Infrared spectral data (wave number ) cm-1 for the ligands, and starting materials

Comp..(O-H)(N-H)primary amine(N-H)Secondary amide(C=O)for COOH(C=O)-lactam(C=N)asm COOsmy COO(C=C)arom.(C-C)aliph.(C-N)(C-O)(C-S)(C-H)arom.(C-H)aliph. Ceph-------32753219 , 304917591689-----15951398157711631280124758030102883 Amox.34563456317617741685-------15851396151911781282124955530392970 Ampi------34463269, 320917741687------15751384149611701296126359030412970 4DMAB------------------------------------------------154811651371------28192796 Vanillin3564----------------------------------------1577111812801053 -----30122970 L1-------------3228 overlap1678 overlap1678 overlap1678 overlap15971373153111681315123058430622924 L23298 overlap-------3298 overlap17351658 overlap1658 overlap1597 1377154611681315123055529622823 L3-----------3228 overlap1678 overlap1678 overlap1597 overlap1597 overlap1373153111681284123057030622924 L43410------3410 , 32441678 overlap1678 overlap1678 overlap1678 overlap1435153611381284125355531092970 L53298------3298 overlap17201662 overlap1662 overlap15971377153111681292124959730622970 L63387-------3387 overlap17321662 overlap1662 overlap1662 overlap1392151911301288123855130602966(U.V-Vis) spectra for the starting materials and the ligands

Electronic spectrum of the (HL1)

Electronic spectrum of the (HL4)

Electronic spectrum of the (HL5) Compound nmABS cm-1 max(molar-1.cm-1)Assignments Ceph2790.77035842770 * Amox.2773300.7320.057361013030373257 * * Ampi2653280.6400.7863773530487640786 *n * 4DMAB2083363420.3381.9610.4934800729761292393381961493 *n *n * Vanillin2102302783050.6740.9610.6730.66147619434783597132786674961673661 * * *n * HL12122422673360.9530.6290.5071.482471694132259880297619536295071482 * * *n * HL22323361.0351.952431032976110351952 *n * HL32122393351.0000.6892.11447169418412985010006892114 * *n * HL42212911.6410.91245248343641641912 * * HL52302751.9581.352434783636319581352 * * HL62222781.6540.99645045359711654996 * *Electronic data for the ligands (HL1-HL6) and starting materials1H NMR spectrum of (HL1):In the 1H NMR spectrum of (HL1), single peaks attributed to methyl groups appeared at ( 3.90) ppm. The signal obtained in range ( 6.65-7.94) ppm was assigned for doublet due one proton of aromatic ring of phenyl. Three groups of double peaks given by (COCH) and (NCH) on the beta-Lactam ring and (NH sec.) amide appeared at ( 4.41), ( 5.02) and ( 8.19) ppm, respectively. One group of four resonance signals attributed to (SCH2) on the dihydrothiazine ring was observed in the ( 2.82-3.657) ppm, The signal obtained at ( 9.67) pp m was assigned for singlet due one .proton of (-CH=N) linkage in the ligand

1H NMR spectrum for the ligand (HL2)In 1H NMR spectrum of the ligand (HL2) in DMSO-d6, single peaks attributed to methyl groups appeared at ( 3.90) ppm (2CH3) and (2CH3) ( 1.55) ppm. The signal obtained in range ( 6.81-7.060) ppm was assigned for doublet due one proton of aromatic ring of phenyl. The signal obtained at ( 8.20) ppm was assigned for singlet due one proton of -CH=N linkage in the ligand. This confirms the formations of imine ligand. This observation was also supported by the FTIR data of the ligand discussed earlier. One group of four resonance signals attributed to (SCH2) on the dihydrothiazine ring was observed in the ( 3.421 - 3.660) ppm, Three groups of double peaks given by (COCH) and (NCH) on the -lactam ring and (NH sec.) amide appeared at ( 4.41), ( 5.00) and ( 8.32) ppm, respectively. single peak attributed to hydroxyl group appeared at ( 8.76) ppm

1H NMR spectrum of the ligand (HL2) in DMSO-d6Synthesis and characterization of mixed ligand complexes

Molar conductance values

Molar conductance values of the soluble complexes in DMSO in 10-3M solution for A) [M(Ceph)(NA)3]Cl, [M(Amox)(NA)3]Cl and [M(Ampi)(NA)3]Cl, Show values lie in the (33-37 -1 cm2 mol-1 ) range, Table(3-9), It is obvious from these data that these chelates are ionic in nature and they are of the type 1:1 electrolytes.B) [M(L1)(NA)2Cl], [M(L2)(NA)2Cl], [M(L3)(NA)2Cl], [M(L4)(NA)2Cl], [M(L5)(NA)2 Cl] and [M(L6)(NA)2 Cl] where M(II) = Fe(II), Co(II), Ni(II), Cu(II), and Zn(II).Show values in range (5.3-17.5 -1 cm2 mol-1) Table(3-10) indicating that they are all non-electrolytic in nature .Molecular weight determined by Rasts Camphor method: The Rast method for determining molar masses uses camphor as the solvent. Camphor melts at 178.4 C, using Rasts relation :

Kf = Molecular depression constant for camphor w = Weight (mass) of unknown complex (solute)W = Weight (mass) of camphor (solvent)

T = Depression of melting pointM = gram molecular weight of solute FT-IR spectral data for the mixed ligands complexes

FT-IR spectrum of the complex [Cu(Ceph)(NA)3]ClTable: Data from the Infrared Spectra for the Free Lingands and there Metal Complexes (cm-1).

Compound (N-H) primary amine (N-H)Secondary amide C=O) (C=O)-lactam asy COO sym COO(-COO) asy-sym (C=C) arom.(C-N) (C-O)(C-H) arom.C_S)) (C-H)alip(M-N) (M-O) Cephalexin3275321930491759168915951398197157712801247301058032883-----------Nicotine amide3367,3159-----------------------------------15931201-----30615812787-----------[Fe(Ceph)(NA)3]Cl 336731861667 overlap16781620139622415891292122630665822789540493[Co(Ceph)(NA)3]Cl 3410332331901666 overlap16661620139224314961269123030745813835563497[Ni(Ceph)(NA)3]Cl 347534143236169716811604139222415391288125330655832831563455[Cu(Ceph)(NA)3]Cl 34023266316717571707167016241604137922715791280124930665822852549487[Zn(Ceph)(NA)3]Cl 35413468323617591666 , 16311616139222415901280119930665852850536459The UV-Visible Spectroscopy for the mixed ligand complexes [Ni(Ceph)(NA)3]Cl: The (U.V- Vis) spectrum, exhibits three peaks. The assignment of the electronic spectral bands for, Ni(II) are 3A2g 3T2,(F) 1=(993nm) 10070cm-1)( max =19 molar-1.cm-1), 3A2g (F) 3T1g(F) 2= (800nm) 12500 cm-1)( max =11 molar-1.cm-1) , and (267nm) 37453 cm-1 for ligand filed transitions ,10Dq=10070 cm-1, B'=966 cm-1, =0.93. Ni (II) complex exhibited a value of eff = 3.18 B, which suggests an octahedral geometry around the central metal ion .

Compound nm cm-1max(molar-1.cm-1)Assignmentseff ( B )geometry Ceph27935842770*--NA220261454543831415481104**--[Fe(Ceph)(NA)3]Cl2789903703710101164518C-T5T2g5Eg4.97Distorted Octahedral[Co(Ceph)(NA)3]Cl2687288339923731313736120041008014897514C-T3A2g 4T1g(P)3A2g 4T1g(P)3A2g (F) 3T1g(F)4.54Octahedral[Ni(Ceph)(NA)3]Cl26780099337453125001007013191119L-F3A2g 4T1g(P)3A2g 3T2(F)3.18Octahedral[Cu(Ceph)(NA)3]Cl2719943690010060188330CT2Eg2T2g1.86distorted Octahedral[Zn(Ceph)(NA)3]Cl270370371556C-T0.00OctahedralElectronic data for the mixed ligands complexes

FT-IR of spectral data for the Schiff base mixed ligands complexes

FT-IR spectrum of the Schiff base complex [Zn(L1)(NA)2Cl]Compound(N-H)primary amine(N-H)Secondary amide(C=O)-lactam (HC=N-)as COOs COO(C=C)arom.(C-C)aliph.(C-N)(C-O)(C-S)(C-H)arom.(C-H)aliph.(M-N)(M-O)HL1-------3228 overlap1678 overlap1678 overlap15971373153111681315123058430622924----------Nicotine amide3367, 3159--------------------------------159311241201-----------30612787-----------[Fe(L1)(NA)2Cl]34413441 overlap1681 overlap15971597 overlap1377153911681288124858330702970540439[Co(L1)(NA)2Cl]34023306 , 32671666 overlap162416001396158111991296123858230782940582482 [ Ni(L1)(NA)2Cl]34063321 , 32671666 overlap16241624 overlap1396158111951292123458330782950528459[Cu(L1)(NA)2Cl]340632361678 overlap1660 overlap1678 overlap1435153111341284124958229662924505478[Zn(L1)(NA)2Cl]34103363 , 32321678 overlap15931593 overlap1377153511661288123058230662850551489Table ( 3-17) Infrared spectral data(wave number ) cm-1 for the ligands, and their complexes

(U.V-Vis) Spectral data for the Schiff bases mixed ligands complexesCu(L1)(NA)2Cl]: The (U.V- Vis) spectrum, Figure (3-99) exhibits two peaks , the first high broad peak at (272 nm)(36764 cm-1)( max =1957 molar-1.cm-1) is due to (C.T) , while the second weak broad peak at (924 nm)(10822 cm-1)( max =30 molar-1.cm-1), which assigned to 2B1g 2Eg (dd), The complex show a magnetic moments in 1.92B.M. corresponding to one unpaired electron. This band is characterstic in position and width with those reported for octahedral [copper (II) complexes.

Compound nmABS cm-1max(molar-1.cm-1)Assignmentseff (BM) Ceph2790.77035842770 *- NA2202611.5481.104454543831415481104 * *- Vanillin2102302783050.6740.9610.6730.66147619434783597132786674961673661 * * *n *- L42212911.6410.91245248343641641912 * *-[Fe(L4)(NA)2Cl]2706998181.3570.0250.01537037153061222413572515 C-T6A1g4A1g,4Eg(D) 5T2g5Eg 4. 18[Co(L4)(NA)2Cl]2687958599841.4830.0030.0020.006373131257811641101621483326C-T3A2g 4T1g(P)4T1 (F) 4T1 (g)4T1(F) 4T2g(F)4.32[Ni(L4)(NA)2Cl]2674999751.4310.0020.006374532004010256143126C-T3A2g(F) 3T1g(F) (2)3A2g(F) 3T2g(F) (1)3.22,[Cu(L4)(NA)2Cl]2748399742.0560.0400.04236496119191026620564042C-T2Eg2T2g1Eg1T2g1.85[Zn(L4)(NA)2Cl]2841.536352111536C-T0.0Electronic Spectral data, magnetic moment, of the studied compoundsthe biological effect results for prepared compoundsThe newly synthesized ligands and their metal complexes were screenedin vitrofor their antibacterial activity against bacteria: Staphyloccus aureus, 1- E-coli 2- Klebsiella3- Salmonella Typhi4- Acinetobacter baumannii5- Pseudomonas.

The Biological Activity 6- Staphyloccus aureusnoCompoundE-coliPseudomonasStaphylococcus aureusKlebsiella pneumoniaeSalmonellaTyphiAcinetobacter baumanniiC Control 5 7 5 6 5 51Ceph12180150202NA0180250143Amox0160230174Ampi161801301154DMAB1215013006Vanillin0120130127HL11218000178HL212 17000129HL312170001510HL412150001311HL512150001412HL620170 0015Biological activity of the starting materials and prepared ligands (Zone of inhibition (mm))Chart of biological effects of some of the studied ligands

noCompoundE-coliPseudomonasStaphylococcus aureus Klebsiella pneumoniaeSalmonellaTyphiAcinetobacter baumanniiC Control 5 7 5 6 5 518[Fe(Amox)(NA)3]Cl1218014122019[Co(Amox)(NA)3]Cl0171211141620[Ni(Amox)(NA)3]Cl1219012121621[Cu(Amox)(NA)3]Cl01400142022[Zn(Amox)(NA)3]Cl014001422Chart : Chart of biological effects of some of the studied complexes

Figure : Biological activity (Acinetobacter baumannii) of the prepared Schiff bases ligands

The biological activity (Klebsiella pneumoniae) of the Schiff bases mixed ligands complexes [M(L3)(NA)2Cl] Where (M() = Fe, Co, Ni,Cu, Zn)

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