الفهرس 
CHAPTER IOnly 14 pages are availabe for public view
 |  | from | 38 |  |  |
| | | from | 38 | | |
Abstract
metalloantibiotics” comprises three chapters.
Chapter I It includes the introduction literature survey involving the classification of antibiotics, their sources, chemistry, different generations and method of analysis of cephalosporins. The biological importance and structural chemistry of metallo antibiotics, specially metallocephradine and metallocefepime were clarified in this chapter. Finally, drug discovery and development was mentioned. The chapter is ended with the aim of the work.
Chapter II It describes the experimental part of the thesis. Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Hg(II) cephradine and cefepime complexes were prepared and analyzed. The simple complexes were separated in 1:1, 1:2, 1:3, 2:1 and 2:3 (M: L) molar ratios. Heteronuclear cephradine and cefepime complexes were also prepared and analyzed, where, [Fe(III)-Co(II)], [Fe(III)-Ni(II)] and [Fe(III)-Cu(II)] cephradine complexes were separated in 1:1:2, 1:1:1 and 1:2:2 mole ratios, respectively, while [Fe(III)-Ni(II)] , [Fe(III)-Cu(II)] and [Co(II)-Cu(II)] complexes were separated in 1:1:3, 1:1:1 and 1:3:1 mole ratios, respectively. The working procedures and standardization of the instruments used for this study were reported. Different spectral measurements UV-Vis, IR, mass spectra, HNMR, ESR of copper complexes, elemental analysis, magnetic susceptibility and thermal analysis (TGA, DTA and DSC), energy dispersive x-ray, electron microscope, potentiometric titration measurements and computer programs. In vitro biological screening for all studied complexes involving antimicrobial, DNA cleavage, anti diabetic, antioxidant, anti-inflammatory, cytotoxicity, and monoamine oxidase and acetylcholin esterase inhibitors and in vivo acute oral toxicity study for copper cefepime complex (4:1) M:L ratio were assessed for 25 male mices to adjust the required dose, which was 5 mg/kg. Finally, induction of Alzheimer like disease by scopolamine and treatment with copper cefepime complex (4:1) M:L ratio was estimated in 28 male rates. Statistical programs were used to obtain different correlations between the data.
Chapter III:
It is concerned with the results and their discussion. The infrared spectra of the organic compounds and their metal complexes assigned the position of the fundamental functional groups. Spectral studies of all synthesized cephradine and cefepime metal complexes indicate that the linking of the drug molecule with the metal ions as a bidentate ligand through the nitrogen of the β-lactone thiozolidine ring and carboxylate ion forming five membered ring. The geometries were suggested for the prepared complexes based on the data evaluated from spectral and magnetic measurements, where all Cr (III), Mn (II) and Fe (III) are with octahedral geometry. However Co (II)-cephradine complex with octahedral geometry, while Co(II)-cefepime complex with tetrahedral geometry. Furthermore, all copper complexes are of square planar geometry, except copper cefepime complex (1:3) in octahedral geometry. Also, Zn(II), Cd(II), Hg(II) and Ni(II) complexes are diamagnetic with tetrahedral and square planar geometry, respectively. Mass spectra and HNMR of the parents and some metallocephradine and metallocefepime were recorded.
The room temperature solid state ESR spectrum of Cu-cephradine complex (3:1), exhibits an axially symmetric g-tensor parameters with g// > g> 2.0023 indicating that the copper site has a dz2 ground state characteristic of square planar stereochemistry, however, Cu-cephradine complex (1:2), (Fe-Cu)-cephradine complex, Cu-cefepime complex (1:3) & (4:1) and (Co-Cu)-cefepime complex are rhombic-compressed, while (Fe-Cu)-cefepime complex showed elongated rhombic symmetry with three g-values, 3.07, 2.55 and 1.92, respectively The thermal analysis of cephradine, cefepime and their metal complexes were examined. The bond between the central metal ion and the ligand dissociates after losing water molecules. The decomposition was usually ended by the formation of metal oxide. The thermodynamic parameters of their decomposition were calculated. The thermal processes proceed in complicated mechanisms with more ordered transition states. from DSC technique, thermal transitions can be determined from the relation between heat flow and temperature. The variation of Cp with temperature was discussed.
Theoretical study is carried out to obtain the charges, bond lengths, bond angles and dihedral angles of the studied organic compounds where the chemical potential, electronegativity, hardness and softness were determined for organic compounds using hyperchemistry program.
The electronic absorption spectra of cephradine, cefepime and their metal complexes were measured in different solvents with variable physical properties. The electronic transitions were assigned. The data were analyzed using the multiple linear regression technique and explained in terms of specific and non specific solute-interactions. The effect of dielectric constant and the refractive index properties of the solvents on the electronic absorption spectral bands have been studied and the correlation equations based on the different solvent parameters are the best to give convenient statistical description of the solvatochromism. The regression correlation is applied using solvatochromic parameters ( , α and β) to measure the ability of the solvent to stabilize the charge or the dipole by its own dielectric effects such as acidity and basicity. The pKa- values cephradine, cefepime and some of their metal complexes were evaluated potentiometry. The mode of ionization was assigned. The positions of its spectral bands and their intensities are pH-dependent. The presence of different isobestic points indicates the existence of different species in equilibria. Distribution of species at different pH’s was given from the distribution diagram for cephradine, cefepime and their metal complexes.
In vitro antimicrobial screening of cephradine, cefepime and their complexes were performed against the following bacterial strains, S.pyogenes , K.pneumoniae , P.mirabilis, E.fecalis, S.pneumoniae, P.aeruginosa, E.coli and S.aureus and their efficiency against the bacteria was compared with the standard cephradine and cefepime. Also, antifungal activity were examined against A.niger, A.flavus, S.racemosum, C.albicans, C.glabrata, F.oxysporum, R.solani and A.solani fungal strains The minimum inhibitory concentration (MIC) of some selected complexes, which showed significant activity against selected bacterial and fungal species were determined in comparison to the standards.
Antidiabetic activity was examined for all synthesized metal complexes, it was found that all cephradine metal complexes act as maltase inhibitors, except Cu (1:2) and (Fe-Ni) complexes did not show inhibitory effect on maltase activity, while Cr-cephradine-complex (2:1) showed the highest inhibitory activity towards maltase activity in comparison with the cephradine and the control so, it may be as a selective maltase inhibitor. Also, all cephradine and cefepime metal complexes showed inhibitory effect on lactase, sucrase and amylase activity. Furthermore, cephradine and cefepime metal complexes act as lipase inhibitors except Mn(II) and Hg(II) cephradine complexes.
Assessment of antioxidant activities of tested compounds showed that the activity of the complexes in scavenging of free radical DPPH is fairly good but less than ascorbic acid as positive control, except Fe-cephradine complex in 2:1(M:L), which showed higher activity than ascorbic acid.
Anti-inflammatory was tested for all prepared complexes, where the maximum nitric oxide scavenging activity of octahedral Fe(III)-cephradine in 2:1(M:L) molar ratio, this may be attributed to the coordination of the two Fe(III) ions with cephradine in a stable five membered ring in Oh geometry, where the first Fe(III) ion is coordinated to the carboxylate group and the adjacent nitrogen atom with a stable five membered ring and the second Fe(III) ion is attached to the nitrogen atom of the group –C=N-O and NH2 with a stable five membered ring. The effect of metallo-cephradine and metallo-cefepime on Human Red Blood Corpuscles (HRBCs) were examined. Metallocephradine showed significant anti-inflammatory activity and safe, except Ni(II)-cephradine complex in 1:1 (M:L) ratio and Cr(III)-cefepime complex in 2:1 (M:L) ratio exhibited toxicity.
The inhibition of acetyl cholinesterase and monoamine oxidase A&B by all prepared metal complexes were examined. Copper (1:2) and iron-copper (1:2:2) cephradine complexes and also, copper (4:1) and mixed metal iron-nickel (1:1:3) cefepime complexes can be used as a good inhibitors towards AChE and MAO-A&B.
In vitro, kinetic study was performed on some selected complexes, which showed higher inhibitory effect for AChE and MAO-A &B, anti-inflammatory and higher antioxidant. The AChE was inhibited by manganese and copper cephradine complexes in 1:1 and 3:1 (M:L) molar ratio, respectively as uncompetitive inhibitors. Also, the inhibition of AChE by manganese (2:3), copper (1:3) & (4:1) , iron-nickel (1:1:3) and cobalt-copper (1:3:1) cefepime complexes indicates a pattern of inhibition of uncompetitive type. from in vitro results, copper-cefepime complex in 4:1 (M:L) ratio is the best complex which had higher inhibitory effect towards AChE and MAO-A &B, anti-inflammatory, antioxidant, anti- diabetic and safe on in vitro human red blood corpuscles (HRBCs). So, in vivo oral acute toxicity study was done for this complex to determine LD50, which equals 5 mg/kg and also different biochemical parameters were measured. Finally, the induction of Alzheimer like disease by scopolamine into 28 male rates and treatment with copper cefepime (4:1) complex (5mg/kg) increased the level of reduced glutathione a potential element of free radical scavenging cycle in the brain as compared to control group. Therefore, it appears that copper cefepime (4:1) complex seeds may possesses the memory improving capacity or useful in the treatment of the disorder related to memory deficits specially Alzheimer’s disease, in the view of its (i) AChE inhibitory activity (ii) cholesterol and glucose lowering activity (iii) on the basis of its antioxidant property a sharp increase in antioxidant process by increase in reduced glutathione level in male rate brain.
The data are collected in (76) Tables and (168) Figures. A list of references (419).
1. INTRODUCTION
1.1. Classification of antibiotics
The term antibiotic assigned to describe any small molecule made by a microbe that antagonizes the growth of other microbes [1]. This excluded both substances that kill bacteria, but are not produced by microorganisms (such as gastric juices and hydrogen peroxide) beside synthetic antibacterial compounds such as the sulfonamides. Most antibacterials are chemically semisynthetic modifications of various natural compounds and classified on the basis of chemical /biosynthetic origin into natural, semisynthetic, and synthetic. Also, this classification system is based on biological activity; that antibacterials are divided into two broad groups according to their biological effect on microorganisms: bactericidal agents kill bacteria, and bacteriostatic agents slow down bacterial growth [2-4]. General classifications of antibiotics were illustrated in Figure 1.