الفهرس 
CHAPTER ONEOnly 14 pages are availabe for public view
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Abstract
omprises three chapters.
Chapter I:
It includes the literature survey concerning the classification of vitamins, their structural chemistry, their properties, preparation and their coordination chemistry, methods of analysis, biological functions, clinical doses, side effects and its sources. Drug development process was given. The chapter is ended with the aim of the work.
Chapter II:
It describes the experimental part of the thesis. The preparation of the metals complexes of thiamine chloride hydrochloride including metal ions: VO2+, Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Se(IV), Pd(II), WO-2 and Hg(II). The analytical data illustrated the formation of complexes with stoichiometry, 1:1, except for VO2+ complex was 2:1 (M:L) molar ratio. Different standardized instruments were used for obtaining the required data (IR, UV-Vis, H NMR, ESR, elemental analysis, magnetic susceptibility, energy dispersive x-ray, thermal analysis (TGA, DTA and DSC). Computer programs Chemistry Office Ultra 12.00 and Hyper Chemistry 8.0.7 were used for molecular modeling of the organic ligand and its complexes. The biological activity study was examined in in vitro for the ligand and three selected complexes, VO2+, Fe(III) and Se(IV) including anticancer, antiviral, DNA cleavage, antioxidant, anti-diabetic, anti-inflammatory, monoamine oxidase, acetylcholine esterase, aldehyde oxidase and cytotoxicity, while the antimicrobial activity was tested for all the prepared complexes. Molecular docking was performed by ACD/Labs and Molsoft L.L.C. softwares for in vivo examination. Some statistical studies were done to obtain the different correlation coefficients between the data.
Chapter III:
It is concerned for the results and their discussions. The IR spectra assigned the different modes of vibrations of the fundamental functional groups in the compound under consideration. On complexation, the shifts in the characteristic IR frequencies serve as a convenient measure of the character of the complex formed. Spectral studies of all synthesized thiamine metal complexes indicated the linking of the organic ligand with metal ions as a monodentate ligand for Fe(III) complex through sulphur atom and bidentate ligand for VO2+, Mn(II), Ni(II), Cu(II), Se(IV) and (WO2)- complexes through sulphur and nitrogen N1‟ atoms. In latter complexes, the ligand acted as a tridentate through OH group, sulphur and nitrogen N1‟ atoms.
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The electronic absorption spectra gathered with the magnetic moment values, assigned the
geometries of the complexes, where, manganese, iron, copper, zinc, tungsten and mercury
complexes are of octahedral geometry with paramagnetic properties except zinc and mercury
complexes are of diamagnetic properties. However, cobalt and nickel complexes are with
tetrahedral geometry and paramagnetic properties. Selenium and palladium complexes are
with square planar geometry and diamagnetic properties, while, vanadium complex is with
square pyramidal geometry and of paramagnetic properties.
Energy dispersive x-ray of the five metal complexes, vanadium, copper, selenium,
palladium, mercury analyzed through the EDX spectrum.
The calculated room temperature solid state ESR data of copper thiamine complex with
the formula, [Cu(th)Cl2(H2O)2]Cl.H2Oshowed anisotropic spectra of axial-elongated type with
two g values, where, gǁǁ> g┴>2.0023 indicating that Cu(II) site has a 2B1g (dx
2-y
2) ground state
of octahedral stereochemistry. The G parameter showed a considerable exchange interaction.
However, F parameter showed that copper complex with a distorted tetragonal geometry. The
covalency parameter, α2, predicted the covalent character and exhibited the involvement of
nitrogen atom in complexation.
Thermal analyses (TGA, DTA and DSC) were studied for thiamine Cl HCl ligand and its
metal complexes: vanadium, iron, cobalt, copper and zinc at heating rate 10 k/min, while
palladium complex at different heating rates (5, 15 and 25 k/min). The first decomposition
step corresponds to dehydration of water molecules, followed by decomposition of complexes.
and ended by formation of metal oxide. The thermodynamic parameters of their
decomposition were calculated. The thermal processes proceed in complicated mechanisms
with more ordered transition states. Thermal transitions can be determined from the relation
between heat flow and temperature from DSC technique. 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 compound and its metal complexes where the highest
occupied molecular orbital energy (EHOMO), the lowest unoccupied molecular orbital energy
(ELUMO), energy gap (ΔE), chemical potential(Pi), electronegativity (), hardness and
softness are determined for organic compound and its metal complexes using
hyperchemistry program.
The in vitro antimicrobial activity was examined by thiamine Cl HCl ligand and its all
prepared complexes were tested against two Gram positive bacteria of Staphylococcus aureus
and Bacillissubtilis and two Gram negative bacteria of Pseudomonas aeruginosa and
Escherichia coli. The results showed that the free ligand do not have antibacterial activity
against all tested microorganisms, while some of the tested metal complexes have a well
considerable activity against some of the test organisms compared to ligand. Most significant
antibacterial activity was recorded for mercury complex followed by selenium complex. The
antifungal activity was examined against one fungi Candida albicans. Thiamine ligand did not
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show antifungal activity. Only two complexes showed antifungal activity, the highest was recorded for mercury complex, while cobalt is of moderate activity compared to ligand.
All latter biological activities were examined for thiamine Cl HCl ligand selected complexes, vanadium, iron and selenium. Anticancer activity was examined against hepatocellular carcinoma cells (HepG2) for thiamine Cl HCl ligand and the selected three complexes. The highest anticancer activity was shown by selenium complex followed by iron complex compared to ligand. Vanadium complex showed anticancer activity but lower than ligand.
Antiviral activity was examined against herps simplex virus type-1 (HSV-1) for thiamine Cl HCl ligand and the three selected complexes. Highest antiviral activity was shown by selenium complex (++) followed by iron complex (+) compared to thiamine ligand that showed –ve effect. Vanadium complex did not show antiviral activity.
DNA cleavage was examined for thiamine Cl HCl ligand and the three selected complexes and studied at different concentrations (10, 5, 1, 0.5, 0.1, 0.05, 0.01 mg/ml). All concentrations of three tested compounds prevented the adverse effect of H2O2 on DNA fragmentation as the smearing decreased, except for concentrations of (0.01 mg/ml) selenium and (10 mg/ml) vanadium complexes did not show effect.
Anti-diabetic activity was examined for thiamine Cl HCl ligand and the three selected complexes. All three metal complexes are sucrase, maltase and lactase inhibitors compared to ligand. The highest inhibitory effect was recorded for vanadium complex for the three digestive enzymes. α-amylase activity was examined and it was found that the three complexes are α-amylase inhibitors compared to ligand. The highest inhibitory effect was observed for iron complex. Lipase activity showed that only vanadium complex is good lipase inhibitor compared to ligand, while iron and selenium complexes showed lipase inhibition lower than ligand.
Antioxidant activity was examined for the ligand and the three selected complexes. The activity of the three complexes showed that their activity in scavenging of free radical DPPH is significant compared to ligand and vitamin C.
Anti-inflammatory effect was tested for ligand and the three selected complexes. The most significant nitric oxide scavenging activity was observed for the octahedral Fe(III) thiamine complex followed by vanadium and selenium complexes compared to ligand. So, they are selective inhibitors for nitric oxide. Therefore, these complexes can be used in improvement of immune response and cell migration, cerebral circulation and the memory cellular basis, hence it can give beneficial treatment for Alzheimer’s and Parkinson’s disease patients.
Neurotransmitter enzymes were examined through the acetylcholine esterase and MAO-A. The inhibition of AChE and MAO-A was examined by thiamine ligand and three selected metal complexes. Significant inhibitory effect was shown by the three complexes compared to ligand. These inhibitors can help in treatment of Alzheimer disease (AD) by maintaining the levels of acetylcholine through inhibition of AChE.
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Aldehyde oxidase activity was examined for thiamine ligand and the three selected complexes. The highest inhibitory effect was observed for selenium complex followed by iron and vanadium complexes. Anti-hemolytic effect was observed for the three complexes, iron, selenium and vanadium agianst Human Red Blood Corpuscles (HRBCs). Structure activity relationship (SAR) was discussed to show the relation between the molecular structure and the resulted biological activity and how its properties are evaluated by the chemical structure. Computer analysis of the obtained data was done, exploring the relationships between the different parameters of the studied complexes.
The thesis contains (369) references and the data are collected in (47) Tables, (71) Figures and (10) schemes.