الفهرس 
Introduction
Mechanism of action of sulfonamides and Sulfa DrugsOnly 14 pages are availabe for public view
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Abstract
Due to the importance of Sulfa drugs, for example sulfaguanidine (SG), because of their cost-effectiveness, low-toxicity coupled with their assorted pharmacological effects. And motivated by the wide-spectrum antimicrobial properties of the natural biopolymer chitosan (CS) against a number of organisms, including bacteria, fungi and algae. We aim in our thesis to synthesize new Schiff bases bearing sulfaguanidine (SG) or chitosan (CS) and ionic-liquids (ILs) terminals followed by metallation in order to obtain novel metallated Schiff bases. Moreover, study there in vitro antimicrobial/ anticancer assessment of the new compounds, which may allow us to develop a new promising therapeutic strategy to combat antibiotic and anticancer resistance against breast and human colon carcinoma.
The work in my thesis was divided into 4 chapters:
Chapter 1 (Introduction)
Gave short account about the Sulfa drug, sulfaguanidine (SG), chitosan (CS), ionic-liquids (ILs), Schiff bases and Pd(II) complexes and their pharmacological importance.
Chapter 2 (Results and Discussions)
Involve the essential work and divided into 4 parts
1. Part 1:
Synthesis of salicaldehyde ionic liquids (Sal-ILs).
Protocol to synthesize these compounds involves four main reactions:
i. o-Formylation of 2-isopropylphenol to create 3-isopropysalicylaldehyde;
ii. Chloromethylation of salicylaldehydes and 3-isopropysalicylaldehyde to yield 5-Chloromethylsalicylaldehydes;
iii. Quaternizationof-methylpyridine (α-picoline, Pic), 1,2-dimethylimidazole ((Me)2Im), 1-nbutylimidazole (nBuIm) or qunioline (Qn)1-methyl imidazole,4 methoxy pyridinium with 5-Chloromethylsalicylaldehydes to generate the Sal-IL chlorides (96-104)
iv. Anion metathesis of Sal-IL chlorides with hexafluorophosphoric acid (HPF6(aq)) and sodium tetrafluoroborate afford the corresponding hexafluorophosphate (103) and tetrafluoroborate salts (104).
(Scheme 1).
Scheme 2 Schematic diagram for the synthesis of salicylaldehydes ionic liquids (Sal-ILs)
The structures of compounds (96-104) were elucidated based on spectral analyses FTIR, NMR (1H,13C, 31P and 19F)
2. Part 2:
Synthesis of ionic Sulfaguanidine-salicyladimine Schiff bases and their metallation by Pd (II )ion
A series of novel N-(salicylidene)-sulfaguanidines (Sal-SG) bearing ionic liquid (IL) terminals (ILSSGH, 105-111) have been synthesized by Schiff base condensation of IL-functionalized salicylaldehydes (ILSal, 96-104) with sulfaguanidine (SG). Unfortunately all trials to metallate ionic sulfaguanidine Schiff bases ILSSGH ligands with palladium(II) chloride were unsuccessful. Instead, Pd(II) complexes, [Pd(II)(SGSIL)Cl(H2O)] (112-118) were obtained: (Scheme 2).
Scheme 2 Synthesis of ionic sulfaguanidine-salicylaldimine Schiff base architectures (ILSSGH, 105-111) and their metalation by Pd(II) ion
The structures of ILSSGH ligands and their Pd(II) complexes were proposed based upon elemental and spectral analysis (FTIR, NMR (1H, 13C, 19F, 31P, 11B), ESI-MS) as well as conductivity measurements.
3. Part 3:
Synthesis of chitosan salicyladimine schiff base and their metallation by Co+2, Ag+ and Pd+2 salts
A series of biopolymeric chitosan Schiff bases bearing salicylidene ionic liquid (IL-Sal) brushes (ILCSB1-3, poly-(GlcNHAc-GlcNH2-(GlcN-Sal-IL)) (119-121) were successfully synthesized by Schiff base condensation of ionic salicylaldehydes salts (2a-c) with a natural biopolymer, chitosan (Scheme 3). Unfortunately, metalation trials of these biopolymeric Schiff bases afford the corresponding Ag(I)/ M(II) complexes (122-130) (where M = Co, Pd).
Scheme 2 Schematic diagram for the synthesis of ionic liquids-based salicylaldehydes (ILs-Sal), surface-functionalized chitosan and their complexes.
These chitosan architectures (119-130) were isolated in high to excellent yields and structurally characterized by elemental analysis, FTIR and NMR (1H, 13C).
Part 4:
Pharmacological assessment of the new products
The antimicrobial profiles of the new compounds (105-130) against a set of common pathogens have been described. Zone of inhibition (ZOI) and minimal inhibitory concentration (MIC) values revealed that most of the new compounds exhibited significant antibacterial and potential inhibitory activity against Staphylococcus aureus (S. aureus), and this activity is modulated by substituent attached to the ionic liquid core as well as the counter-ion.
The biocidal activity of newly synthesized N-(salicylidene) sulfaguanidine bearing ionic liquids compartments (ILSSGH, 105-111) and their Pd(II) complexes (112-118) has been investigated against common bacterial and fungal pathogens. Both the ZOIs and MIC values revealed that ILSSGH have the ability to inhibit the growth of fungal strains < E. coli < S. aureus. The structure–activity relationship (SAR) study demonstrated that changes of the ionic liquids fragments exhibited different antimicrobial activities levels. Also, alkyl substituent on IL-Sal backbone play a more important role in determining the biocidal properties of ILSSGH/Pd(II)-ILSSG architectures. Where, exchanging of H atom on IL-Sal by isopropyl substituent dramatically decrease the minimal inhibitory concentrations.
Both the ZOIs and MIC values revealed that the designed biopolymeric chitosan Schiff bases (119-121) and their complexes (122-120) exhibit moderate to excellent broad-spectrum antibacterial efficacy in comparison to the parent chitosan and standard antibiotic with an ability to inhibit the growth of A. flavus < C. albicans < E. coli < S. aureus. Interestingly, the metal complexes are potent than parent ILCSBs and exhibited moderate fungicidal efficacy in relation to the standard antibiotic. Structure–activity relationship (SAR) for new compounds against HCT-116 cell line show that the cytotoxicity of metal complexes were superior to that of the parent ligand and the cytotoxic effect of poly ionic Schiff bases complexes was tuned by metal ion and ionic terminal exchange. Furthermore, the Ag(I)-ILCSBs (124) (IC50 = 9.13 and 11.1 μg for Ag(I)-ILCSB2 (127) and Ag(I)-ILCSB1(124), respectively) are more effective in inducing cell death than Co(II)-ILCSB3 (IC50 = 24.4 μg).
In conclusion functionalization of chitosan with IL-Sal brushes coupled with metalation of formed ILCSBs were synergistically enhanced its antimicrobial and antitumor efficiency to great extent. Noteworthy, Ag-ILCSB2 (127) (IC50 = 9.13 μg) was ca. 5-fold more cytotoxic against HCT-116 cell line than ILCSB2 (120) (IC50 = 43.30