Cell penetrating peptide as cell delivery vectors

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Antibacterial and antifungal activity

The Schiff base formed from pyridine-2-carboxaldehyde SMDTC and its Zn complex showed marked and broad antimicrobial and antifungal activities compared to the S-benzyl derivatives with MIC values as low as 12.5 !g/mL (Zhang et al., 2011a). The antibacterial activity of the Schiff bases of SBDTC with ferrocenebased chalcones containing a F or Cl substituent in the para position or a pyridine ring were the most active in the series and their activity against Gram-negative bacterial (Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa)) strains was found to be higher than that for the drugs ketoconazole, kanamycin and penicillin (Liu et al., 2012). In another closely related investigation, the Zn(II) and Cu(II) complexes of SBDTC with ferrocene-based chalcone Schiff base ligand containing a para-Cl substituent and the Zn(II) complex of SBDTC with ferrocenebased chalcone having a methyl group in the aromatic ring were the most active in the series with MIC values in the range of 1.319 ! 10″8 M to 3.750 ! 10″7 M against bacteria and fungi tested (Staphylococcus aureus (S. aureus), Bacillus cereus (B. cereus), E. coli, P. aeruginosa, Aspergillus niger (A. niger), Aspergillus fumigatus A. fumigates) (Liu et al., 2013). SMDTC-2-benzolpyridine and its Cu(II) complex showed excellent activity against Gram positive bacteria (Bacillus subtilis (B. subtilis), S. aureus) and yeast (Candida lusitaniae (C. lusitaniae)) with MIC values of 1-5 !g/mL. It was found that the SMDTC derived ligand was more potent than the SBDTC derivative towards the tested microorganisms and complexation with metals also had a synergetic effect resulting in enhanced antimicrobial activity (Li et al., 2012). Both the Cu(II) complex of the Schiff base S4PDTC with pyridine- 2-carboxaldehyde and the Cd(II) complex of S4PDTC 4-carboxybenzaldehyde (Cb4PDTC) showed good antifungal activity against Candida albicans (C. albicans) with MIC values lower than Nystatin (Khoo et al., 2014) . The Schiff base derived from SBDTC with pyrrole-2-carboxaldehyde was a stronger antifungal agent than Nystatin against Saccaromyces ceciricaee (S. ceciricaee) and Candida lypolytica ( C. lypolytica) (Tarafder et al., 2002a). The NSS Schiff bases of S2PDTC with 2- acetylfuran showed better activity than Nystatin toward against the fungus, C. lypolytica while its metal complexes were not active (Crouse et al., 2004). Co(II) complex of SMDTC with 2-furyl-methylketone and Cd (II) complex of SMDTC with 5-methyl-2-furaldehyde gave the most effective activity against fungi tested (C. lypolytica and Aspergillus ochraceus (A. ochraceous) (Chew et al., 2004) while the Cu(II) complex of SMDTC with 2-furylmethylketone showed clear activity against C. lypolytica with better activity than Nystatin (Tarafder et al., 2002c). Bi(III) and As(III) metal complexes of SBDTC-3-acetylcoumarin (L) with the formula [ClBi(L)2] and [PhAs(L)2] showed low MIC values (10#!g/mL for bacterial strain B. subtilis and 16#!g/mL for fungal strain Fusarium oxysporum (F. oxysporum)). The metal complexes were more active against fungal strains compared to bacterial strains and had better activity than the free ligands (Dawara et al., 2012). In the series with salicylaldehyde Schiff base of isonicotinoyldithiocarbazic acid, the best activity was shown by the Ni(II) complex (MIC = 75 !g/mL) against the gramnegative pathogenic strain of E. coli (Kalia et al., 2012). The Cd complex of the SNNS Schiff base SBDTC-benzil was active against bacteria P. aeroginosa and B. cereus with the MIC values better or comparable to kanamycin (Tarafder et al., 2000b). The Cu(II) complex of SBDTC-salicylaldehyde proved to be the best in the series against B. cereus (MIC=79.6 !g/mL) (Tarafder et al., 2000a).

Antituberculosis activity

Ni, Co and Zn complexes of a non-Schiff base isonicotinoyldithiocarbazic acid ligand synthesized from isoniazid with carbon disulphide showed MIC values of 2, 2 and 50 !g/mL against Mycobacterium tuberculosis (M. tuberculosis) H37Rv, and 10, 100 and 50 !g/mL against a multi-drug-resistant strain of M. tuberculosis. They had little cytotoxic effect on the transformed human rhabdomyosarcoma cell line RD cells making them potentially useful to treat multi-drug resistant tuberculosis infections (Kanwar et al., 2008). Others dithiocarbazate derivatives such as 2-/3-/4- pyridinecarbonimidoyldithiocarbazic acid esters, methyl 3-[amino(pyrazin-2- yl)methylidene]-2 methyldithiocarbazate and benzyl 3-[amino(pyrazin-2- yl)methylidene]-2-methyldithio carbazate have been studied and were among the promising classes of compounds showing action against tuberculosis (Olczak et al., 2010). In another study by Pavan et al. (2010), dithiocarbazate compounds derived from benzoylacetone showed poor activity. The low activity was associated with the difference in the molecular structures from the potent analogues which contained pyridine rings further affirming that the aromatic heteroatom N moiety played an important role in the anti-tuberculosis activity of the compounds (Pavan et al., 2010).

Potentially bidentate NS or tridentate ONS ligands with an acid or ester functionality

The open chain series in this work consisting ligands of methyl levulinate and levulinic acid with SBDTC and SMDTC as well as their corresponding Cu(II) complexes will be a worthy comparison to their macroacyclic Cu(II) tetradentate system with 2,5-hexanedione bis(dithiocarbazate). Furthermore, the Schiff base derivatives containing the acid or ester functional group have proved to be attractive from both biological and physico-chemical aspects. For instance, recent attention was dedicated to metal complexes of &-ketoglutaric acid (Baldini et al., 2004) and pyruvic acid thiosemicarbazone (Diaz et al., 1994; Wiecek et al., 2009). These aliphatic ligands with a variety of potential donor atoms and many possible conformations provided a versatile chelating behavior. In addition, the metal complexes were found to be potent against the selected human leukemia and cancer cell lines tested and thus may be regarded as potentially significant antitumor agent (Baldini et al., 2004; Diaz et al., 1994; Wiecek et al., 2009). Similiarly, the analogous Schiff base keto-ester methylpyruvate with SMDTC has been screened by the National Cancer Institute, Bethesda, Maryland and has been found to exhibit promising activity against leukemia cells as mentioned by Ali et al. (2001b). The authors also stated that the “ligand coordinated to the metal(II) ion as a uninegatively charged tridentate chelating agent via the carbonylic oxygen atom, the azomethine nitrogen atom and the thiolato sulfur atom” but resulted in varied conformation geometry with different metal (Ali et al., 2001b p. 1037). The Cu(II) complexes have the general formula, CuLX (L= Schiff base; X=Cl », Br ») with a distorted square-planar structure whereas the Zn(II), Cd (II) and Ni(II) complexes of empirical formula, ML2 supported a six-coordinate distorted octahedral structure for
these complexes as confirmed by the X-ray crystallographic structural analysis (Ali et al., 2001b; Ali et al., 1999; Ali et al., 2004). To date, metal complexes of methyl levulinate or levulinic acid dithiocarbazate have not been reported although semicarbazone derivatives of levulinic acid have been identified as potent anticonvulsant agents showing broad spectrum of activity with low neurotoxicity (Navneet and Pradeep, 2005).

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Potentially bidentate NS or tridentate ONS ligands with natural potent aldehyde or ketones moieties.

In order to expand the synthesis and exploration of dithiocarbazate derivatives, attention was also directed herein to aromatic dithiocarbazate derived from natural aldehydes or ketones that had well established medicinal properties. The rationale behind this attempt was based on the prospect of the synergistic effects developed from integration of the promising bioactivity of individual components (i.e. metal center and ligand comprising the carbonyl group and substituted dithiocarbazate moiety). A number of publications had highlighted the potential of utilizing such natural aromatic compounds like chromone (Barve et al., 2006; Khan et al., 2009), chalcone (Zhang et al., 2011b) and curcumin (Padhye et al., 2009). This prompted the preparation of new metal complexes with Schiff base formed from the condensation of SBDTC and 3-acetylcoumarin in this work. Coumarin derivatives are attractive because of their wide variety of biological activities including antioxidant, antibacterial, antifungal and cytotoxic (Datta et al., 2011; Bagihalli et al., 2008; Phaniband et al., 2011; Kulkarni et al., 2009; Creaven et al., 2009).
Moreover, the reported coumarin Schiff bases and their metal complexes were shown to exhibit outstanding luminescence properties which may provide advantage for application of these compounds as probes (Datta et al., 2011). Further findings reveal that the coumarin derivatives interact strongly with DNA and can cause DNA cleavage (Phaniband et al., 2011; Kulkarni et al., 2009).

Table of contents :

ABSTRACT
ABSTRAK
RÉSUMÉ
ACKNOWLEDGEMENTS
APPROVAL
DECLARATION
LIST OF TABLES
LIST OF FIGURES
LIST OF SCHEMES
LIST OF APPENDICES
LIST OF ABBREVIATIONS
CHAPTER
1 INTRODUCTION
2 LITERATURE REVIEW
2.1 S-substituted dithiocarbazate
2.2 Schiff bases and metal complexes
2.3 Biological activity
2.3.1 Anticancer activity
2.3.2 Antibacterial and antifungal activity
2.3.3 Iron chelators
2.3.4 Antituberculosis activity
2.3.5 Antiamoebic activity
2.3.6 Other biological properties
2.4 Objectives
3 NON-CONJUGATED PARENTS COMPOUNDS
3.1 Introduction
3.1.1 Types of ligands systems
3.1.1.1 Tetradentate NNSS
3.1.1.2 Potentially bidentate NS or tridentate ONS ligands with an acid or ester functionality
3.1.1.3 Potentially bidentate NS or tridentate ONS ligands with natural potent aldehyde or ketones moieties
3.1.2 Choice of metals
3.1.2.1 Copper
3.1.2.2 Zinc
3.1.2.3 Rhenium
3.2 Methodology
3.2.1 Materials
3.2.2 Instrumentation
3.2.3 Synthesis
3.2.3.1 Macroacyclic Cu(II) system with tetradentate NNSS ligands
3.2.3.2 Open chain Cu(II) system with bidentate NS ligands with acid or ester functionality
3.2.3.3 Open chain metal system with bidentate NS ligands with natural ketone moiety
3.3 Results and Discussion
3.3.1 Synthesis
3.3.2 Characterization of metal complexes in solid state
3.3.2.1 FT-IR
3.3.2.2 Single crystal XRD description
3.3.3 Characterization of metal complexes in solution
3.3.3.1 NMR
3.3.3.2 UV-VIS
3.3.3.3 EPR
3.3.3.4 Electrochemistry
3.4 Conclusion
4 FUNCTIONALIZED COMPOUNDS
4.1 Introduction
4.1.1 Key drawbacks of metallodrugs
4.1.2 Conjugated metal complexes
4.1.2.1 Schiff base conjugates
4.1.2.2 PEGylation
4.1.2.3 Cell penetrating peptide as cell delivery vectors
4.1.2.4 Design of metal complex-conjugates
4.2 Methodology
4.2.1 Materials
4.2.2 Instrumentation
4.2.3 Synthesis
4.3 Results and Discussion
4.3.1 Synthesis
4.3.2 Characterization of ligand conjugates
4.3.2.1 NMR
4.3.2.2 MALDI-TOF-MS/ESI-MS
4.3.3 Characterization of metal-complexes conjugates
4.3.3.1 UV-VIS
4.3.3.2 LC-MS
4.3.3.3 ITC
4.3.3.4 EPR
4.3.3.5 Electrochemistry
4.4 Conclusion
5 BIOLOGICAL ACTIVITIES
5.1 Introduction
5.1.1 Mechanism of actions of antimicrobial agents and multi-drug resistance
5.1.2 Antimicrobial peptides
5.1.3 Efflux pumps and inhibitors
5.1.4 Contribution of metal complexes to the improvement of antimicrobial agents
5.2 Methodology
5.2.1 Antimicrobial testing (MIC determination)
5.2.1.1 Bacterial strains, culture media and chemicals
5.2.1.2 Determination of bacterial susceptibility
5.2.2 In vitro cytotoxicity testing
5.3 Results and Discussion
5.3.1 Antimicrobial evaluation
5.3.1.1 Macroacyclic Cu(II) system with tetradentate NNSS ligands
5.3.1.2 Open chain Cu(II) system with bidentate NS ligands with acid or ester functionality
5.3.1.3 Functionalized compounds
5.3.2 Cytotoxicity
5.4 Conclusion
6 SUMMARY AND RECOMMENDATION
REFERENCES
APPENDICES
LIST OF PUBLICATIONS AND CONFERENCES ATTENDED
BIODATA OF STUDENT

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