Mechanism of actions of antimicrobial agents and multi-drug resistance

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Tetradentate NNSS

Macrocyclic and macroacyclic Schiff bases have been widely studied (Vigato and Tamburini, 2004). They show various coordination abilities and potential applications in biology which range from therapeutic drug candidates to diagnostic agents (Holland et al., 2008) and they provide synthetic models for the metal containing sites in metalloproteins and metalloenzymes (Gennari et al., 2012). It is therefore worthwhile to explore these interesting properties by investigating the synthesis and characterization of new Cu(II) bis(dithiocarbazate) in this work. The compounds are analogues of the Cu(II) bis(thiosemicarbazone) that have garnered much attention resulting in biological breakthroughs (Paterson and Donnelly, 2011) particularly as radiopharmaceuticals (Donnelly, 2011).
It is anticipated that the replacement of nitrogen atom with sulphur may provide interesting results warranting further exploration into dithiocarbazate compounds. Moreover, to form the Schiff bases, the 2,5-hexanedione has been chosen to expand the ligand flexibility by introducing backbones containing more than two carbons.
This enhanced flexibility may facilitate increased tetrahedral distortion leading to incorporation of metal cations that prefer non-square planar geometries such as Cu(I) ion. Previous studies have shown that physico-chemical properties such as redox potential as well as biological activity have been related to the geometry at the metal site (Durot et al., 2005; Drew et al., 1995; Rorabacher, 2004; Basha et al., 2012; Jansson et al., 2010). These were fine examples demonstrating the marked influence of ligand environment towards the redox potential of their respective Cu(II)/Cu(I), Fe(III)/Fe(II) and Mn(III/II) metal systems. While choice of the metal ions and substituent functional groups of the ligands have been carefully chosen to affect the geometry of metal complexes (Ostermeier et al., 2010; Jones and McCleverty, 1970; Cowley et al., 2004; Stefani et al., 2012), the studies by Diaz et al. (1998;1999) that highlighted the differences in coordination geometry identified using EPR by comparing the open chain and cyclic metal complex system which subsequently affect their biological activity was found to be particularly attractive since this analytical tool enabled a structural view of the complexes in solution. The group noted that the Cu(II) complexes of the open chain mono(thiosemicarbazone) with a higher degree of tetrahedral distortion should be further explored as potentially better SOD-like mimics than the macroacyclic bis(thiosemicarbazone) complexes. Although the reports were primarily focused on superoxide dismutase (SOD) mimics, it would also be meaningful to carry out such comparison in this work as the open chain system will be envisaged to offer interesting diversity and aid towards the understanding of the structure-bioactivity relationship.

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).

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).

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Macroacyclic Cu(II) system with tetradentate NNSS ligands

SBHD The title compound was synthesized with some modification of the method described by Ali et al. (1987). 2,5-hexanedione (0.587 mL, 0.005 mol, 1 equiv) was added to a hot solution of SBDTC (1.983 g, 0.01 mol, 2 equiv) in absolute ethanol (150 mL) and the mixture was further heated for 5 min. A white precipitate was formed and was immediately filtered off, washed with cold ethanol and dried in vacuo over silica gel to yield the expected Schiff base (0.997 g, Yield 42%). Elemental analysis for C22H26N4S4: Calcd. C 55.66, H 5.52, N 11.80; Found C 54.79, H 5.59, N 11.75. 1H NMR (300 MHz, DMSO-d6) ) 12.18 (s, 2H), 7.39 -7.20 (m, 10H), 4.40 (s, 4H), 1.96 (s, 6H). 13C NMR (75 MHz, DMSO-d6) ) 197.16, 158.26, 137.15, 129.15, 128.41, 127.05, 37.56, 34.05, 17.74. IR: # (cm-1) = 3147 (m, b), 1640 (w), 1054 (s), 981 (m), 828 (m). UV-Vis in DMSO: « max nm (log ! ) = 276 (4.32), 308 (4.41), *360 (3.32, sh). RP-HPLC: RT (min) = 15.3, 18.3, 22.4.  SMHD SMDTC (1.222 g, 0.01 mol, 2 equiv) was dissolved in hot ethanol (150 mL) and 2,5-hexanedione (0.587 mL, 0.005 mol, 1 equiv) was added to this solution. The mixture was heated while being stirred to reduce the volume to 1/3 of the original volume. The mixture was kept at 4°C overnight and white precipitate was formed. The product was filtered off, washed with cold ethanol and dried in vacuo over silica gel to afford 1.129 g of SMHD (Yield 70%). The compound was further recrystallized from methanol and crystals suitable for X-ray diffraction analysis were obtained from the same solvent through slow evaporation at room temperature. Elemental analysis for C10H18N4S4: Calcd. C 37.24, H 5.63, N 17.37; Found C 37.86, H 4.87, N 17.84. 1H NMR (300 MHz, DMSO-d6) ) 12.13 (s, 2H), 2.57 (s, 4H), 2.43 (s, 6H), 2.00 (s, 6H). 13C NMR (75 MHz, DMSO-d6) ) 198.95, 157.63, 33.97, 17.77, 16.94. IR: # (cm–1) = 3111 (m, b), 1628 (m), 1046 (s), 988 (m), 827 (m). UV-Vis in DMSO: « max nm (log ! ) = 276 (4.25), 305 (4.37), *360 (2.75, sh). RP-HPLC: RT (min) = 6.4, 11.1, 18.7.

Table of contents :

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
3.1 Introduction
3.1.1 Types of ligands systems Tetradentate NNSS Potentially bidentate NS or tridentate ONS ligands with an acid or ester functionality Potentially bidentate NS or tridentate
ONS ligands with natural potent
aldehyde or ketones moieties
3.1.2 Choice of metals Copper Zinc Rhenium
3.2 Methodology
3.2.1 Materials
3.2.2 Instrumentation
3.2.3 Synthesis Macroacyclic Cu(II) system with tetradentate NNSS ligands Open chain Cu(II) system with bidentate NS ligands with acid or ester functionality 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 FT-IR Single crystal XRD description
3.3.3 Characterization of metal complexes in solution NMR UV-VIS EPR Electrochemistry
3.4 Conclusion
4.1 Introduction
4.1.1 Key drawbacks of metallodrugs
4.1.2 Conjugated metal complexes Schiff base conjugates PEGylation Cell penetrating peptide as cell delivery vectors 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 NMR MALDI-TOF-MS/ESI-MS
4.3.3 Characterization of metal-complexes conjugates UV-VIS LC-MS ITC EPR Electrochemistry
4.4 Conclusion
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) Bacterial strains, culture media and chemicals Determination of bacterial susceptibility
5.2.2 In vitro cytotoxicity testing
5.3 Results and Discussion
5.3.1 Antimicrobial evaluation Macroacyclic Cu(II) system with tetradentate NNSS ligands Open chain Cu(II) system with bidentate NS ligands with acid or ester functionality Functionalized compounds
5.3.2 Cytotoxicity
5.4 Conclusion


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