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Title: Copper(II) and Zinc(II) complexes of aroyl hydrazones as potential antitubercular agents
Author: Jamadar, Abeda
ISNI:       0000 0004 2723 2530
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2012
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There is a continuing need to make new antitubercular drugs due to development of resistance towards present drugs. To do this, series of pyruvate hydrazones (PVAHs) and their respective Cu(II) complexes and Zn(II) complexes were synthesized and fully characterised. Variable temperature NMR studies of PVAHs indicate the presence of E and Z isomers in the solution. Determination of the obtained single crystal X-ray structures reveals that Cu(II) ion binds to PVAH ligand in 1:1 ratio resulting in square pyramidal geometry in most of the Cu(II) complexes, whereas Zn(II) ion binds to two PVAH ligands in 1:2 ratio giving rise to octahedral geometry. The electrochemical studies of Cu(II) complexes of PVAH performed using cyclic voltammogram indicate the presence of quasi-reversible behaviour assigned to a Cu2+/Cu1+ peak potential. This indicates structural reorganisation of Cu(II) square pyramidal geometry towards Cu(I) tetrahedral geometry. The tetrahedral geometry of a synthesized Cu(I) complex of PVAHs was confirmed by X-ray crystal structure. The stability studies of selected PVAH ligands and their metal complex indicate that the investigated compounds were stable in extreme basic conditions, but they were unstable in extreme acidic conditions due hydrolysis of azomethine bond. However, stability of these compounds in physiological conditions, i.e. in PBS buffer, reveals that ligand hydrolyses slowly over a period of time, whereas the Cu(II) complex remains quite stable over a monitored period of 120 hours. Interestingly, dihydrazide analogue of PVAH was fairly stable in PBS buffer. EPR studies of investigated Cu(II) complexes in DMSO indicate that PVAHs remains strongly coordinated to Cu(II) centre. The evaluation of the antimycobacterial activity showed that the anionic PVAHs and Zn(II) complexes are essentially inactive. Some of the corresponding neutral Cu(II) complexes, however, exhibit promising antimycobacterial activities if tested under high iron (8 μg Fe per mL) conditions. As observed for the related antimycobacterial agent isoniazid, the activity of the complexes decreases if the M. tuberculosis cells are grown under low iron (0.02 μg Fe per mL) conditions. The Cu(II) complexes may thus have a similar mode of action and may require an iron-containing heme-dependent peroxidase for activation. A series hydrophobic cinnamaldehyde hydrazones (CAHs) and their Cu(II) complexes were also synthesized and tested for their antitubercular activity under similar conditions to that of PVAH series. But they failed to show any inhibitory activity due to their poor cellular uptake owing to their limited solubility in aqueous buffer.
Supervisor: Duhme-Klair, Anne Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available