Synthesis, characterization and in vitro extracellular and intracellular activity against Mycobacterium tuberculosis infection of new second-line antitubercular drug-palladium complexes

Objectives The aim of this work was to characterize novel palladium (Pd) complexes with second‐line antitubercular drugs, namely capreomycin (C), kanamycin (K) and ofloxacin (Ofx), and to address the in vitro extracellular and intracellular activity against Mycobacterium tuberculosis infection. Meth...

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Bibliographic Details
Published in:	Journal of pharmacy and pharmacology 2014-01, Vol.66 (1), p.106-121
Main Authors:	Giovagnoli, Stefano, Marenzoni, Maria Luisa, Nocchetti, Morena, Santi, Claudio, Blasi, Paolo, Schoubben, Aurelie, Ricci, Maurizio
Format:	Article
Language:	eng
Subjects:	Antitubercular Agents - chemical synthesis Antitubercular Agents - pharmacology capreomycin Capreomycin - pharmacology drug-palladium complexes Infections intracellular antitubercular activity kanamycin Kanamycin - pharmacology Microbial Sensitivity Tests - methods Mycobacterium tuberculosis - drug effects ofloxacin Ofloxacin - pharmacology Palladium - chemistry Palladium - pharmacology Particle Size Solubility Tuberculosis Tuberculosis - drug therapy
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Summary:	Objectives The aim of this work was to characterize novel palladium (Pd) complexes with second‐line antitubercular drugs, namely capreomycin (C), kanamycin (K) and ofloxacin (Ofx), and to address the in vitro extracellular and intracellular activity against Mycobacterium tuberculosis infection. Methods Synthesis reaction kinetics and complex properties were assessed. Kf was calculated from the transition state quasi‐equilibrium approximation and Arrhenius plot. The complexes were characterized for qualitative solubility, stoichiometry, powder size and morphology, element analysis, and thermal behaviour. Structural analyses were performed by Fourier transform infrared spectroscopy and nuclear magnetic resonance. Activity was evaluated against H37Ra M. tuberculosis strain and in infected THP‐1 cells, and compared with that of the parent drugs. Key findings The complexes showed log Kf of 6 for CPd and OfxPd, and 10 for KPd indicating good stability. Stoichiometry of 1 : 1, 2 : 3 and 1 : 3 resulted for OfxPd, KPd, and CPd. OfxPd structure matched that in literature, while K and C had more complex structures with possible multiple coexisting species. The complexes had extracellular activity comparable with drugs and an improved efficacy against intracellular infection of M. tuberculosis. Conclusions The novel anti‐tuberculosis (TB) complexes had promising properties, and extracellular and intracellular activity, which makes them potential tools for intracellular targeting of pulmonary TB.
ISSN:	0022-3573 2042-7158