ABSTRACT
Rifampicin, discovered more than 50 years ago, represents the last novel class of antibiotics introduced for the first-line treatment of tuberculosis. Drugs in this class form part of a 6-month regimen that is ineffective against MDR and XDR TB, and incompatible with many antiretroviral drugs. Investments in R&D strategies have increased substantially in the last decades. However, the number of new drugs approved by drug regulatory agencies worldwide does not increase correspondingly. Ruthenium complexes (SCAR) have been tested in our laboratory and showed promising activity against Mycobacterium tuberculosis. These complexes showed up to 150 times higher activity against MTB than its organic molecule without the metal (free ligand), with low cytotoxicity and high selectivity. In this study, promising results inspired us to seek a better understanding of the biological activity of these complexes. The in vitro biological results obtained with the SCAR compounds were extremely promising, comparable to or better than those for first-line drugs and drugs in development. Moreover, SCAR 1 and 4, which presented low acute toxicity, were assessed by Ames test, and results demonstrated absence of mutagenicity.
Subject(s)
Antitubercular Agents/pharmacology , Coordination Complexes/pharmacology , Imines/pharmacology , Mycobacterium tuberculosis/drug effects , Phosphines/pharmacology , Picolinic Acids/pharmacology , Ruthenium/pharmacology , Animals , Antitubercular Agents/adverse effects , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Drug Resistance, Bacterial/drug effects , Female , Humans , Imines/chemical synthesis , Imines/chemistry , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Mutagenesis/drug effects , Mutagenicity Tests , Mycobacterium tuberculosis/growth & development , Mycobacterium tuberculosis/isolation & purification , Phosphines/chemical synthesis , Phosphines/chemistry , Picolinic Acids/chemical synthesis , Picolinic Acids/chemistry , Ruthenium/chemistry , Toxicity Tests, AcuteABSTRACT
This paper describes the synthesis and characterization of four new ruthenium complexes containing 1,4 bis(diphenylphosphino)butane (dppb), 2-pyridinecarboxylic acid anion (pic) and the diimines [(2,2'-bipyridine (bipy), 4,4'-dimethyl-2,2'-bipyridine (Me-bipy), 4,4'-dichloro-2,2'-bipyridine (Cl-bipy) and 1,10-phenanthroline (phen) as ligands, with formulae [Ru(pic)(dppb)(bipy)]PF(6) (SCAR01), [Ru(pic)(dppb)(Me-bipy)]PF(6) (SCAR02), [Ru(pic)(dppb)(Cl-bipy)]PF(6) (SCAR03) and [Ru(pic)(dppb)(phen)]PF(6) (SCAR04). Additionally, the in vitro anti-Mycobacterium tuberculosis (MTB) activity, cytotoxicity and activity against in vitro infection of these complexes and two more complexes, cis-[Ru(pic)(dppe)(2)]PF(6) (SCAR05) and cis-[RuCl(2)(dppb)(bipy)] (SCAR06), and their free ligands are described and discussed. All compounds showed excellent MIC against MTB, low cytotoxicity and a selectivity index higher than 10. Also, all compounds showed significant intracellular inhibition and the compound SCAR05 showed a better activity than rifampin and SQ109. This is the first report of activity against in vitro infection of ruthenium compounds.
