title: Antitubercular activity of Ru (II) isoniazid complexes.
abstract: Despite the resistance developed by the Mycobacterium tuberculosis (MTb) strains, isoniazid (INH) has been recognized as one of the best drug for treatment of Tuberculosis (Tb). The coordination of INH to ruthenium metal centers was investigated as a strategy to enhance the activity of this drug against the sensitive and resistant strains of MTb. The complexes trans-[Ru(NH3)4(L)(INH)](2+) (L=SO2 or NH3) were isolated and their chemical and antituberculosis properties studied. The minimal inhibitory concentration (MIC) data show that [Ru(NH3)5(INH)](2+) was active in both resistant and sensitive strains, whereas free INH (non-coordinated) showed to be active only against the sensitive strain. The coordination of INH to the metal center in both [Ru(NH3)5(INH)](2+) and trans-[Ru(NH3)4(SO2)(INH)](2+) complexes led to a shift in the INH oxidation potential to less positive values compared to free INH. Despite, the ease of oxidation of INH did not lead to an increase in the in vitro INH activity against MTb, it might have provided sensitivity toward resistant strains. Furthermore, ruthenium complexes with chemical structures analogous to those described above were synthesized using the oxidation products of INH as ligands (namely, isonicotinic acid and isonicotinamide). These last compounds were not active against any strains of MTb. Moreover, according to DFT calculations the formation of the acyl radical, a proposed intermediate in the INH oxidation, is favored in the [Ru(NH3)5(INH)](2+) complex by 50.7kcalmol(-1) with respect to the free INH. This result suggests that the stabilization of the acyl radical promoted by the metal center would be a more important feature than the oxidation potential of the INH for the antituberculosis activity against resistant strains.
authors: Instituto de Química, Universidade de São Paulo, São Carlos, SP 13566-590, Brazil.
authors: Inara de
authors: Id
authors: Aguiar
authors: Instituto de Química, Universidade de São Paulo, São Carlos, SP 13566-590, Brazil.
authors: Aline
authors: A
authors: Tavares
authors: Instituto de Química, Universidade de São Paulo, São Carlos, SP 13566-590, Brazil.
authors: Antonio C
authors: AC
authors: Roveda
authors: Instituto de Química, Universidade de São Paulo, São Carlos, SP 13566-590, Brazil.
authors: Augusto C H
authors: AC
authors: da Silva
authors: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista "Julio de Mesquita Filho", Araraquara, SP 14801-902, Brazil.
authors: Leonardo B
authors: LB
authors: Marino
authors: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista "Julio de Mesquita Filho", Araraquara, SP 14801-902, Brazil.
authors: Érica O
authors: ÉO
authors: Lopes
authors: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista "Julio de Mesquita Filho", Araraquara, SP 14801-902, Brazil.
authors: Fernando R
authors: FR
authors: Pavan
authors: Departamento de Química Orgânica e Inorgânica, Universidade Federal do Ceará, Fortaleza, CE 60455-970, Brazil.
authors: Luiz G F
authors: LG
authors: Lopes
authors: Instituto de Química, Universidade de São Paulo, São Carlos, SP 13566-590, Brazil. Electronic address: douglas@iqsc.usp.br.
authors: Douglas W
authors: DW
authors: Franco
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002522:Chlorocebus aethiops; D007538:Isoniazid / Q000494:pharmacology* / Q000627:therapeutic use; D008826:Microbial Sensitivity Tests / Q000379:methods; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000502:physiology; D012428:Ruthenium / Q000494:pharmacology* / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D012428:Ruthenium; D007538:Isoniazid
keywords: Isoniazid; Metal complexes; Metallodrugs; Resistant strains; Tetraammine- and pentaammine ruthenium complexes; Tuberculosis