Aguiar Inara de, Tavares Aline, Roveda Antonio C, da Silva Augusto C H, Marino Leonardo B, Lopes Érica O, Pavan Fernando R, Lopes Luiz G F, Franco Douglas W
Instituto de Química, Universidade de São Paulo, São Carlos, SP 13566-590, Brazil.
Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista "Julio de Mesquita Filho", Araraquara, SP 14801-902, Brazil.
Eur J Pharm Sci. 2015 Apr 5;70:45-54. doi: 10.1016/j.ejps.2015.01.008. Epub 2015 Jan 28.
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) (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) 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) and trans-Ru(NH3)4(SO2)(INH) 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) 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.
尽管结核分枝杆菌（MTb）菌株产生了耐药性，但异烟肼（INH）仍被认为是治疗结核病（Tb）的最佳药物之一。研究了INH与钌金属中心的配位情况，以此作为增强该药物对MTb敏感菌株和耐药菌株活性的一种策略。分离出了配合物反式-[Ru(NH₃)₄(L)(INH)]²⁺（L = SO₂或NH₃），并研究了它们的化学性质和抗结核特性。最低抑菌浓度（MIC）数据表明，[Ru(NH₃)₅(INH)]²⁺对耐药菌株和敏感菌株均有活性，而游离INH（未配位）仅对敏感菌株有活性。与游离INH相比，INH在[Ru(NH₃)₅(INH)]²⁺和反式-[Ru(NH₃)₄(SO₂)(INH)]²⁺配合物中与金属中心的配位导致INH氧化电位向更正的值移动。尽管INH易于氧化并未导致其对MTb的体外活性增加，但它可能赋予了对耐药菌株的敏感性。此外，使用INH的氧化产物作为配体（即异烟酸和异烟酰胺）合成了化学结构与上述类似的钌配合物。这些最后合成的化合物对任何MTb菌株均无活性。此外，根据密度泛函理论（DFT）计算，相对于游离INH，在[Ru(NH₃)₅(INH)]²⁺配合物中，酰基自由基（一种在INH氧化过程中提出的中间体）的形成比游离INH更有利，能量差为50.7千卡/摩尔。该结果表明，对于抗耐药菌株的抗结核活性而言，金属中心促进的酰基自由基的稳定化比INH的氧化电位更为重要。
