Síntese, caracterização e estudos de reatividade de novos compostos de rutênio com ligantes derivados terpiridínicos e benzimidazólicos

Abstract

Tuberculosis (TB) is a disease that reaches mainly poor Countries but has caught worldwide attention due to the number of resistant strains. During the last years, metal complexes have been studied as potential anti-TB agents. Polypyridine ruthenium complexes have been developed as potential therapeutic agents, including in phototerapy. Thus, new potential pro-drugs with polypyridinic and benzimidazolic ligands coordinated to a ruthenium metal center were synthetized, their properties, such as stability and reactivity, were studied and possible biological activity and photoactivation were evaluated. All compounds were characterized employing spectroscopic (1H NMR, electronic and vibrational spectroscopy), electrochemical technique (cyclic voltammetry) and elemental analysis along with computational simulations (DFT and TD-DFT). Photochemical reactivity studies were carried out by electronic spectroscopy and photogeneration of radical species, such is singlet oxygen (1O2) measured. Biological activity assays were done using Gram-positive and Gram-negative bacteria, Mycobacterium tuberculosis, and also using mammalian cell lines. Our results supported the proposed structures for the metal complexes prepared. The complex trans-[Ru(phtpy)(INH)Cl2] showed appealing 1O2 generation yield even using red light (Δ= 0.38), while trans-[Ru(pybbzd)(INH)Cl2] promising yield using blue light (Δ= 0.37). Interestingly, it was also noticed suggestive data of photoisomerization of the metal complexes containing phenylterpyridine ligand in the conformation cis and trans with likely release of isoniazid. Microbiological investigation using Gram-positive and Gram-negative bacteria did not show any bacteriostatic/bactericidal activity either with or without light irradiation for the metal complexes. However, assays with M. tuberculosis using the metal complexes cis-[Ru(phtpy)(DMSO)Cl2] and trans-[Ru(phtpy)(INH)Cl2], exhibited MIC values of 44.8 and 40.6 µM, respectively, supporting a moderated activity. The metal compounds showed hydrophilic profile in the lipophilicity assays (LogP). In general, all the compounds showed low cytotoxicity either in healthy or cancer cells, even upon light irradiation, preliminarily suggesting they might be safe for biological applications. Based on that, new structural changes in these metal complexes aiming to improve their biological activity, along with the investigation of other cell lines, are new steps of this work.