Síntese, caracterização, análise in silico e atividades biológicas de um novo nitro complexo de rutênio (FOR711A)

Abstract

Nitric oxide donors induce vascular relaxation in normotensive and hypertensive rats. This study aimed to investigate the synthesis, in silico and in vivo toxicity, and the potential vasodilatory effect, in silico and in vitro, of a new ruthenium complex, cis-[Ru(bpy)2(2-MIM)(NO2)]PF6 (bpy = 2,2'-bipyridine and 2-MIM = 2-methylimidazole) (FOR711A), containing an imidazole derivative. The PROTOX-II program showed low class III toxicity. Cytotoxicity, hepatotoxicity, immunotoxicity, mutagenicity, nephrotoxicity and carcinogenicity were negative for FOR711A in the eMolTox program. An LD50 greater than 175 mg/kg was revealed in Swiss mice. FOR711A interacted with sites of the β1H-NOX domain of reduced and oxidized soluble guanylate cyclase (sGC), demonstrating shorter binding distances to several residues and negative values of total energy. Biological network and molecular docking analysis showed the involvement of vasodilator proteins. The predictive study revealed molar refractivity (MR): 127.65; Log Po/w = 1.29; topological polar surface area (TPSA): 86.26 Å2; molar mass (MM) = 541.55 g/mol; low solubility, high unsaturation, high gastrointestinal absorption; failure to cross the blood-brain barrier and to react with the cytochrome P450 (CYP) enzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4. After the HET-CAM assay, the FOR711A complex was classified as non-irritating (N.I.) and its vasodilating effect was confirmed by the increased evidence of blood vessels after administration and the end of the 5-minute observation period. The vasorelaxant effects were analyzed by the concentration response curve for FOR711A (0.01 to 30 μmol/L) in rat aortic rings (n=6) in the absence or presence of endothelium and different inhibitors of vasodilation pathways were used. FOR711A was able to induce total relaxation in preparations pre-contracted with PHE, while in preparations pre-contracted with KCL the relaxation was partial and therefore less effective. In

preparations with PHE without endothelium, there was total relaxation of the aortic rings. FOR711A- induced relaxation was significantly reduced in the presence of the ODQ inhibitor (1H-[1,2,4]-

oxadiazolo-[4,3,-a]quinoxalin-1-one) and partially reduced in the presence of L-NAME (Nω-nitro-L- arginine methyl ester) and hydroxocobalamin. FOR711A showed low toxicity and promoted a

vasodilatory effect by stimulating/activating sGC via NO/sGC/cGMP and the partially NO species

(NO●) and nitric oxide synthase. Thus, representing a potential compound for continuity in future pre- clinical studies. However, the results indicate the need for a vehicle for oral administration.