Explorando as propriedades biofísicas, antiproliferativa, antioxidante e de inibições enzimáticas de azometinas

Abstract

Azomethine group (C=N) stands out for providing the opportunity to create a wide variety of molecular hybrids with diverse structures, manifesting remarkable biological properties, such as antifungal, anticancer, anti-inflammatory, antiviral and antioxidant activity, among others. Thus, considering the importance of bioactive molecules with such properties, this study evaluated the biological profile of three classes of C=N molecular hybrid compounds. Initially, the evaluation of aminoguanidine hydrazones was carried out, of which the AGH-3 derivative with an indole nucleus offered the greatest antioxidant capacity with results comparable to Trolox in DPPH• , ABTS•+, FRAP and •NO radical scavenging assays. In addition, AGH-3 showed the greatest antiproliferative activity against human kidney cancer cells with GI50 = 6.3 M. In the biophysical studies, it was noted that AGH-3 interacted with ctDNA forming a fluorescent supramolecular complex with a Kb=2.89×103 M-1, preferably via an intercalator mechanism. The results demonstrated the potential of aminoguanidine hydrazones as a strategic class of compounds with multitarget biological activity. Subsequently, the urease inhibition potential of a class of Schiff bases derived from thiosemicarbazones and hybridized with pyrazoles. Derivative 312 showed the highest activity (IC50 = 24.72±1.09 M), being comparable to the standard Thiourea (Tukey test, p ≤ 0.05), showing a mixed type of inhibition. Thermodynamic studies have shown that the formation of the complex (312- urease) occurs spontaneously (G < 0) and is stabilized by hydrophobic interactions (H and S >0). UV-vis studies suggest that 312 interacts with Ni(II), a cofactor of urease. Molecular docking studies corroborated experimental studies, showing that 312 interacts with amino acid residues close to the enzyme's active site, mainly through hydrogen bonds and hydrophobic interactions, as well as with Ni(II) present in the enzyme's active site. Compound 312 also showed urease inhibition in soil samples, being superior to NBPT in S2 (Tukey test, p ≤ 0.05). In addition, this compound was effective in inhibiting ureolytic enzymes in urine samples. The results highlight the potential of compound 312 for various biotechnological applications. Finally, compounds analogous to resveratrol and hybrids with lipoic acid were synthesized, characterized and applied, using Schiff bases and amines as model structures. This resulted in compounds with yields ranging from 49 to 98%, which were characterized by 1H, 13C, Noesy NMR and FTIR-ATR. Compound 6 showed an IC50=22.91±0.90 μM of tyrosinase inhibition and mixed-type inhibition, demonstrating superior activity to the kojic acid and resveratrol standards (Tukey test, p ≤ 0.05). In the SPF-UVB evaluation, the C=N bond had a significant influence, with Schiff bases standing out, with compound 17 exhibiting the highest SPF value (21.53 ± 0.74), surpassing BZF-3 (Tukey test, p ≤ 0.05). In addition, the compounds showed promising antioxidant activities, with compound 7 being outstanding in the ABTS-+ method (IC50 = 0.016 ± 0.0001 μM). Molecular docking studies showed that the compounds interact with amino acid residues near the enzyme's active site mainly via van der Waals interactions and hydrogen bonds. Finally, these results highlight the bioactive potential of the compounds evaluated to be explored in future studies.