Estudos das superfícies de Hirshfeld, docking molecular e análise de parâmetros farmacocinéticos de ADME de complexos de Níquel(II) com tiossemicarbazonas

Abstract

Thiosemicarbazones (TSCs) are compounds that have diverse biological and pharmacological applications. Previous biological studies involving the antibacterial activity of Co(III), Cu(II) and Mn(II) complexes derived from TSCs revealed complexes with promising biological potential. Thus, the present study aimed to evaluate the theoretical antibacterial activity of Ni(II) complexes containing TSCs against five bacterial cultures (S. mutans, S. mitis, S. sanguinis, L. paracasei and E. faecalis) through of molecular docking and to analyze in silico the pharmacokinetic parameters of ADME. For these experiments two different types of Ni(II) complexes with tridentate ligands of the type 2-acetylpyridine-N(4)-R-thiosemicarbazone (Hatc-R) were used. The R group of the Hatc-R ligand was replaced by ethyl (Et, 1) and phenyl (Ph, 2), to form [Ni(atc-Et)2, 3] and [Ni(atc-Ph)2, 4] complexes. The analysis of the Hirshfeld surface of the complex 3 revealed that the supramolecular structure is stabilized by interactions of the type H···H, C···H/H···C, N··· H/H···N and S···H/H···S. Molecular docking studies of the free ligands 1 and 2 and metal complexes 3 and 4 were performed with the crystalline structures of the enzymes of the bacteria mentioned above and the results showed highly exergonic ΔG values that reveal good orientation and binding affinity. The complex 4 showed the best results among all compounds tested. The ΔG values for the 4 complex were –10.09 kcal mol–1 for L. paracasei, followed by –8.95 kcal mol–1 for S. mutans while the best value of ΔG of the 3 complex was –7.24 kcal mol–1 for L. paracasei. The results of the in silico study of ADME for 1, 2, 3 and 4 showed that these compounds are in accordance with the rules of Lipinski, Ghose, Veber and Egan, in addition to having good solubility and characteristics suitable for oral use. The compounds were also evaluated for human intestinal absorption (HIA), blood-brain barrier (BBB) penetration, inhibition of isoenzymes belonging to the CYP450 system and none of the compounds are able to cross the blood-brain barrier and inhibit CYP2D6 and CYP3A4 isoenzymes belonging to the CYP450 system. Thus, this study demonstrates that the compounds have a promising pharmacokinetic profile aiming their therapeutic application through antibacterial activity.