Novos ligantes e complexos de Sn(IV) com potencial atividade biológica: avaliação da atividade antimicrobiana e estudos cristalográficos

Abstract

In this work, we present structural variations of compounds that have biological activity reported in the literature through the insertion of R-benzenesulfonyl and isoxazole groups, as well as the complexation of some of these compounds with tin(IV). Seven new thiosemicarbazones containing the isoxazol ring (HL1 - HL7) were obtained. The analysis of X-ray diffraction by single crystal showed that the variation of Rgroups in the structures directly affected the relevant interactions to the stabilization of the crystalline networks. The suppression constant values obtained for the interaction between thiosemicarbazones and human serum albumin (HSA) indicated a moderate binding strength with the protein and dynamic and static interaction mechanisms. The interaction with the calf thymus DNA (ctDNA) showed that the insertion of alkyl or aryl groups to the thiosemicarbazone skeleton disfavored the interaction and the study with the EB-ctDNA system indicated that the compounds interact with the ctDNA by intercalation. 5-bis(2-nitrophenyl)-1,3,4-thiadiazol-2,5-diamine was obtained by reaction following the one-pot methodology. This compound had two strong intramolecular hydrogen bonds, forming two S11(6) rings, and two other classic intramolecular hydrogen bonds. In the second part of the work, fifteen N,R-sulfonylaminobenzoic acids were obtained by inserting the R-benzenesulfonyl group to the R-aminobenzoic acids (oABA:HM1 HM5, mABA: HM6 HM10 and pABA: HM11 HM15 series).The crystallographic analyzes present intrinsic characteristics to the series, where the intramolecular hydrogen bonds directly affect the conformation and the intermolecular interaction of the compounds. Analyzes of the Hirshfeld surface and the fingerprint plots showed that the variation of the R groups in the aromatic ring of the sulfonamide fractiondirectly affected the percentage of the intermolecular interactions.The binding strength of the compounds with the HSA was moderate, with static mechanism being predominant for the interaction, where the compounds of the series oABA have a greater interaction with albumin.The characterization data for the tribulyltin(IV) complex with the HM11 indicated the presence of a monomer in the solid state with 1:1 metal:ligand ration. A change in the coordination number observed in the solid state (NC = 5) for NC = 4 was observed in solution, which was justified by the weak interaction between one of the two carboxylateoxygens and the metal center in the solid state, being undone in solution.The crystallization of the complex resulted in the formation of a polymeric structure by the bonding of the metal center with one of the carboxylate oxygens of the neighboring molecule, where Sn(IV) is in a slightly distorted trigonal bipyramidal geometry. The last stage of the work was the development of eight new fluoroquinolones by insertion of the R-benzenesulfonyl group into norfloxacin and ciprofloxacin (nfx: oNO2-nfx,mNO2-nfx, pNO2-nfx e pCH3-nfx, and the cfx: oNO2-cfx, mNO2-cfx, pNO2-cfx and pCH3-cfx series). Insertion of the R-benzenesulfonyl group improved the solubility of these 2nd generation fluoroquinolones in organic solvents. The X-ray diffraction by single crystals ofpNO2-nfx and oNO2-cfx confirmed the structures and the O1H1···O3 and C12H12···F1 intramolecular hydrogen bonds formation.The new fluoroquinolones presented biological activity against the strains tested in the order of 10 to 103 times higher than the drug norfloxacin, where the compounds with nitro group in the para position presented better biological activity. The study of the interaction of the compounds with the HSA indicated a mechanism of interaction predominantly static.Two tin(IV) complexes with levofloxacin (Sn1 and Sn2) were also obtained and characterized in this work. The characterization of these complexes suggested the unusual coordination of Sn(IV) to the piperazine nitrogen.The MIC values for the complexes antimicrobial activity of the complexes were close to the values obtained for tin salts against the bacteria and lower than the tin salts and the nystatin and miconazole controls against the tested yeast strains. The interaction mechanisms of the complexes with the HSA were distinct, presenting a predominantly dynamicmechanism for the Sn1 complex, and a static mechanism for Sn2