Biological evaluation of levofloxacin and its thionated derivatives: antioxidant activity, aldehyde dehydrogenase enzyme inhibition, and cytotoxicity on A549 cell line.

Levofloxacin (LVX) is among the fluoroquinolones antibiotics that has also been studied in vitro and in vivo for its anticancer effects. In this study, we used LVX and novel LVX thionated derivatives; compounds 2 and 3, to evaluate their antioxidant activity, aldehyde dehydrogenase (ALDH) enzymes activity inhibition, and anticancer activity. Combination treatments with doxorubicin (DOX) were investigated as well. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used to determine the antioxidant activity. The NADH fluorescence spectrophotometric activity assay was used to determine the ALDH inhibitory effects. Resazurin dye method was applied for cell viability assays. Molecular Operating Environment software was used for the molecular docking experiments. Compared to ascorbic acid, DPPH assay showed that compound 3 had the highest antioxidant activity among the tested compounds with approximately 35% scavenging activity. On ALDH enzymes, compound 3 showed a significant ALDH activity inhibition compared to compound 2 at 200 µM. The IC50 values for the tested compounds were approximately 100 µM on A549 cell line, a non-small cell lung cancer (NSCLC) cell line. However, significant enhancement of cytotoxicity and reduction of IC50 values were observed by combining DOX and synergism was achieved with LVX with a combination index value of 0.4. The molecular docking test showed a minimum binding energy with a good affinity for compound 3 towards ALDH enzymes. Thionated LVX derivatives, may be repurposed for NSCLC therapy in combination with DOX, taking into account the antioxidant activity, ALDH activity inhibition, and the molecular docking results of compound 3.

Design and Synthesis of Thionated Levofloxacin: Insights into a New Generation of Quinolones with Potential Therapeutic and Analytical Applications.

Levofloxacin is a widely used fluoroquinolone in several infectious diseases. The structure-activity relationship of levofloxacin has been studied. However, the effect of changing the carbonyl into thiocarbonyl of levofloxacin has not been investigated up to the date of this report. In this work, levofloxacin structure was slightly modified by making a thionated form (compound 3), which was investigated for its antibacterial activity, biocompatibility, and cytotoxicity, as well as spectroscopic properties. The antibacterial susceptibility testing against five different bacteria showed promising minimum inhibitory concentrations (MICs), particularly against B. spizizenii and E. coli, with an MIC value of 1.9 µM against both bacteria, and 7.8 µM against P. mirabilis. The molecular docking experiment showed similar binding interactions of both levofloxacin and compound 3 with the active site residues of topoisomerase IV. The biocompatibility and cytotoxicity results revealed that compound 3 was more biocompatible with normal cells and more cytotoxic against cancer cells, compared to levofloxacin. Interestingly, compound 3 also showed an excitation profile with a distinctive absorption peak at λmax 404 nm. Overall, our results suggest that the thionation of quinolones may provide a successful approach toward a new generation with enhanced pharmacokinetic and safety profiles and overall activity as potential antibacterial agents.

Dual Function of ß-Hydroxy Dithiocinnamic Esters: RAFT Agent and Ligand for Metal Complexation.

The reversible addition-fragmentation chain-transfer (RAFT) process has become a versatile tool for the preparation of defined polymers tolerating a large variety of functional groups. Several dithioesters, trithiocarbonates, xanthates, or dithiocarbamates have been developed as effective chain transfer agents (CTAs), but only a few examples have been reported, where the resulting end groups are directly considered for a secondary use besides controlling the polymerization. Herein, it is demonstrated that ß-hydroxy dithiocinnamic esters represent a hitherto overlooked class of materials, which are originally designed for the complexation of transition metals but may as well act as reversible CTAs. Modified with a suitable leaving group (R-group), these vinyl conjugated dithioesters indeed provide reasonable control over the polymerization of acrylates, acrylamides, or styrene via the RAFT process. Kinetic studies reveal linear evolutions of molar mass with conversion, while different substituents on the aromatic unit has only a minor influence. Block extensions prove the livingness of the polymer chains, although extended polymerization times may lead to side reactions. The resulting dithiocinnamic ester end groups are still able to form complexes with platinum, which verifies that the structural integrity of the end group is maintained. These findings open a versatile new route to tailor-made polymer-bound metal complexes.

Novel [FeFe]-Hydrogenase Mimics: Unexpected Course of the Reaction of Ferrocenyl α-Thienyl Thioketone with Fe3(CO)12.

The influence of the substitution pattern in ferrocenyl α-thienyl thioketone used as a proligand in complexation reactions with Fe3(CO)12 was investigated. As a result, two new sulfur-iron complexes, considered [FeFe]-hydrogenase mimics, were obtained and characterized by spectroscopic techniques (1H, 13C{1H} NMR, IR, MS), as well as by elemental analysis and X-ray single crystal diffraction methods. The electrochemical properties of both complexes were studied and compared using cyclic voltammetry in the absence and in presence of acetic acid as a proton source. The performed measurements demonstrated that both complexes can catalyze the reduction of protons to molecular hydrogen H2. Moreover, the obtained results showed that the presence of the ferrocene moiety at the backbone of the linker of both complexes improved the stability of the reduced species.

Iron(0)-Mediated Stereoselective (3+2)-Cycloaddition of Thiochalcones via a Diradical Intermediate.

Reactions of α,ß-unsaturated aromatic thioketones 1 (thiochalcones) with Fe3 (CO)12 leading to η4 -1-thia-1,3-diene iron tricarbonyl complexes 2, [FeFe] hydrogenase mimics 3, and the thiopyrane adduct 4 are described. Obtained products have been characterized by X-ray crystallography and by computational methods. Completely regio- and diastereoselective formation of the five-membered ring system in products 3, containing four stereogenic centers, can be explained by an unprecedented, stepwise (3+2)-cycloaddition of two thiochalcone molecules mediated by Fe3 (CO)12 . Quantum chemical calculations aimed at elucidation of the reaction mechanism, suggest that the formal (3+2)-cycloaddition proceeds via sequential intramolecular radical transfer events upon homolytic cleavage of one carbon-sulfur bond leading to a diradical intermediate.

[FeFe]-Hydrogenase H-Cluster Mimics with Various -S(CH2)nS- Linker Lengths (n = 2-8): A Systematic Study.

The effect of the nature of the dithiolato ligand on the physical and electrochemical properties of synthetic H-cluster mimics of the [FeFe]-hydrogenase is still of significant concern. In this report we describe the cyclization of various alkanedithiols to afford cyclic disulfide, tetrasulfide, and hexasulfide compounds. The latter compounds were used as proligands for the synthesis of a series of [FeFe]-hydrogenase H-cluster mimics having the general formulas [Fe2(CO)6{µ-S(CH2)nS}] (n = 4-8), [Fe2(CO)6{µ-S(CH2)nS}]2 (n = 6-8), and [Fe2(CO)6{(µ-S(CH2)nS)2}] (n = 6-8). The resulting complexes were characterized by 1H and 13C{1H} NMR and IR spectroscopic techniques, mass spectrometry, and elemental analysis as well as X-ray analysis. The purpose of this research was to study the influence of the systematic increase of n from 2 to 7 on the redox potentials of the models and the catalytic ability in the presence of acetic acid (AcOH) by applying cyclic voltammetry.

[FeFe]-Hydrogenase H-cluster mimics mediated by naphthalene monoimide derivatives of peri-substituted dichalcogenides.

Synthetic models of the active site of [FeFe]-hydrogenase containing naphthalene monoimide (NMI) of peri-substituted dichalcogenides as bridging linkers have been prepared and characterized using different spectroscopic methods. The influence of the imide functionality and the chalcogen atoms on the redox properties and the catalytic behaviour of complexes 7-10 was studied using cyclic voltammetry. The results revealed that the imide functionality has improved the chemical stability of the reduced species and the replacement of the S atoms by Se caused a cathodic shift in the oxidation peaks. Moreover, the optical properties of compounds 1, 2, 4, and 5 and the respective diiron complexes 7-10 were investigated by UV-Vis absorption and fluorescence spectroscopy assisted by quantum chemical simulations. The structures of complexes 6-9 were confirmed by X-ray diffraction analysis.

Selenium makes the difference: protonation of [FeFe]-hydrogenase mimics with diselenolato ligands.

The synthetic models of the active site of an [FeFe]-hydrogenase containing a Sn atom in the bridgehead of the diselenato ligand, namely [Fe2(CO)6{µ-(SeCH2Se)SnMe2}], 3 and [Fe2(CO)6{µ-(SeCH2)2SnMe2}], 4 have been synthesized and characterized by different spectroscopic methods. The protonation properties of complex 4 have been investigated by monitoring the IR spectra in the carbonyl stretching region, 1H NMR in the hydride region as well as the 77Se{H} NMR upon addition of strong and moderate acids wherein the protonation of the active site of the [FeFe]-hydrogenase at one of its internal basic sites is considered an essential step in the catalytic cycle. Furthermore, we investigated the redox properties and the catalytic behaviour of complexes 3 and 4 in the presence of AcOH as a source of protons suggesting an ECE (E = electrochemical process, C = chemical process) mechanism.

[FeFe]-Hydrogenase H-Cluster Mimics with Unique Planar µ-(SCH2 )2 ER2 Linkers (E=Ge and Sn).

Analogues of the [2Fe-2S] subcluster of hydrogenase enzymes in which the central group of the three-atom chain linker between the sulfur atoms is replaced by GeR2 and SnR2 groups are studied. The six-membered FeSCECS rings in these complexes (E=Ge or Sn) adopt an unusual conformation with nearly co-planar SCECS atoms perpendicular to the Fe-Fe core. Computational modelling traces this result to the steric interaction of the Me groups with the axial carbonyls of the Fe2 (CO)6 cluster and low torsional strain for GeMe2 and SnMe2 moieties owing to the long C-Ge and C-Sn bonds. Gas-phase photoelectron spectroscopy of these complexes shows a shift of ionization potentials to lower energies with substantial sulfur orbital character and, as supported by the computations, an increase in sulfur character in the predominantly metal-metal bonding HOMO. Cyclic voltammetry reveals that the complexes follow an ECE-type reduction mechanism (E=electron transfer and C=chemical process) in the absence of acid and catalysis of proton reduction in the presence of acid. Two cyclic tetranuclear complexes featuring the sulfur atoms of two Fe2 S2 (CO)6 cores bridged by CH2 SnR2 CH2 , R=Me, Ph, linkers were also obtained and characterized.