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This work describes the synthesis of four gold(I) [AuClL] compounds containing chloro and biologically active protonated thiosemicarbazones based on 5‐nitrofuryl (L=HSTC). The stability of the compounds in dichloromethane, DMSO, and DMSO/culture media solutions was investigated by spectroscopy, cyclic voltammetry, and conductimetry, indicating the formation overtime of cationic monometallic [Au(HTSC)(DMSO)]± or [Au(HTSC)2]±, and/or dimeric species. Neutral [{Au(TSC)}2] species were obtained from one of the compounds in dichlomethane/n‐hexane solution and characterized by X‐ray crystallography revealing a Au−Au bond, and deprotonated thiosemicarbazone (TSC). The cytotoxicity of the gold compounds and thiosemicarbazone ligands was evaluated against selected cancer cell lines and compared to that of Auranofin. Studies of the most stable, cytotoxic, and selective compound on a renal cancer cell line (Caki‐1) demonstrated its relevant antimigratory and anti‐angiogenic properties, and preferential accumulation in the cell nuclei. Its mode of action seems to involve interaction with DNA, and subsequent cell death via apoptosis. The stability of new gold(I) containing chloro and biologically active thiosemicarbazones in coordinating and non‐coordinating solvents is presented, allowing for a description of potential species formed. The most stable compound (2) results cytotoxic, apoptotic, antimetastatic, and antiangiogenic in a renal cancer cell line like Auranofin but with higher selectivity. 2 accumulates in the nuclei and shows interaction with CT DNA.

Dipeptidyl peptidase-4 (DPP-4) inhibition has been recognized as a promising approach to develop safe and potent antidiabetic agents for the management of type 2 diabetes. In this context, new thiosemicarbazones ( - ) were prepared efficiently by the reaction of aromatic aldehydes with 4-[4-(1 -pyrazol-1-yl)phenyl]thiosemicarbazide ( ), which was obtained via the reaction of 4-(1 -pyrazol-1-yl)phenyl isothiocyanate with hydrazine hydrate. Compounds - were evaluated for their DPP-4 inhibitory effects based on a convenient fluorescence-based assay. 4-[4-(1 -pyrazol-1-yl)phenyl]-1-(4-bromobenzylidene)thiosemicarbazide ( ) was identified as the most effective DPP-4 inhibitor in this series with an IC value of 1.266 ± 0.264 nM when compared with sitagliptin (IC = 4.380 ± 0.319 nM). MTT test was carried out to assess the cytotoxic effects of compounds - on NIH/3T3 mouse embryonic fibroblast (normal) cell line. According to cytotoxicity assay, compound showed cytotoxicity towards NIH/3T3 cell line with an IC value higher than 500 µM pointing out its favourable safety profile. Molecular docking studies indicated that compound presented π-π interactions with Arg358 and Tyr666 via pyrazole scaffold and 4-bromophenyl substituent, respectively. Overall, in vitro and in silico studies put emphasis on that compound attracts a great notice as a drug-like DPP-4 inhibitor for further antidiabetic research.

The enormous burden of the COVID-19 pandemic in economic and healthcare terms has cast a shadow on the serious threat of antimicrobial resistance, increasing the inappropriate use of antibiotics and shifting the focus of drug discovery programmes from antibacterial and antifungal fields. Thus, there is a pressing need for new antimicrobials involving innovative modes of action (MoAs) to avoid cross-resistance rise. Thiosemicarbazones (TSCs) stand out due to their easy preparation and polypharmacological application, also in infectious diseases. Recently, we reported a small library of TSCs ( ) that emerged for their non-cytotoxic behaviour. Inspired by their multifaceted activity, we investigated the antibacterial, antifungal, and antidermatophytal profiles of derivatives , highlighting a new promising research line. Furthermore, the ability of these compounds to inhibit selected microbial and human carbonic anhydrases (CAs) was assessed, revealing their possible involvement in the MoA and a good selectivity index for some derivatives.

The reaction of [Ru Cl (μ-Cl) (η - -cymene) ] with two thiosemicarbazones obtained by the condensation of N-(4-methoxybenzyl) thiosemicarbazide and 1,4-hydroxy-3-methoxyphenyl)ethan-1-one ( ) or 2-fluoro-4-hydroxybenzaldehyde ( ) was studied. The cationic complexes of formula [RuCl(η - -cymene)(HL)] were isolated as solid chloride and trifluoromethylsulfate (TfO) salts. A study of the solid state and NMR spectra suggests the presence in the material of two isomers that differ in the configuration in the iminic bond, C2=N3, of the coordinated thiosemicarbazone in the triflate salts and only the isomer in the chloride. An X-ray study of single crystals of the complexes supports this hypothesis. The thiosemicarbazone ligand coordinates with the ruthenium center through the iminic and sulfur atoms to form a five-membered chelate ring. Furthermore, the isolation of single crystals containing the thiosemicarbazonate complex [Ru (μ-L ) (η - -cymene) ] suggests the easy labilization of the coordinated chloride in the complex. The redox behavior of the ligands and complexes was evaluated by cyclic voltammetry. It seems to be more difficult to oxidize the complex derived from HL than HL . The ability of the complexes to inhibit cell growth against the NCI-H460, A549 and MDA-MB-231 lines was evaluated. The complexes did not show greater potency than cisplatin, although they did have greater efficacy, especially for the complex derived from .

The antioxidant/pro-oxidant activity of drugs and dietary molecules and their role in the maintenance of redox homeostasis, as well as the implications in health and different diseases, have not yet been fully evaluated. In particular, the redox activity and other interactions of drugs with essential redox metal ions, such as iron and copper, need further investigation. These metal ions are ubiquitous in human nutrition but also widely found in dietary supplements and appear to exert major effects on redox homeostasis in health, but also on many diseases of free radical pathology. In this context, the redox mechanistic insights of mainly three prototype groups of drugs, namely alpha-ketohydroxypyridines (alpha-hydroxypyridones), e.g., deferiprone, anthraquinones, e.g., doxorubicin and thiosemicarbazones, e.g., triapine and their metal complexes were examined; details of the mechanisms of their redox activity were reviewed, with emphasis on the biological implications and potential clinical applications, including anticancer activity. Furthermore, the redox properties of these three classes of chelators were compared to those of the iron chelating drugs and also to vitamin C, with an emphasis on their potential clinical interactions and future clinical application prospects in cancer, neurodegenerative and other diseases.

The thiosemicarbazone derivatives have a wide range of biological activities, such as antioxidant activity. In this study, the antiradical activities of six camphene-based thiosemicarbazones ( ) were investigated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and peroxyl radical scavenging capacity (PSC) assays, respectively, and the results reveal that exhibited good abilities for scavenging free radicals in a dose-dependent way. Compound exhibited the best effect of scavenging DPPH radical, with the lowest EC (0.208 ± 0.004 mol/mol DPPH) as well as the highest bimolecular rate constant K (4218 M s ), which is 1.18-fold higher than that of Trolox. Meanwhile, also obtained the lowest EC (1.27 µmol of Trolox equiv/µmol) of scavenging peroxyl radical. Furthermore, the density functional theory (DFT) calculation was carried out to further explain the experimental results by calculating several molecular descriptors associated with radical scavenging activity. These theoretical data suggested that the electron-donating effect of the diethylamino group in leads to the enhancement of the scavenging activities and the studied compounds may prefer to undergo the hydrogen atom transfer process.

The issue of food contamination by aflatoxins presently constitutes a social emergency, since they represent a severe risk for human and animal health. On the other hand, the use of pesticides has to be contained, since this generates long term residues in food and in the environment. Here we present the synthesis of a series of chelating ligands based on the thiosemicarbazone scaffold, to be evaluated for their antifungal and antiaflatoxigenic effects. Starting from molecules of natural origin of known antifungal properties, we introduced the thio- group and then the corresponding copper complexes were synthesised. Some molecules highlighted aflatoxin inhibition in the range 67-92% at 100 μM. The most active compounds were evaluated for their cytotoxic effects on human cells. While all the copper complexes showed high cytotoxicity in the micromolar range, one of the ligand has no effect on cell proliferation. This hit was chosen for further analysis of mutagenicity and genotoxicity on bacteria, plants and human cells. Analysis of the data underlined the importance of the safety profile evaluation for hit compounds to be developed as crop-protective agents and at the same time that the thiosemicarbazone scaffold represents a good starting point for the development of aflatoxigenic inhibitors.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, H- and C-NMR). In vitro inhibitory results revealed compound as a promising and lead inhibitor with an IC value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC = 0.62 ± 0.01 μM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer's disease.

The aim of this work is to explore a new library of coordination compounds for medicinal applications. Gallium is known for its various applications in this field. Presently, indium is not particularly important in medicine, but it shares a lot of chemical traits with its above-mentioned lighter companion, gallium, and is also used in radio imaging. These metals are combined with thiosemicarbazones, ligating compounds increasingly known for their biological and pharmaceutical applications. In particular, the few ligands chosen to interact with these hard metal ions share the ideal affinity for a high charge density. Therefore, in this work we describe the synthesis and the characterization of the resulting coordination compounds. The yields of the reactions vary from a minimum of 21% to a maximum of 82%, using a fast and easy procedure. Nuclear Magnetic Resonance (NMR) and Infra Red (IR) spectroscopy, mass spectrometry, elemental analysis, and X-ray Diffraction (XRD) confirm the formation of stable compounds in all cases and a ligand-to-metal 2:1 stoichiometry with both cations. In addition, we further investigated their chemical and biological characteristics, via UV-visible titrations, stability tests, and cytotoxicity and antibiotic assays. The results confirm a strong stability in all explored conditions, which suggests that these compounds are more suitable for radio imaging applications rather than for antitumoral or antimicrobic ones.

The current research describes the synthesis and characterization of 2-acetylpyridine N(4)-cyclohexyl-thiosemicarbazone ligand (HL) and their two metal complexes, [Au(L)Cl][AuCl ] and [Pd(L)Cl]·DMF . The molecular structures of the compounds were determined by physicochemical and spectroscopic methods. Single crystal X-ray diffraction was employed in the structural elucidation of the new complexes. The complexes showed a square planar geometry to the metal center Au(III) and Pd(II), coordinated with a thiosemicarbazone molecule by the -donor system and a chloride ion. Complex also shows the [AuCl ] counter-ion in the asymmetric unit, and complex has one DMF solvent molecule. These molecules play a key role in the formation of supramolecular structures due to different interactions. Noncovalent interactions were investigated through the 3D Hirshfeld surface by the function and the 2D fingerprint plots. The biological activity of the compounds was evaluated in vitro against the human glioma U251 cells. The cytotoxicity results revealed great antitumor activity in complex compared with complex and the free ligand. Molecular docking simulations were used to predict interactions and properties with selected proteins and DNA of the synthesized compounds.