Desulfurization of thiosemicarbazones: the role of metal ions and biological implications.

Thiosemicarbazones are biologically active substances whose structural formula is formed by an azomethine, an hydrazine, and a thioamide fragments, to generate a R2C=N-NR-C(=S)-NR2 backbone. These compounds often act as ligands to generate highly stable metal-organic complexes. In certain experimental conditions, however, thiosemicarbazones undergo reactions leading to the cleavage of the chain. Sometimes, the breakage involves desulfurization processes. The present work summarizes the different chemical factors that influence the desulfurization reactions of thiosemicarbazones, such as pH, the presence of oxidant reactants or the establishment of redox processes as those electrochemically induced, the effects of the solvent, the temperature, and the electromagnetic radiation. Many of these reactions require coordination of thiosemicarbazones to metal ions, even those present in the intracellular environment. The nature of the products generated in these reactions, their detection in vivo and in vitro, together with the relevance for the biological activity of these compounds, mainly as antineoplastic agents, is discussed.

Proving the Antimicrobial Therapeutic Activity on a New Copper-Thiosemicarbazone Complex.

The misuse and overdose of antimicrobial medicines are fostering the emergence of novel drug-resistant pathogens, providing negative repercussions not only on the global healthcare system due to the rise of long-term or chronic patients and inefficient therapies but also on the world trade, productivity, and, in short, to the global economic growth. In view of these scenarios, novel action plans to constrain this antibacterial resistance are needed. Thus, given the proven antiproliferative tumoral and microbial features of thiosemicarbazone (TSCN) ligands, we have here synthesized a novel effective antibacterial copper-thiosemicarbazone complex, demonstrating both its solubility profile and complex stability under physiological conditions, along with their safety and antibacterial activity in contact with human cellular nature and two most predominant bacterial strains, respectively. A significant growth inhibition (17% after 20 h) is evidenced over time, paving the way toward an effective antibacterial therapy based on these copper-TSCN complexes.

Unveiling anti-diabetic potential of new thiazole-sulfonamide derivatives: Design, synthesis, in vitro bio-evaluation targeting DPP-4, α-glucosidase, and α-amylase with in-silico ADMET and docking simulation.

Diabetes mellitus type 2 (T2DM) can be managed by targeting dipeptidyl peptidase-4 (DPP-4), an enzyme that breaks down and deactivates peptides such as GIP and GLP-1. In this context, a new series of 2-(2-substituted hydrazineyl)thiazole derivatives 4, 5, 6, 8, 10, and 11 conjugated with the 2-hydroxy-5-(pyrrolidin-1-ylsulfonyl)benzylidene fragment were designed and synthesized. The virtual screening of the designed derivatives inside DPP-4 demonstrated good to moderate activity, with binding affinity ranging from -6.86 to -5.36 kcal/mol compared to Sitagliptin (S=-5.58 kcal/mol). These results encourage us to evaluate DPP-4 using in-vitro fluorescence-based assay. The in-vitro results exhibited inhibitory percentage (IP) values ranging from 40.66 to 75.62 % in comparison to Sitagliptin (IP=63.14 %) at 100 µM. Subsequently, the IC50 values were determined, and the 5-aryl thiazole derivatives 10 and 11 revealed strong potent IC50 values 2.75 ± 0.27 and 2.51 ± 0.27 µM, respectively, compared to Sitagliptin (3.32 ± 0.22 µM). The SAR study exhibited the importance of the substituents on the thiazole scaffold, especially with the hydrophobic fragment at C5 of the thiazole, which has a role in the activity. Compounds 10 and 11 were further assessed toward α-glucosidase and α-amylase enzymes and give promising results. Compound 10 showed good activity against α-glucosidase with IC50 value of 3.02 ± 0.23 µM compared to Acarbose 3.05 ± 0.22 µM and (11 = 3.34 ± 0.10 µM). On the other hand, for α-amylase, compound 11 was found to be most effective with IC50 value of 2.91 ± 0.23 µM compared to compound 10 = 3.30 ± 0.16 µM and Acarbose (2.99 ± 0.21 µM) indicating that these derivatives could reduce glucose by more than one target. The most active derivatives 10 and 11 attracted great interest as candidates for oral bioavailability and safe toxicity profiles compared to positive controls. The in-silico docking simulation was performed to understand the binding interactions inside the DPP-4, α-glucosidase, and α-amylase pockets, and it was found to be promising antidiabetic agents through a number of interactions.

Synthesis and characterization of novel bis(thiosemicarbazone) complexes and investigation of their acetylcholinesterase and glutathione S-transferase activities with in silico and in vitro studies.

In this study, firstly, bis(thiosemicarbazone) ligand [L: 2,2'-(2-(2-(4-methoxyphenyl)hydrazineylidene)cyclohexane-1,3-diylidene)bis(hydrazine-1-carbothioamide)] was synthesized by the condensation reaction of thiosemicarbazide and ketone compound (2-(2-(4-methoxyphenyl)hydrazone)cyclohexane-1,3-dione). The metal complexes were synthesized by the reaction of obtained ligand (L) with CuCl2·2H2O, NiCl2·6H2O, CoCl2·6H2O, and MnCl2·4H2O salts. The structures of synthesized ligand and their complexes were characterized using elemental analysis, IR, UV-Vis, 1H-NMR spectra, 13C-NMR spectra, magnetic susceptibility, mass spectra (LC-MS), thermogravimetry analysis-differential thermal analysis (TGA-DTA), and differential scanning calorimetry techniques. According to the results of the analysis, square plane geometry was suggested for Cu and Co complexes. However, the structures of Ni and Mn complexes were in agreement with octahedral geometry. Molecular docking analysis and pharmacological potential of the compound were evaluated to determine the inhibitory potential against acetylcholinesterase (AChE) and Glutathione-S-transferases (GST) enzymes. The compound exhibited strong binding/docking indices of - 5.708 and - 5.928 kcal/mol for the respective receptors. In addition, L-Ni(II) complex was found to be the most effective inhibitor for AChE enzyme with a Ki value of 0.519. However, with a Ki value of 1.119, L-Cu(II) complex was also found to be an effective inhibitor for the GST enzyme.

Palladium(II) Complexes of 4-Phenyl-3-thiosemicarbazone Ligands: Insights Into Cytotoxic Properties and Mode of Cell Death.

Reactions between sodium tetrachloropalladate and 2- (or 4-) substituted 4-phenyl-3-thiosemicarbazone ligands (HLR), with various electron-donating and electron-withdrawing substituents (R = OCH3, NO2, and Cl), afford square-planar complexes of the general formula [Pd(LR)2]. Ground-state geometry optimization and the vibrational analysis of cis- and trans-isomers of the complexes were carried out to get an insight into the stereochemistry of the complexes. Natural bond orbital analysis was used to analyze how the nature of the substituent affects the natural charge of the metal center, the type of hybridization, and the strength of the M-N and M-S bonds. Using spectrophotometry, the stability of the complexes, and their DNA binding abilities were assessed. The Pd(II) complexes showed moderate cytotoxicity against MCF-7 and Caco-2 cell lines, two of the assessed malignant cell lines, resulting in all known cell death types, including early apoptotic bodies and late apoptotic vacuoles as well as evident necrotic bodies.

A Comparison of In Vitro Studies between Cobalt(III) and Copper(II) Complexes with Thiosemicarbazone Ligands to Treat Triple Negative Breast Cancer.

Metal complexes have gained significant attention as potential anti-cancer agents. The anti-cancer activity of [Co(phen)2(MeATSC)](NO3)3•1.5H2O•C2H5OH 1 (where phen = 1,10-phenanthroline and MeATSC = 9-anthraldehyde-N(4)-methylthiosemicarbazone) and [Cu(acetylethTSC)Cl]Cl•0.25C2H5OH 2 (where acetylethTSC = (E)-N-ethyl-2-[1-(thiazol-2-yl)ethylidene]hydrazinecarbothioamide) was investigated by analyzing DNA cleavage activity. The cytotoxic effect was analyzed using CCK-8 viability assay. The activities of caspase 3/7, 9, and 1, reactive oxygen species (ROS) production, cell cycle arrest, and mitochondrial function were further analyzed to study the cell death mechanisms. Complex 2 induced a significant increase in nicked DNA. The IC50 values of complex 1 were 17.59 µM and 61.26 µM in cancer and non-cancer cells, respectively. The IC50 values of complex 2 were 5.63 and 12.19 µM for cancer and non-cancer cells, respectively. Complex 1 induced an increase in ROS levels, mitochondrial dysfunction, and activated caspases 3/7, 9, and 1, which indicated the induction of intrinsic apoptotic pathway and pyroptosis. Complex 2 induced cell cycle arrest in the S phase, ROS generation, and caspase 3/7 activation. Thus, complex 1 induced cell death in the breast cancer cell line via activation of oxidative stress which induced apoptosis and pyroptosis while complex 2 induced cell cycle arrest through the induction of DNA cleavage.

Synthesis of the chromone-thiosemicarbazone scaffold as promising α-glucosidase inhibitors: An in vitro and in silico approach toward antidiabetic drug design.

Diabetes is a serious metabolic disorder affecting individuals of all age groups and prevails globally due to the failure of previous treatments. This study aims to address the most prevalent form of type 2 diabetes mellitus (T2DM) by reporting on the design, synthesis, and in vitro as well as in silico evaluation of chromone-based thiosemicarbazones as potential α-glucosidase inhibitors. In vitro experiments showed that the tested compounds were significantly more potent than the standard acarbose, with the lead compound 3n exhibiting an IC50 value of 0.40 ± 0.02 µM, ~2183-fold higher than acarbose having an IC50 of 873.34 ± 1.67 µM. A kinetic mechanism analysis demonstrated that compound 3n exhibited reversible inhibition of α-glucosidase. To gain deeper insights, in silico molecular docking, pharmacokinetics, and molecular dynamics simulations were conducted for the investigation of the interactions, orientation, stability, and conformation of the synthesized compounds within the active pocket of α-glucosidase.

New Stable Gallium(III) and Indium(III) Complexes with Thiosemicarbazone Ligands: A Biological Evaluation.

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.

Synthesis, Structural Characterisation, and Electrochemical Properties of Copper(II) Complexes with Functionalized Thiosemicarbazones Derived from 5-Acetylbarbituric Acid.

The reaction between 5-acetylbarbituric acid and 4-dimethylthiosemicarbazide or 4-hexamethyleneiminyl thiosemicarbazide produces 5-acetylbarbituric-4-dimethylthiosemicarbazone (H2AcbDM) and 5-acetylbarbituric-4N-hexamethyleneiminyl thiosemicarbazone (H2Acbhexim). Eight new complexes with different copper(II) salts have been prepared and characterized using elemental analysis, molar conductance, UV-Vis, ESI-HRMS, FT-IR, magnetic moment, EPR, and cyclic voltammetry. In addition, three-dimensional molecular structures of [Cu(HAcbDM)(H2O)2](NO3)·H2O (3a), [Cu(HAcbDM)(H2O)2]ClO4 (4), and [Cu(HAcbHexim)Cl] (6) were determined by single crystal X-ray crystallography, and an analysis of their supramolecular structure was carried out. The H-bonded assemblies were further studied energetically using DFT calculations and MEP surface and QTAIM analyses. In these complexes, the thiosemicarbazone coordinates to the metal ion in an ONS-tridentate manner, in the O-enolate/S-thione form. The electrochemical behavior of the thiosemicarbazones and their copper(II) complexes has been investigated at room temperature using the cyclic voltammetry technique in DMFA. The Cu(II)/Cu(I) redox system was found to be consistent with the quasi-reversible diffusion-controlled process.

Palladium(II) and Platinum(II) Complexes Bearing ONS-Type Pincer Ligands: Synthesis, Characterization and Catalytic Investigations.

This work describes the synthesis of eight new Pd(II) and Pt(II) complexes with the general formula [M(TSC)Cl], where TSC represents the 4N-monosubstituted thiosemicarbazone derived from 2-acetylpyridine N-oxide with the substituents CH3 (H4MLO), C2H5 (H4ELO), phenyl (H4PLO) and (CH3)2 (H4DMLO). These complexes have been characterized by elemental analysis, molar conductivity, IR spectroscopy, 1H, 13C, 195Pt and ESI-MS. The complexes exhibit a square planar geometry around the metallic center coordinated by a thiosemicarbazone molecule acting as a donor ONS-type pincer ligand and by a chloride, as confirmed by the molecular structures of the complexes, [Pd(4ELO)Cl] (3) and [Pd(4PLO)Cl] (5), determined by single-crystal X-ray diffraction. The 195Pt NMR spectra of the complexes of formulae [Pt(4PLO)Cl] (6) and [Pt(4DMLO)Cl] (8) in DMSO show a single signal at -2420.4 ppm, confirming the absence of solvolysis products. Complexes 3 and 5 have been tested as catalysts in the Suzuki-Miyaura cross-coupling reactions of aryl bromides with phenylboronic acid, with yields of between 50 and 90.

Ternary Phenolate-Based Thiosemicarbazone Complexes of Copper(II): Magnetostructural Properties, Spectroscopic Features and Marked Selective Antiproliferative Activity against Cancer Cells.

The new diprotic ligand 3,5-di-tert-butylsalicylaldehyde 4-ethyl-3-thiosemicarbazone, abbreviated H2(3,5-t-Bu2)-sal4eT, exists as the thio-keto tautomer and adopts the E-configuration with respect to the imine double bond, as evidenced by single-crystal X-ray analysis and corroborated by spectroscopic characterisation. Upon treatment with Cu(OAc)2·H2O in the presence of either 2,9-dimethyl-1,10-phenanthroline (2,9-Me2-phen) or 1,10-phenanthroline (phen) as a co-ligand in MeOH, this thiosemicarbazone undergoes conformational transformation (relative donor-atom orientations: syn,anti → syn,syn) concomitantly with tautomerisation and double deprotonation to afford the ternary copper(II) complexes [Cu{(3,5-t-Bu2)-sal4eT}(2,9-Me2-phen)] (1) and [Cu2{3,5-t-Bu2)-sal4eT}2(phen)] (2). Crystallographic elucidation has revealed that complex 1 is a centrosymmetric dimer of mononuclear copper(II) complex molecules brought about by intermolecular H-bonding. The coordination geometry at the copper(II) centre is best described as distorted square pyramidal in accordance with the trigonality index (τ = 0.14). The co-ligand adopts an axial-equatorial coordination mode; hence, there is a disparity between its two Cu-N coordinate bonds arising from weakening of the apical one as a consequence of the tetragonal distortion. The axial X-band ESR spectrum of complex 1 is consistent with retention of this structure in solution. Complex 2 is a centrosymmetric dimer of dinuclear copper(II) complex molecules exhibiting intermolecular H-bonding and π-π-stacking interactions. The two copper(II) centres, which are 4.8067(18) Å apart and bridged by the thio-enolate nitrogen of the quadridentate thiosemicarbazonate ligand, display two different coordination geometries, one distorted square planar (τ4 = 0.082) and the other distorted square pyramidal (τ5 = 0.33). Such dinuclear copper(II) thiosemicarbazone complexes, which are crystallographically characterised, are extremely rare. In vitro, complexes 1 and 2 outperform cisplatin as antiproliferative agents in terms of potency and selectivity towards HeLa and MCF-7 cancer cell lines.

Combined In Silico and In Vitro Analyses to Assess the Anticancer Potential of Thiazolidinedione-Thiosemicarbazone Hybrid Molecules.

The number of people affected by cancer and antibiotic-resistant bacterial infections has increased, such that both diseases are already seen as current and future leading causes of death globally. To address this issue, based on a combined in silico and in vitro approach, we explored the anticancer potential of known antibacterials with a thiazolidinedione-thiosemicarbazone (TZD-TSC) core structure. A cytotoxicity assessment showed encouraging results for compounds 2-4, with IC50 values against T98G and HepG2 cells in the low micromolar range. TZD-TSC 3 proved to be most toxic to cancer cell lines, with IC50 values of 2.97 ± 0.39 µM against human hepatoma HepG2 cells and IC50 values of 28.34 ± 2.21 µM against human glioblastoma T98G cells. Additionally, compound 3 induced apoptosis and showed no specific hemolytic activity. Furthermore, treatment using 3 on cancer cell lines alters these cells' morphology and further suppresses migratory activity. Molecular docking, in turn, suggests that 3 would have the capacity to simultaneously target HDACs and PPARγ, by the activation of PPARγ and the inhibition of both HDAC4 and HDAC8. Thus, the promising preliminary results obtained with TZD-TSC 3 represent an encouraging starting point for the rational design of novel chemotherapeutics with dual antibacterial and anticancer activities.

Novel mono-, bi-, tri- and tetra-nuclear copper complexes that inhibit tumor growth through apoptosis and anti-angiogenesis.

To develop the next-generation metal agents for efficiently inhibiting tumor growth, a series of novel mononuclear, binuclear and trinuclear copper (Cu) thiophene-2-formaldehyde thiosemicarbazone complexes and a tetranuclear Cu 1,2,4-triazole-derived complex have been synthesized and their structure-activity relationships have been studied. The trinucleated Cu complex showed the strongest inhibitory activity against T24 cells among all the Cu complexes. Its antitumor effect in vivo was superior to that of cisplatin, with reduced side effects. Further studies on the antitumor mechanism have showed that Cu complexes not only induced apoptosis of cancer cells but also inhibited tumor angiogenesis by inhibiting the migration and invasion of vascular endothelial cells, blocking the cell cycle in the G1 phase, and inducing autophagy.

Thiazolyl-isatin derivatives: Synthesis, in silico studies, in vitro biological profile against breast cancer cells, mRNA expression, P-gp modulation, and interactions of Akt2 and VIM proteins.

The literature reports that thiazole and isatin nuclei present a range of biological activities, with an emphasis on anticancer activity. Therefore, our proposal was to make a series of compounds using the molecular hybridization strategy, which has been used by our research group, producing hybrid molecules containing the thiazole and isatin nuclei. After structural planning and synthesis, the compounds were characterized and evaluated in vitro against breast cancer cell lines (T-47D, MCF-7 and MDA-MB-231) and against normal cells (PBMC). The activity profile on membrane proteins involved in chemoresistance and tumorigenic signaling proteins was also evaluated. Among the compounds tested, the compounds 4c and 4a stood out with IC50 values of 1.23 and 1.39 µM, respectively, against the MDA-MB-231 cell line. Both compounds exhibited IC50 values of 0.45 µM for the MCF-7 cell line. Compounds 4a and 4c significantly decreased P-gp mRNA expression levels in MCF-7, 4 and 2 folds respectively. Regarding the impact on tumorigenic signaling proteins, compound 4a inhibited Akt2 in MDA-MB-231 and compound 4c inhibited the mRNA expression of VIM in MCF-7.

Exploration of morpholine-thiophene hybrid thiosemicarbazones for the treatment of ureolytic bacterial infections via targeting urease enzyme: Synthesis, biochemical screening and computational analysis.

An important component of the pathogenicity of potentially pathogenic bacteria in humans is the urease enzyme. In order to avoid the detrimental impact of ureolytic bacterial infections, the inhibition of urease enzyme appears to be an appealing approach. Therefore, in the current study, morpholine-thiophene hybrid thiosemicarbazone derivatives (5a-i) were designed, synthesized and characterized through FTIR, 1H NMR, 13C NMR spectroscopy and mass spectrometry. A range of substituents including electron-rich, electron-deficient and inductively electron-withdrawing groups on the thiophene ring was successfully tolerated. The synthesized derivatives were evaluated in vitro for their potential to inhibit urease enzyme using the indophenol method. The majority of compounds were noticeably more potent than the conventional inhibitor, thiourea. The lead inhibitor, 2-(1-(5-chlorothiophen-2-yl)ethylidene)-N-(2-morpholinoethyl)hydrazinecarbothioamide (5g) inhibited the urease in an uncompetitive manner with an IC50 value of 3.80 ± 1.9 µM. The findings of the docking studies demonstrated that compound 5g has a strong affinity for the urease active site. Significant docking scores and efficient binding free energies were displayed by the lead inhibitor. Finally, the ADME properties of lead inhibitor (5g) suggested the druglikeness behavior with zero violation.

{[(E)-(1,3-Benzodioxol-5-yl)methyl-idene]amino}thio-urea.

The synthesis and crystallographic analysis of the title compound, C9H9N3O2S, are reported. The compound crystallizes in the monoclinic space group P21/c, revealing characteristic bond lengths and angles typical of thio-semicarbazone groups. The supra-molecular organization primarily arises from hydrogen bonding and π-π stacking inter-actions, leading to distinctive dimeric formations.

Synthesis, crystal structure and Hirshfeld analysis of N-ethyl-2-{3-methyl-2-[(2Z)-pent-2-en-1-yl]cyclo-pent-2-en-1-yl-idene}hydrazinecarbo-thio-amide.

The title compound (C14H23N3S, common name: cis-jasmone 4-ethyl-thio-semicarbazone) was synthesized by the equimolar reaction of cis-jasmone and 4-ethyl-thio-semicarbazide in ethanol facilitated by acid catalysis. There is one crystallographically independent mol-ecule in the asymmetric unit, which shows disorder of the terminal ethyl group of the jasmone carbon chain [site-occupancy ratio = 0.911 (5):0.089 (5)]. The thio-semicarbazone entity [N-N-C(=S)-N] is approximately planar, with the maximum deviation of the mean plane through the N/N/C/S/N atoms being 0.0331 (8) Å, while the maximum deviation of the mean plane through the five-membered ring of the jasmone fragment amounts to -0.0337 (8) Å. The dihedral angle between the two planes is 4.98 (7)°. The mol-ecule is not planar due to this structural feature and the sp 3-hybridized atoms of the jasmone carbon chain. Additionally, one H⋯N intra-molecular inter-action is observed, with graph-set motif S(5). In the crystal, the mol-ecules are connected through pairs of H⋯S inter-actions with R 2 2(8) and R 2 1(7) graph-set motifs into centrosymmetric dimers. The dimers are further connected by H⋯N inter-actions with graph-set motif R 2 2(12), which are related by an inversion centre, forming a mono-periodic hydrogen-bonded ribbon parallel to the b-axis. The crystal structure and the supra-molecular assembly of the title compound are compared with four known cis-jasmone thio-semicarbazone derivatives (two crystalline modifications of the non-substituted form, the 4-methyl and the 4-phenyl derivatives). A Hirshfeld surface analysis indicates that the major contributions for the crystal cohesion are from H⋯H (70.7%), H⋯S/S⋯H (13.5%), H⋯C/C⋯H (8.8%), and H⋯N/N⋯H (6.6%) inter-faces (only the disordered atoms with the highest s.o.f. were considered for the evaluation).

Synthesis, crystal structure and Hirshfeld surface analysis of 4-{(1E)-1-[(car-bamo-thioyl-amino)-imino]-eth-yl}phenyl propano-ate.

The title compound, C12H15N3O2S, adopts an E configuration with respect to the C=N bond. The propionate group adopts an anti-periplanar (ap) conformation. There are short intra-molecular N-H⋯N and C-H⋯O contacts, forming S(5) and S(6) ring motifs, respectively. In the crystal, mol-ecules are connected into ribbons extending parallel to [010] by pairs of N-H⋯S inter-actions, forming rings with R 2 2(8) graph-set motifs, and by pairs of C-H⋯S inter-actions, where rings with the graph-set motif R 2 1(7) are observed. The O atom of the carbonyl group is disordered over two positions, with a refined occupancy ratio of 0.27 (2):0.73 (2). The studied crystal consisted of two domains.

Patient-Derived Blood-Brain Barrier Model for Screening Copper Bis(thiosemicarbazone) Complexes as Potential Therapeutics in Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent cause of dementia characterized by a progressive cognitive decline. Addressing neuroinflammation represents a promising therapeutic avenue to treat AD; however, the development of effective antineuroinflammatory compounds is often hindered by their limited blood-brain barrier (BBB) permeability. Consequently, there is an urgent need for accurate, preclinical AD patient-specific BBB models to facilitate the early identification of immunomodulatory drugs capable of efficiently crossing the human AD BBB. This study presents a unique approach to BBB drug permeability screening as it utilizes the familial AD patient-derived induced brain endothelial-like cell (iBEC)-based model, which exhibits increased disease relevance and serves as an improved BBB drug permeability assessment tool when compared to traditionally employed in vitro models. To demonstrate its utility as a small molecule drug candidate screening platform, we investigated the effects of diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (CuII(atsm)) and a library of metal bis(thiosemicarbazone) complexes─a class of compounds exhibiting antineuroinflammatory therapeutic potential in neurodegenerative disorders. By evaluating the toxicity, cellular accumulation, and permeability of those compounds in the AD patient-derived iBEC, we have identified 3,4-hexanedione bis(N(4)-methylthiosemicarbazonato)copper(II) (CuII(dtsm)) as a candidate with good transport across the AD BBB. Furthermore, we have developed a multiplex approach where AD patient-derived iBEC were combined with immune modulators TNFα and IFNγ to establish an in vitro model representing the characteristic neuroinflammatory phenotype at the patient's BBB. Here, we observed that treatment with CuII(dtsm) not only reduced the expression of proinflammatory cytokine genes but also reversed the detrimental effects of TNFα and IFNγ on the integrity and function of the AD iBEC monolayer. This suggests a novel pathway through which copper bis(thiosemicarbazone) complexes may exert neurotherapeutic effects on AD by mitigating BBB neuroinflammation and related BBB integrity impairment. Together, the presented model provides an effective and easily scalable in vitro BBB platform for screening AD drug candidates. Its improved translational potential makes it a valuable tool for advancing the development of metal-based compounds aimed at modulating neuroinflammation in AD.

N-Methyl-2-{3-methyl-2-[(2Z)-pent-2-en-1-yl]cyclo-pent-2-en-1-yl-idene}hydrazinecarbo-thio-amide.

The equimolar and hydro-chloric acid-catalysed reaction between cis-jasmone and 4-methyl-thio-semicarbazide in ethano-lic solution yields the title compound, C13H21N3S (common name: cis-jasmone 4-methyl-thio-semicarbazone). Two mol-ecules with all atoms in general positions are present in the asymmetric unit. In one of them, the carbon chain is disordered [site occupancy ratio = 0.821 (3):0.179 (3)]. The thio-semicarbazone entities [N-N-C(=S)-N] are approximately planar, with the maximum deviation from the mean plane through the selected atoms being -0.0115 (16) Š(r.m.s.d. = 0.0078 Å) for the non-disordered mol-ecule and 0.0052 (14) Š(r.m.s.d. = 0.0031 Å) for the disordered one. The mol-ecules are not planar, since the jasmone groups have a chain with sp 3-hybridized carbon atoms and, in addition, the thio-semicarbazone fragments are attached to the respective carbon five-membered rings and the dihedral angles between them for each mol-ecule amount to 8.9 (1) and 6.3 (1)°. In the crystal, the mol-ecules are connected through pairs of N-H⋯S and C-H⋯S inter-actions into crystallographically independent centrosymmetric dimers, in which rings of graph-set motifs R 2 2(8) and R 2 1(7) are observed. A Hirshfeld surface analysis indicates that the major contributions for the crystal cohesion are from H⋯H (70.6%), H⋯S/S⋯H (16.7%), H⋯C/C⋯H (7.5%) and H⋯N/N⋯H (4.9%) inter-actions [considering the two crystallographically independent mol-ecules and only the disordered atoms with the highest s.o.f. for the evaluation].