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.

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.

Developing a Copper(II) Isopropyl 2-Pyridyl Ketone Thiosemicarbazone Compound Based on the IB Subdomain of Human Serum Albumin-Indomethacin Complex: Inhibiting Tumor Growth by Remodeling the Tumor Microenvironment.

To develop a next-generation metal agent and dual-agent multitargeted combination therapy, we developed a copper (Cu) compound based on the properties of the human serum albumin (HSA)-indomethacin (IND) complex to remodel the tumor microenvironment (TME). We optimized a series of Cu(II) isopropyl 2-pyridyl ketone thiosemicarbazone compounds to obtain a Cu(II) compound (C4) with significant cytotoxicity and then constructed an HSA-IND-C4 complex (HSA-IND-C4) delivery system. IND and C4 bind to the hydrophobic cavities of the IB and IIA domains of HSA, respectively. In vivo, the HSA-IND-C4 not only showed enhanced antitumor efficacy relative to C4 and C4 + IND but also improved their targeting ability and decreased their side effects. The antitumor mechanism of C4 + IND involved acting on the different components of the TME. IND inhibited tumor-related inflammation, while C4 not only induced apoptosis and autophagy of cancer cells but also inhibited tumor angiogenesis.

Larvicidal Activity of Some Aromatic Thiosemicarbazone and Metal Complexes [Ni (II), Cu (II), Co (II)] Against Aedes (Stegomyia) aegypti (Linnaeus, 1762) and Aedes albopictus (Skuse, 1894) (Diptera: Culicidae) Larvae.

Objective: A series of aromatic thiosemicarbazone-oxime [TP1 and TP2] derivatives and their Ni(II), Cu(II), and Co(II) complexes were synthesized, and their larvicidal activity was evaluated against Aedes aegypti and Aedes albopictus larvae. The efficacy of these substances to Aedes albopictus larvae has been demonstrated for the first time. Methods: Laboratory colonized Aedes aegypti and Aedes albopictus larvae were subjected to larvicidal activity tests. Larval mortality rates at 24 and 48 hours were recorded and LC50 values were calculated. The study was carried out at Aydin Adnan Menderes University in 2021. Results: For Aedes aegypti, LC50 of TP1 and its Co(II) complex were 15.41, 9.75, µg/mL whereas for TP2 and its Co(II) complex, LC50 were 21.62, 20.50 µg/mL after 24 and 48 h respectively. For Aedes albopictus, TP1 and its Co(II) complex showed an LC50 of 12.06, 8.75 µg/mL, whereas TP2 and its Co(II) complex showed an LC50 of 32.87, 25.48 µg/mL, for 24, and 48 h respectively. Conclusion: Both TP1 and TP2 compounds and their Co(II) complexes presented high efficacy against the larvae; it can be said that C=S groups in thiosemicarbazone derivatives are effective in showing activity and for this reason, studies should be continued to make these components effective.

Copper-mediated cyclization of thiosemicarbazones leading to 1,3,4-thiadiazoles: Structural elucidation, DFT calculations, in vitro biological evaluation and in silico evaluation studies.

Cancer's global impact necessitates innovative and less toxic treatments. Thiosemicarbazones (TSCs), adaptable metal chelators, offer such potential. In this study, we have synthesized N (4)-substituted heterocyclic TSCs from syringaldehyde (TSL1, TSL2), and also report the unexpected copper-mediated cyclization of the TSCs to form thiadiazoles (TSL3, TSL4), expanding research avenues. This work includes extensive characterization and studies such as DNA/protein binding, molecular docking, and theoretical analyses to demonstrate the potential of the as-prepared TSCs and thiadiazoles against different cancer cells. The DFT results depict that the thiadiazoles exhibit greater structural stability and reduced reactivity compared to the corresponding TSCs. The docking results suggest superior EGFR inhibition for TSL3 with a binding constant value of - 6.99 Kcal/mol. According to molecular dynamics studies, the TSL3-EGFR complex exhibits a lower average RMSD (1.39 nm) as compared to the TSL1-EGFR complex (3.29 nm) suggesting that both the thiadiazole and thiosemicarbazone examined here can be good inhibitors of EGFR protein, also that TSL3 can inhibit EGFR better than TSL1. ADME analysis indicates drug-likeness and oral availability of the thiadiazole-based drugs. The DNA binding experiment through absorption and emission spectroscopy discovered that TSL3 is more active towards DNA which is quantitatively calculated with a Kb value of 4.74 × 106 M-1, Kq value of 4.04 × 104 M-1and Kapp value of 5 × 106 M-1. Furthermore, the BSA binding studies carried out with fluorescence spectroscopy showed that TSL3 shows better binding capacity (1.64 × 105 M-1) with BSA protein. All the compounds show significant cytotoxicity against A459-lung, MCF-7-breast, and HepG2-liver cancer cell lines; TSL3 exhibits the best cytotoxicity, albeit less effective than cisplatin. Thiadiazoles demonstrate greater cytotoxicity than the TSCs. Overall, the promise of TSCs and thiadiazoles in cancer research is highlighted by this study. Furthermore, it unveils unexpected copper-mediated cyclization of the TSCs to thiadiazoles.

Role of the auxiliary ligand in determining the genotoxicity and mode of cell death of thiosemicarbazone Pd(II) complexes.

A series of Pd(II) complexes of the general formula [PdX(NNS)] (X = Cl, Br, I, NCS and phenyl-tetrazole-thiolato; NNS = 2-quinolinecarboxyaldehyde-N4-phenylthiosemicarbazone) was tested against four malignant cell lines for their antiproliferative properties and the outcomes were compared to those seen in normal mouse splenocytes. Various auxiliary ligands were substituted in order to investigate the impact of the character of the ligand on the cytotoxicity of this class of Pd(II) complexes. The iodo complex was the most cytotoxic compound towards the Caco-2 cell line in this study. The improved apoptosis and necrosis cell modes were in accordance with the fragmentation results of DNA, which revealed increased fragmentation terminals, especially in isothiocyanate and tetrazole-thiolato complexes. After 24 hours, at half the IC50 of each complex, the complex-treated cells exhibited considerable genotoxicity when compared to the corresponding non-treated control especially in the case of isothiocyanate and tetrazole-thiolato complexes.

Methyl 4-pyridyl ketone thiosemicarbazone (4-PT) as an effective and safe inhibitor of mushroom tyrosinase and antibrowning agent.

Enzymatic browning is of concern as it can affect food safety and quality. In this study, an effective and safe tyrosinase inhibitor and anti-browning agent, methyl 4-pyridyl ketone thiosemicarbazone (4-PT), was synthesised and characterised using Fourier-transform infrared (FTIR) spectroscopy, CHNS elemental analysis, and proton (1H) and carbon-13 (13C) nuclear magnetic resonance (NMR) spectroscopy. The vibrational frequencies of 4-PT were studied theoretically using vibrational energy distribution analysis (VEDA). Density functional theory (DFT) was applied to elucidate its chemical properties, including the Mulliken atomic charges, molecular electrostatic potential (MEP), quantum theory of atoms in molecules (QTAIM) and reduced density gradient non-covalent interactions (RDG-NCIs). Moreover, 4-PT was compared with kojic acid in terms of its effectiveness as a tyrosinase inhibitor and anti-browning agent. The toxicity and physicochemical properties of 4-PT were predicted via ADME evaluation, which proved that 4-PT is safer than kojic acid. Experimentally, 4-PT (IC50 = 5.82 µM, browning index (10 days) = 0.292 ± 0.002) was proven to be an effective tyrosinase inhibitor and anti-browning agent compared to kojic acid (IC50 = 128.17 µM, browning index (10 days) = 0.332 ± 0.002). Furthermore, kinetic analyses indicated that the type of tyrosinase inhibition is a mixed inhibition, with Km and Vmax values of 0.85 mM and 2.78 E-09 µM/s, respectively. Finally, the mechanism of 4-PT for tyrosinase inhibition was proven by 1D, second derivative and 2D IR spectroscopy, molecular docking and molecular dynamic simulation approaches.

Gold(III) complexes with thiosemicarbazone ligands: insights into their cytotoxic effects on lung cancer cells.

Cancer continues to pose a global threat, underscoring the urgent need for more effective and safer treatment options. Gold-based compounds have recently emerged as promising candidates due to their diverse range of biological activities. In this study, three gold(III) complexes derived from thiosemicarbazone ligands have been synthesized, fully characterized, including their X-ray crystal structures. We conducted initial mode-of-action studies on DNA and BSA, followed by a comprehensive investigation into the cytotoxic effects of these novel gold(III) complexes on lung cancer cells (A549, H2052, and H28). The results demonstrated a concentration-dependent cytotoxic response, with H28 cells exhibiting the highest sensitivity to the treatment. Furthermore, the analysis of the cell cycle revealed that these compounds induce cell cycle arrest and promote apoptosis as a response to treatment. We also observed distinct morphological changes and increased oxidative stress, contributing significantly to cell death. Notably, these complexes exhibited the ability to suppress interleukin-6 production in mesothelioma cell lines, and this highlights their anti-inflammatory potential. To gain an initial understanding of cytotoxicity on healthy cells, hemolysis tests were conducted against human blood cells, with no evidence of hemolysis. Furthermore, a toxicity assessment through the in vivo Galleria mellonella model underscored the absence of detectable toxicity. These findings prove that these complexes are promising novel therapeutic agents for lung cancer.

Synthesis, characterization, computational assay and anti-inflammatory activity of thiosemicarbazone derivatives: Highly potent and efficacious for COX inhibitors.

Multiple studies in the literature have demonstrated that synthetic compounds containing heterocyclic rings possess a reparative potential against acute and chronic inflammation. In the present study, two novel thiosemicarbazone derivatives based on l-ethyl-6-(thiophen-2-yl)indoline-2,3-dione with different phenyl substituted thiosemicarbazides were synthesized by condensation reaction and the structures of proposed target compounds (KP-2 and KP-5) were confirmed by UV-VIS, FTIR, 1H-NMR and 13C-NMR. In-vitro anti-inflammatory behavior of KP-2 and KP-5 was confirmed by bovine serum albumin (BSA) and ovine serum albumin (OSA) analysis. Acute and chronic anti-inflammatory potential of synthesized compounds were evaluated by using carrageenan and complete Freund's adjuvant (CFA) as inflammation-inducing agents, respectively. Inhibition of pro-inflammatory mediators and prevention of protein denaturation owing to synchronization of more electronegative flouro-groups substituted on phenyl rings along with heterocyclic indoline ring provides anti-inflammatory effects and are corroborated by radiological, histopathological analysis. Additional support was provided through density functional theory (DFT) and molecular docking. KP-5 exhibited excellent lead-likeness based on its physicochemical parameters, making it a viable drug candidate. The synthesized compounds also showed promising ADMET properties, enhancing their potential as therapeutic agents. These findings emphasize the pivotal role of new compounds for drug design and development.

Exploring the antimalarial and antioxidant efficacy of transition metal(II) chelates of thiosemicarbazone ligands: spectral investigations, molecular docking, DFT, MESP and ADMET.

Malaria, a relentless and ancient adversary, continues to cast its shadow over vast swathes of the globe, afflicting millions of people and have a heavy toll on human health and well-being. Despite substantial progress in the fight against this parasitic disease in recent decades, malaria still persists as a substantial global health concern, especially in some specific region which have limited resources and vulnerable populations. Thus, to ascertain an combating agent for malaria and its associated dysfunction, 4-(4-ethylphenyl)-3-thiosemicarbazide and benzaldehydes based two new thiosemicarbazone ligands (1-2) and their cobalt(II), nickel(II), copper(II), zinc(II) metal complexes (3-10) were synthesized in the present research work. The synthesized compounds were comprehensive characterized through spectral and physical investigations, demonstrating octahedral stereochemistry of the complexes. Further, the antimalarial and antioxidant potential of the compounds (1-10) were analyzed by micro assay and DPPH assay protocols, respectively, to examine the therapeutic aspect of the compounds. The performed biological evaluations revealed that the complexes are more efficient in controlling infectious ailment in comparison of ligands. The complexes (5), (6), (10) shows significant efficiency for malarial and oxidant dysfunctions whereas Zn(II) complex (6) exhibit highest potency with 1.02 ± 0.07 and 2.28 ± 0.05 µM IC50 value. Furthermore, to support the highest antimalarial potency of the (3-6) complexes and their associated ligand (1), the computational studies like molecular docking, DFT, MESP and ADMET analysis were executed which were supported the biological efficacy of the complex (6) by providing numerous parameters like binding interaction electronegativity, electrophilicity, HOMO value and electron density.

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.

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure-Activity Relationships of the Novel PPP4pT Series.

The di-2-pyridylketone thiosemicarbazones demonstrated marked anticancer efficacy, prompting progression of DpC to clinical trials. However, DpC induced deleterious oxy-myoglobin oxidation, stifling development. To address this, novel substituted phenyl thiosemicarbazone (PPP4pT) analogues and their Fe(III), Cu(II), and Zn(II) complexes were prepared. The PPP4pT analogues demonstrated potent antiproliferative activity (IC50: 0.009-0.066 µM), with the 1:1 Cu:L complexes showing the greatest efficacy. Substitutions leading to decreased redox potential of the PPP4pT:Cu(II) complexes were associated with higher antiproliferative activity, while increasing potential correlated with increased redox activity. Surprisingly, there was no correlation between redox activity and antiproliferative efficacy. The PPP4pT:Fe(III) complexes attenuated oxy-myoglobin oxidation significantly more than the clinically trialed thiosemicarbazones, Triapine, COTI-2, and DpC, or earlier thiosemicarbazone series. Incorporation of phenyl- and styryl-substituents led to steric blockade, preventing approach of the PPP4pT:Fe(III) complexes to the heme plane and its oxidation. The 1:1 Cu(II):PPP4pT complexes were inert to transmetalation and did not induce oxy-myoglobin oxidation.

Targeting the Schistosoma mansoni nutritional mechanisms to design new antischistosomal compounds.

The chemical classes of semicarbazones, thiosemicarbazones, and hydrazones are present in various compounds, each demonstrating diverse biological activities. Extensive studies have revealed their potential as schistosomicidal agents. Thiosemicarbazones, in particular, have shown inhibitory effects on Schistosoma mansoni's cathepsin B1 enzyme (SmCB1), which plays a crucial role in hemoglobin degradation within the worm's gut and its nutrition processes. Consequently, SmCB1 has emerged as a promising target for novel schistosomiasis therapies. Moreover, chloroquinoline exhibits characteristics in its aromatic structure that hold promise for developing SmCB1 inhibitors, along with its interaction with hemoglobin's heme group, potentially synergizing against the parasite's gut. In this context, we report the synthesis of 22 hybrid analogs combining hydrazones and quinolines, evaluated against S. mansoni. Five of these hybrids demonstrated schistosomicidal activity in vitro, with GPQF-8Q10 being the most effective, causing worm mortality within 24 h at a concentration of 25 µM. GPQF-8Q8 proved to be the most promising in vivo, significantly reducing egg presence in feces (by 52.8%) and immature eggs in intestines (by 45.8%). These compounds exhibited low cytotoxicity in Vero cells and an in in vivo animal model (Caenorhabditis elegans), indicating a favorable selectivity index. This suggests their potential for the development of new schistosomiasis therapies. Further studies are needed to uncover specific target mechanisms, but these findings offer a promising starting point.

In vitro antiproliferative and apoptotic effects of thiosemicarbazones based on (-)-camphene and R-(+)-limonene in human melanoma cells.

A series of 38 thiosemicarbazone derivatives based on camphene and limonene were evaluated for their antiproliferative activity. Among them, 19 were synthesized and characterized using proton and carbon-13 nuclear magnetic resonance (1H and 13C NMR). For initial compound selection, human melanoma cells (SK-MEL-37) were exposed to a single concentration of a compound (100 µM) for 24, 48, and 72 hours, and cell detachment was visually observed. Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Nineteen compounds (4, 6, 8, 11, 13, 14, 15, 16, 17, 18, 20, 22, 25, 26, 31, 3', 4', 6', and 9') yielded cell viability below 20%. Subsequently, IC50 values for these compounds were determined, ranging from 11.56 to 55.38 µM, after 72 hours of treatment. Compound 17 (o-hydroxybenzaldehyde (-)-camphene-based thiosemicarbazone) demonstrated the lowest IC50 value, followed by compound 4 (benzaldehyde (-) camphene-based thiosemicarbazone) at 12.84 µM. Regarding compound 4, we observed the induction of a characteristic ladder pattern of DNA fragmentation through gel electrophoresis. Furthermore, fluorescence, flow cytometry and scanning microscopy assays revealed morphological changes consistent with apoptosis induction. Additionally, the measurement of caspase 6 and 8 activity in cellular extracts after treatment for 2, 4, 6, and 24 hours suggested the potential involvement of the extrinsic apoptosis pathway in the mechanism of action of compound 4. Further investigations, including molecular docking studies, are required to fully explore the potential of compound 4 and the other selected compounds, highlighting their promising role in future melanoma therapy research.

Synthesis of novel coumarin-based thiosemicarbazones and their implications in diabetic management via in-vitro and in-silico approaches.

Diabetes mellitus has a high prevalence rate and it has been deemed a severe chronic metabolic disorder with long-term complications. This research aimed to identify compounds that could potentially inhibit the vital metabolic enzyme α-glucosidase and thereby exert an anti-hyperglycemic effect. The main goal was to establish an effective approach to control diabetes. To proceed with this study, a series of novel coumarin-derived thiosemicarbazones 3a-3m was synthesized and examined using a variety of spectroscopic methods. Moreover, all the compounds were subjected to α-glucosidase inhibition bioassay to evaluate their antidiabetic potential. Fortunately, all the compounds exhibited several folds potent α-glucosidase inhibitory activities with IC50 values ranging from 2.33 to 22.11 µM, in comparison to the standard drug acarbose (IC50 = 873.34 ± 1.67 µM). The kinetic studies of compound 3c displayed concentration-dependent inhibition. Furthermore, the binding modes of these molecules were elucidated through a molecular docking strategy which depicted that the thiosemicarbazide moiety of these molecules plays a significant role in the interaction with different residues of the α-glucosidase enzyme. However, their conformational difference is responsible for their varied inhibitory potential. The molecular dynamics simulations suggested that the top-ranked compounds (3c, 3g and 3i) have a substantial effect on the protein dynamics which alter the protein function and have stable attachment in the protein active pocket. The findings suggest that these molecules have the potential to be investigated further as novel antidiabetic medications.

Antifungal efficacy of imidazo[1,2-a]pyrazine-based thiosemicarbazones and thiazolidinediones against Sporothrix species.

Aim: To evaluate antifungal potential of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hybrids based on thiosemicarbazones and thiazolidinediones against pathogenic Sporothrix species. Methods: Antifungal activity of nine compounds were assessed by broth microdilution. Interactions between active compounds and itraconazole were evaluated by the checkerboard assay using non-wild-type isolates. Cytotoxicity of the compounds was determined. Results: Four C-3 substituted analogs showed antifungal activity, unrelated to thiosemicarbazone or thiazolidinedione functions. Synergistic interactions between the four compounds and itraconazole, and low toxicity on mouse fibroblast cells were observed. Activity of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hybrids against Sporothrix depended on the substitution on the imidazopyrazine ring. Conclusion: Antifungal potential, overcoming itraconazole resistance and low toxicity indicate the possible use of that series of compounds in a therapeutic alternative for treatment of sporotrichosis.

Cytotoxic pathways activated by multifunctional thiosemicarbazones targeting sigma-2 receptors in breast and lung carcinoma cells.

BACKGROUND: Multifunctional thiosemicarbazones (TSCs) able to bind sigma receptors and chelate metals are considered as a promising avenue for the treatment of pancreatic cancer due to the encouraging results obtained on in vitro and in vivo models. Here, we assessed the biochemical mechanism of these TSCs also on lung (A549) and breast (MCF7) cancer cells. METHODS: The density of sigma-2 receptors in normal (BEAS-2B and MCF10A) and in lung and breast (A549 and MCF7) cancer cells was evaluated by flow cytometry. In these cells, cytotoxicity (MTT assay) and activation of ER- and mitochondria-dependent cell death pathways (by spectrofluorimetric assays to measure Caspases 3/7/9; qRT-PCR detection of GRP78, ATF6, IRE1, PERK; MitoSOX, DCFDA-AM and JC-1 staining), induced by the TSCs FA4, MLP44, PS3 and ACThio1, were evaluated. RESULTS: FA4 and PS3 exerted more potent cytotoxicity than MLP44 and ACThio1 in all cancer cell lines, where the density of sigma-2 receptors was higher than in normal cells. Remarkably, FA4 promoted ER- and mitochondria-dependent cell death pathways in both cell models, whereas the other TSCs had variable, cell-dependent effects on the activation of the two proapoptotic pathways. CONCLUSIONS: Our data suggest that FA4 is a promising compound that deserves to be further studied for lung and breast cancer treatment. However, the other multifunctional TSCs also hold promise for the development of therapies towards a personalized medicine approach. Indeed, the presence of the sigma-2 receptor-targeting moiety would lead to a more specific tumor delivery embracing the characteristics of individual tumor types.

Design, synthesis, biological activities, and evaluation of molecular docking-dynamics studies of new thiosemicarbazones that may be effective against Alzheimer's disease.

Donepezil is one of the most used drugs in the treatment of Alzheimer's disease. Its activity as an AChE inhibitor makes new studies with these enzyme inhibitors attractive. For this purpose, in this study, 12 compounds including thiosemicarbazone pharmacophore, have been synthesized for the treatment of the Alzheimer's disease. 3,4-Dimethoxybenzene or 1,3-benzodioxolone rings were used for the PAS region. The substituted piperazine benzene structure is preferred for the CAS region. At the same time, the thiosemicarbazone pharmacophore structure with known ChE enzyme inhibition potential was used as a bridge connecting the CAS and PAS regions. Structure determination of compounds 3a-3l were revealed using 13 C-NMR, 1 H-NMR, and HRMS spectroscopic methods. The inhibition profile of obtained compounds (3a-3l) against ChE was evaluated using in vitro modified Ellman method. Compounds 3a, 3b, 3f, 3g and 3i exhibited inhibitory activity against the AChE enzyme. Compound 3a showed the highest inhibitory potential with an IC50 = 0.030 ± 0.001 µM. As a result of molecular docking studies, compound 3a displayed important interactions compared to other active derivatives. Molecular dynamics studies are important to see the stability of the complex formed by ligand and protein. RMSD, RMSF ang Rg parameters were calculated via dynamic studies. In conclusion, compound 3a may be a potential AChE enzyme inhibitor with its strong inhibitory potential and behavior in silico.

2-Oxoquinoline-based-thiosemicarbazones as multitargeting neurotherapeutics against Alzheimer's disease: In vitro and in silico studies of MAO and ChE inhibitors.

Alzheimer's disease (AD) presents a multifactorial neurological disorder with multiple enzyme involvement in its onset. Conventional monotherapies fall short in providing long-term relief, necessitating the exploration of alternative multitargeting approaches to address the complexity of AD. Therefore, the design, synthesis, and in vitro and in silico evaluation of 2-oxoquinoline-based thiosemicarbazones 9a-r as multipotent analogs, able to simultaneously inhibit the cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of AD, are reported. In the in vitro experimental evaluation of MAO and ChE inhibition, all tested compounds demonstrated remarkable potency exhibiting nonselective inhibition of both MAO-A and MAO-B, and selective inhibition of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE), with 9d, 9j, and 9m evolving as lead compounds for MAO-A, MAO-B, and AChE, displaying IC50 values of 0.35 ± 0.92, 0.50 ± 0.02, and 0.25 ± 0.13 µM, respectively. Moreover, the kinetic studies revealed that all tested compounds inhibited all three enzymes through a competitive mode of inhibition. Furthermore, the molecular docking studies of the most active compounds revealed several crucial interactions, particularly hydrogen bonding interactions. These interactions were observed between the nitrogen and sulfur atoms of thiosemicarbazone and the nitrogen and oxygen atoms of the quinoline ring with various amino acids, suggesting the strong interactions of these compounds with the enzymes.

A novel palladium complex with a coumarin-thiosemicarbazone hybrid ligand inhibits Trypanosoma cruzi release from host cells and lowers the parasitemia in vivo.

In this work, two analogous coumarin-thio and semicarbazone hybrid compounds were prepared and evaluated as a potential antichagasic agents. Furthermore, palladium and platinum complexes with the thiosemicarbazone derivative as ligand (L1) were obtained in order to establish the effect of metal complexation on the antiparasitic activity. All compounds were fully characterized both in solution and in solid state including the resolution of the crystal structure of the palladium complex by X-ray diffraction methods. Unexpectedly, all experimental and theoretical characterizations in the solid state, demonstrated that the obtained palladium and platinum complexes are structurally different: [PdCl(L1)] and [PtCl2(HL1)]. All the studied compounds lower the proliferation of the amastigote form of Trypanosoma cruzi while some of them also have an effect on the trypomastigote stage. Additionally, the compounds inhibit T. cruzi release from host cells in variable extents. The Pd compound presented a remarkable profile in all the in vitro experiments, and it showed no toxicity for mammalian cells in the assayed concentrations. In this sense, in vivo experiments were performed for this compound using an acute model of Chagas disease. Results showed that the complex significantly lowered the parasite count in the mice blood with no significant toxicity.