Thiazolation of phenylthiosemicarbazone to access new thiazoles: anticancer activity and molecular docking.

Aim: Novel thiazole hybrids were synthesized via thiazolation of 4-phenylthiosemicarbazone (4). Materials & methods: The anticancer activity against the NCI 60 cancer cell line panel. Results: Methyl 2-(2-((1-(naphthalen-2-yl)ethylidene)hydrazineylidene)-4-oxo-3-phenylthiazolidin-5-ylidene)acetate (6a) showed significant anticancer activity at 10 µM with a mean growth inhibition (GI) of 51.18%. It showed the highest cytotoxic activity against the ovarian cancer OVCAR-4 with an IC50 of 1.569 ± 0.06 µM. Compound 6a inhibited PI3Kα with IC50 = 0.225 ± 0.01 µM. Moreover, compound 6a revealed a decrease of Akt and mTOR phosphorylation in OVCAR-4 cells. In addition, antibacterial activity showed that compounds 11 and 12 were the most active against Staphylococcus aureus. Conclusion: Compound 6a is a promising molecule that could be a lead candidate for further studies.

Novel naphthalene-azine-thiazole hybrids 5-12 were synthesized via late-stage thiazolation of the corresponding 4-phenylthiosemicarbazone 4. Compound 6a showed significant anticancer activity at single-dose screening and yielded excellent inhibitory activity with a mean GI of 51.18%. Compound 6a showed the highest cytotoxic activity against OVCAR-4 with an IC₅₀ of 1.569 ± 0.06 µM. Moreover, compound 6a exhibited an IC₅₀ of 31.89 ± 1.19 µM against normal ovarian cell line (OCE1) and a selectivity index of 19.1. Compound 6a inhibited PI3Kα with IC₅₀ = 0.225 ± 0.01 µM compared with alpelisib (IC₅₀ = 0.061 ± 0.003 µM). Moreover, compound 6a revealed a powerful decrease of Akt and mTOR phosphorylation in the OVCAR-4 cell line. The cell cycle analysis showed that compound 6a caused an arrest at the G2/M phase. The compound also increased the total apoptosis by 26.8-fold and raised the level of caspase-3 by 4.34 times in OVCAR-4. In addition, antibacterial activity was estimated against Gram-positive and Gram-negative bacterial strains. Compounds 11 and 12 were the most active derivatives, with MIC value of 256 µg/ml against Staphylococcus aureus. Molecular docking was done and showed that 6a interlocked and fitted well into the ATP binding site of PI3Kα kinase (Protein Data Bank ID: 4JPS) with a fitness value (-119.153 kcal/mol) and forms the key H-bonds with Val851 and Ser854 like the marketed PI3Kα inhibitor alpelisib. Consequently, 6a is the most promising molecule that could be a lead candidate for further studies.

The role of cyclin-dependent kinase inhibitor 3 in the proliferation and migration of renal cell carcinoma.

The cyclin-dependent kinase inhibitor 3 (CDKN3) gene, is over expressed in renal cell carcinoma (RCC). However, the cell biology functions of RCC are not well understood. The present study aimed to verify the ability of CDKN3 to promote the proliferation and migration of RCC through in vitro experiments. Subsequently, the clinical prognostic effects were analyzed using The Cancer Genome Atlas (TCGA; https://www.cancer.gov/) and Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/). The chelators, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), an analogue of the anti-tumor agent, were screened through bioinformatics analysis. The expression of CDKN3 is positively correlated with the IC50 of Dp44mT. In two RCC cell lines, 786-0 and Caki-1, we conducted small interfering RNA (siRNA) knockdown of CDKN3 and overexpression of CDKN3 by transfection plasmid. Subsequently, we administered Dp44mT to examine the resulting alterations in cell proliferation, migration, and apoptosis, thereby elucidating the role of CDKN3 and Dp44mT in these processes. The results of the experiment revealed a positive association between CDKN3 expression and the proliferation of RCC cell lines. Down-regulating CDKN3 significantly increased the apoptosis rate and inhibited cell migration in 786-0 and Caki-1 cells. Furthermore, bioinformatics analysis revealed a high expression of CDKN3 in RCC and a negative association between CDKN3 expression and survival. Gene set enrichment analysis (GSEA) revealed a significant association between high CDKN3 expression and the cell cycle pathway. Furthermore, we identified Dp44mT as a drug highly correlated with CDKN3 through the database. Subsequent addition of Dp44mT resulted in similar findings to those observed upon CDKN3 knockdown. Our findings have important implications for the diagnosis and treatment of CDKN3 in RCC. Additionally, Dp44mT is likely to be a promising candidate for future clinical applications.

1H-Indole-2,3-dione 3-thiosemicarbazones carrying a 4-sulfamoylphenyl moiety with selective antiviral activity against reovirus-1.

1H-indole-2,3-dione 3-[4-(4-sulfamoylphenyl)thiosemicarbazones] (6a-j) were evaluated against Para-influenza-3, Reovirus-1, Sindbis, Coxsackie B4 and Punto Toro viruses. New 1-methyl-1H-indole-2,3-dione 3-[4-(4-sulfamoylphenyl)thiosemicarbazones] (7a-c) were synthesized to evaluate the contribution of methyl substitution at position 1- of the indole ring to antiviral activity. The test results showed that compounds 5-trifluoromethoxy- substituted 6c (EC50: 2-9 µM) and 5-bromo- substituted 6f (EC50: 2-3 µM) have non-toxic selective antiviral activity while not all standards are active against Reovirus-1. Molecular docking studies of 6c and 6f were carried out to determine the possible binding positions with Reovirus-1. Trifluoromethoxy and bromine substitutions at position 5- of the indole ring provided selective antiviral activity, while methyl substitution at position 1- of the indole ring significantly decreased the activity and increased toxicity against Reovirus-1.

In silico prediction of ADMET parameters and in vitro evaluation of antioxidant and cytotoxic activities promoted by indole-thiosemicarbazone compounds.

Cancer is a complex and multifactorial disease characterized by uncontrolled cell growth and is one of the main causes of death in the world. This work aimed to evaluate a small series of 10 different indole-thiosemicarbazone compounds as potential antitumor agents. This is a pioneering study. For this, the antioxidant and cytotoxic capacity against normal and tumor cells was evaluated. The results showed that the compounds were able to promote moderate to low antioxidant activity for the ABTS radical scavenging assay. ADMET in silico assays showed that the compounds exhibited good oral bioavailability. As for toxicity, they were able to promote low cytotoxicity against normal cells, in addition to not being hemolytic. The compounds showed promising in vitro antitumor activity against the T47D, MCF-7, Jurkat and DU-145 strains, not being able to inhibit the growth of the Hepg2 strain. Through this in vitro study, it can be concluded that the compounds are potential candidates for antitumor agents.

Copper(II) Complexes with Isomeric Morpholine-Substituted 2-Formylpyridine Thiosemicarbazone Hybrids as Potential Anticancer Drugs Inhibiting Both Ribonucleotide Reductase and Tubulin Polymerization: The Morpholine Position Matters.

The development of copper(II) thiosemicarbazone complexes as potential anticancer agents, possessing dual functionality as inhibitors of R2 ribonucleotide reductase (RNR) and tubulin polymerization by binding at the colchicine site, presents a promising avenue for enhancing therapeutic effectiveness. Herein, we describe the syntheses and physicochemical characterization of four isomeric proligands H2L3-H2L6, with the methylmorpholine substituent at pertinent positions of the pyridine ring, along with their corresponding Cu(II) complexes 3-6. Evidently, the position of the morpholine moiety and the copper(II) complex formation have marked effects on the in vitro antiproliferative activity in human uterine sarcoma MES-SA cells and the multidrug-resistant derivative MES-SA/Dx5 cells. Activity correlated strongly with quenching of the tyrosyl radical (Y•) of mouse R2 RNR protein, inhibition of RNR activity in the cancer cells, and inhibition of tubulin polymerization. Insights into the mechanism of antiproliferative activity, supported by experimental results and molecular modeling calculations, are presented.

Development of new steroid-based hydrazide and (thio)semicarbazone compounds with anticancer properties.

Most breast and prostate cancers are caused by abnormal production or action of steroidal hormones. Hormonal drugs based on steroid scaffolds represent a significant class of chemotherapeutics that are routinely used in chemotherapy. In this study, the synthesis of new 17a-homo lactone and 17α-(pyridine-2-ylmethyl) androstane derivatives with hydrazide and semicarbazone motifs is presented. All compounds were screened for their effect on cell viability against a panel of five cancer cell lines and one healthy cell line. Two compounds showed significant cytotoxicity against cancer cells, with low toxicity against healthy cells. The relative binding affinities of compounds for the ligand-binding domains of estrogen receptor α, estrogen receptor ß, androgen receptor and glucocorticoid receptor were tested using a fluorescence screen in yeast. Potential for inhibition of aldo-keto reductase 1C3 and 1C4 activity was measured in vitro. Experimental results are analyzed in the context of molecular docking simulations. Our results could help guide design of steroid compounds with improved anticancer properties against androgen- and estrogen-dependent cancers.

Thiosemicarbazone Mixed-Valence Cu(I/II) Complex against Lung Adenocarcinoma Cells through Multiple Pathways Involving Cuproptosis.

Induction of cuproptosis and targeting of multiple signaling pathways show promising applications in tumor therapy. In this study, we synthesized two thiosemicarbazone-copper complexes ([CuII(L)Cl] 1 and [CuII2CuI(L)2Cl3] 2, where HL is the (E)-N-methyl-2-(phenyl(pyridin-2-yl)methylene ligand), to assess their antilung cancer activities. Both copper complexes showed better anticancer activity than cisplatin and exhibited hemolysis comparable to that of cisplatin. In vivo experiments showed that complex 2 retarded the A549 cell growth in a mouse xenograft model with low systemic toxicity. Primarily, complex 2 kills lung cancer cells in vitro and in vivo by triggering multiple pathways, including cuproptosis. Complex 2 is the first mixed-valent Cu(I/II) complex to induce cellular events consistent with cuproptosis in cancer cells, which may stimulate the development of mixed-valent copper complexes and provide effective cancer therapy.

Assessment of tumor hypoxia in spontaneous canine tumors after treatment with OMX, a novel H-NOX oxygen carrier, with [18F]FMISO PET/CT.

BACKGROUND: Hypoxia is a detrimental factor in solid tumors, leading to aggressiveness and therapy resistance. OMX, a tunable oxygen carrier from the heme nitric oxide/oxygen-binding (H-NOX) protein family, has the potential to reduce tumor hypoxia. [18F]Fluoromisonidazole ([18F]FMISO) positron emission tomography (PET) is the most widely used and investigated method for non-invasive imaging of tumor hypoxia. In this study, we used [18F]FMISO PET/CT (computed tomography) to assess the effect of OMX on tumor hypoxia in spontaneous canine tumors. RESULTS: Thirteen canine patients with various tumors (n = 14) were randomly divided into blocks of two, with the treatment groups alternating between receiving intratumoral (IT) OMX injection (OMX IT group) and intravenous (IV) OMX injection (OMX IV group). Tumors were regarded as hypoxic if maximum tumor-to-muscle ratio (TMRmax) was greater than 1.4. In addition, hypoxic volume (HV) was defined as the region with tumor-to-muscle ratio greater than 1.4 on [18F]FMISO PET images. Hypoxia was detected in 6/7 tumors in the OMX IT group and 5/7 tumors in the OMX IV injection group. Although there was no significant difference in baseline hypoxia between the OMX IT and IV groups, the two groups showed different responses to OMX. In the OMX IV group, hypoxic tumors (n = 5) exhibited significant reductions in tumor hypoxia, as indicated by decreased TMRmax and HV in [18F]FMISO PET imaging after treatment. In contrast, hypoxic tumors in the OMX IT group (n = 6) displayed a significant increase in [18F]FMISO uptake and variable changes in TMRmax and HV. CONCLUSIONS: [18F]FMISO PET/CT imaging presents a promising non-invasive procedure for monitoring tumor hypoxia and assessing the efficacy of hypoxia-modulating therapies in canine patients. OMX has shown promising outcomes in reducing tumor hypoxia, especially when administered intravenously, as evident from reductions in both TMRmax and HV in [18F]FMISO PET imaging.

Evaluation of anticancer activity of novel platinum(II) bis(thiosemicarbazone) complex against breast cancer.

The study aims to synthesize a novel bis(thiosemicarbazone) derivative based on platinum (thioPt) and evaluate its anticancer properties against MFC-7 and MDA-MB-231 breast cancer cells. A new platinum complex was synthesised by reacting K2PtCl4 with 2,2'-(1,2-diphenylethane-1,2-diylidene)bis(hydrazine-1-carbothioamide) in ethanol in the presence of K2CO3. In the obtained complex, the platinum atom is coordinated by a conjugated system = N-NC-S-The structures of the new compound were characterised using NMR spectroscopy, HR MS, IR, and X-ray structural analysis. The obtained results of the cytotoxicity assay indicate that compound thioPt had potent anticancer activity (MCF-7: 61.03 ± 3.57 µM, MDA-MB-231: 60.05 ± 5.40 µM) with less toxicity against normal MCF-10A breast epithelial cells, even compared to the reference compound (cisplatin). In addition, subsequent experiments found that thioPt induces apoptosis through both an extrinsic (↑caspase 8 activity) and intrinsic (↓ΔΨm) pathway, which ultimately leads to an increase in active caspase 3/7 levels. The induction of autophagy and levels of proteins involved in this process (LC3A/B and Beclin-1) were examined in MCF-7 and MDA-MB-231 breast cancer cells exposed to tested compounds (thio, thioPt, cisPt) at a concentration of 50 µM for 24 h. Based on these results, it can be concluded that thio and thioPt do not significantly affect the autophagy process. This demonstrates their superiority over cisplatin, which can stimulate cancer cell survival through its effect on stimulation of autophagy.

Preliminary evaluation of the toxicological, antioxidant and antitumor activities promoted by the compounds 2,4-dihydroxy-benzylidene-thiosemicarbazones an in silico, in vitro and in vivo study.

Thiosemicarbazones are promising classes of compounds with antitumor activity. For this study, six 2,4-dihydroxy-benzylidene-thiosemicarbazones compounds were synthesized. These compounds were submitted to different assays in silico, in vitro and in vivo to evaluate the toxicological, antioxidant and antitumor effects. The in silico results were evaluated by the SwissADME and pkCSM platforms and showed that all compounds had good oral bioavailability profiles. The in vitro and in vivo toxicity assays showed that the compounds showed low cytotoxicity against different normal cells and did not promote hemolytic effects. The single dose acute toxicity test (2000 mg/kg) showed that none of the compounds were toxic to mice. In in vitro antioxidant activity assays, the compounds showed moderate to low activity, with PB17 standing out for the ABTS radical capture assay. The in vivo antioxidant activity highlighted the compounds 1, 6 and 8 that promoted a significant increase in the concentration of liver antioxidant enzymes. Finally, all compounds showed promising antitumor activity against different cell lines, especially MCF-7 and DU145 lines, in addition, they inhibited the growth of sarcoma 180 at concentrations lower than 50 mg/kg. These results showed that the evaluated compounds can be considered as potential antitumor agents.

Antimicrobial macrozones interact with biological macromolecules via two-site binding mode of action: Fluorimetric, NMR and docking studies.

Macrozones are novel conjugates of azithromycin and thiosemicarbazones, which exhibit very good in vitro antibacterial activities against susceptible and some resistant bacterial strains thus showing a potential for further development. A combination of spectrometric (fluorimetry, STD and WaterLOGSY NMR) and molecular docking studies provided insights into atomic details of interactions between selected macrozones and biological receptors such as E. coli ribosome and bovine serum albumin. Fluorimetric measurements revealed binding constants in the micro-molar range while NMR experiments provided data on binding epitopes. It has been demonstrated that both STD and WaterLOGSY gave comparable and consistent results unveiling atoms in intimate contacts with biological receptors. Docking studies pointed towards main interactions between macrozones and E. coli ribosome which included specific π - π stacking and hydrogen bonding interactions with thiosemicarbazone part extending down the ribosome exit tunnel. The results of the docking experiments were in fine correlation with those obtained by NMR and fluorimetry. Our investigation pointed towards a two-site binding mechanism of interactions between macrozones and E. coli ribosome which is the most probable reason for their activity against azithromycin-resistant strains. Much better activity of macrozone-nickel coordinated compound against E. coli ribosome compared to other macrozones has been attributed to the higher polarity which enabled better bacterial membrane penetration and binding of the two thiosemicarbazone units thus additionally contributing to the overall binding energy. The knowledge gained in this study should play an important role in anti-infective macrolide design in the future.

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.

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.

Synthesis, in vitro, and in silico studies of morpholine-based thiosemicarbazones as ectonucleotide pyrophosphatase/phosphodiesterase-1 and -3 inhibitors.

An extensive range of new biologically active morpholine based thiosemicarbazones derivatives 3a-r were synthesized, characterized by spectral techniques and evaluated as inhibitors of ENPP isozymes. Most of the novel thiosemicarbazones exhibit potent inhibition towards NPP1 and NPP3 isozymes. Compound 3 h was potent inhibitor of NPP1 with IC50 value of 0.55 ±â€¯0.02. However, the most powerful inhibitor of NPP3 was 3e with an IC50 value of 0.24 ±â€¯0.02. Furthermore, Lineweaver-Burk plot for compound 3 h against NPP1 and for compound 3e against NPP3 was devised through enzymes kinetics studies. Molecular docking and in silico studies was also done for analysis of interaction pattern of all newly synthesized compounds. The results were further validated by molecular dynamic (MD) simulation where the stability of conformational transformation of the best protein-ligand complex (3e) were justified on the basis of RMSD and RMSF analysis.

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.

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.

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.

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.

Thiosemicarbazone-benzenesulfonamide Derivatives as Human Carbonic Anhydrases Inhibitors: Synthesis, Characterization, and In silico Studies.

INTRODUCTION: Carbonic anhydrases (CAs) are widespread metalloenzymes with the core function of catalyzing the interconversion of CO2 and HCO3 -. Targeting these enzymes using selective inhibitors has emerged as a promising approach for the development of novel therapeutic agents against multiple diseases. METHODS: A series of novel thiosemicarbazone-containing derivatives were synthesized, characterized, and tested for their inhibitory activity against pharmaceutically important human CA I (hCA I), II (hCA II), IX (hCA IX), and XII (hCA XII) using the single tail approach. RESULTS: The compounds generally inhibited the isoenzymes at low nanomolar concentrations, with compound 6b having Ki values of 7.16, 0.31, 92.5, and 375 nM against hCA I, II, IX and XII, respectively. Compound 6e exhibited Ki values of 27.6, 0.34, 872, and 94.5 nM against hCA I, II, IX and XII, respectively. CONCLUSION: To rationalize the inhibition data, molecular docking studies were conducted, providing insight into the binding mechanisms, molecular interactions, and selectivity of the compounds towards the isoenzymes.