Thiosemicarbazone Research Articles

Functionalizing Thiosemicarbazones for Covalent Conjugation.

Thiosemicarbazones (TSCs) with their modular character (thiosemicarbazides + carbonyl compound) allow broad variation of up to four substituents on the main R1R2C=N(1)-NH-C(S)-N(4)R3R4 core and are thus interesting tools for the formation of conjugates or the functionalization of nanoparticles (NPs). In this work, di-2-pyridyl ketone was introduced for the coordination of metals and 9-anthraldehyde for luminescence as R1 and R2 to TSCs. R3 and R4 substituents were varied for the formation of conjugates. Amino acids were introduced at the N4 position to produce [R1R2TSC-spacer-amino acid] conjugates. Further, functions such as phosphonic acid (R-P(O)(OH)2), D-glucose, o-hydroquinone, OH, and thiol (SH) were introduced at the N4 position producing [R1R2TSC-spacer-anchor group] conjugates for direct NP anchoring. Phenyl, cyclohexyl, benzyl, ethyl and methyl were used as spacer units. Both phenyl phosphonic acid TSC derivatives were bound on TiO2 NPs as a first example of direct NP anchoring. [R1R2TSC-spacer-end group] conjugates including OH, S-Bn (Bn = benzyl), NH-Boc (Boc = tert-butyloxycarbonyl), COOtBu, C≡CH, or N3 end groups were synthesized for potential covalent binding to functional molecules or functionalized NPs through amide, ester, or triazole functions. The synthesis of the thiosemicarbazides H2NNH-C(S)-NR3R4 starting from amines, including amino acids, SCCl2 or CS2, and hydrazine and their condensation with dipyridyl ketone and anthraldehyde led to 34 new TSC derivatives. They were synthesized in up to six steps with overall yields ranging from 10 to 85% and were characterized by a combination of nuclear magnetic resonance spectroscopy and mass spectrometry. UV-vis absorption and photoluminescence spectroscopy allowed us to easily trace the dipyridyl imine and anthracene chromophores.

Mechanistic insights and in vivo efficacy of thiosemicarbazones against methicillin-resistant Staphylococcus aureus

Staphylococcus aureus poses a significant threat in both community and hospital settings due to its infective and pathogenic nature combined with its ability to resist the action of chemotherapeutic agents. Methicillin-resistant S. aureus (MRSA) poses a critical challenge. Metal-chelating thiosemicarbazones (TSCs) have shown promise in combating MRSA and while previous studies hinted at the antimicrobial potential of TSCs, their mechanisms of action against MRSA are still under investigation. We screened a chemical library for anti-staphylococcal compounds and identified a potent molecule named R91 that contained the NNSN structural motif found within TSCs. We identified that R91 and several structural analogs exhibited antimicrobial activity against numerous S. aureus isolates as well as other Gram-positive bacteria. RNAseq analysis revealed that R91 induces copper and oxidative stress responses. Checkerboard assays demonstrated synergy of R91 with copper, nickel, and zinc. Mutation of the SrrAB two-component regulatory system sensitizes S. aureus to R91 killing, further linking the oxidative stress response to R91 resistance. Moreover, R91 was found to induce hydrogen peroxide production, which contributed to its antimicrobial activity. Remarkably, no mutants with elevated R91 resistance were identified, despite extensive attempts. We further demonstrate that R91 can be used to effectively treat an intracellular reservoir of S. aureus in cell culture and can reduce bacterial burdens in a murine skin infection model. Combined, these data position R91 as a potent TSC effective against MRSA and other Gram-positive bacteria, with implications for future therapeutic development.

Cytotoxicity and activity of thiosemicarbazones and semicarbazones in Mycobacterium tuberculosis: a systematic review

Mycobacterium tuberculosis (M. tuberculosis), causing agent of tuberculosis (TB), is a slow growth with a lipid-rich-cell wall, that confers protection against the action of a significant number of drugs. Thiosemicarbazones (TSCs) and semicarbazones (SCs) have a broad spectrum of pharmacological properties, especially antimicrobial. To the best of our knowledge, there is no systematic review reporting evidence of the anti-M. tuberculosis activity of these substances. This research carried out a systematic review to assess the available literature on the activity of TSCs and SCs on M. tuberculosis, as well as the cytotoxicity in different cell types. Four electronic databases (PubMed, Embase, Web of Science and Scopus), were searched according to the PRISMA statement. The search resulted in 2,187 articles. Among the 32 selected, 27 addressed the activity and cytotoxicity of substances related to TSCs and/or SCs. For M. tuberculosis, MIC ranged from 0.031-1,403 µM. Among all substances analyzed, 63 were considered active in relation to standard drugs. The predominant cytotoxicity assay was MTT (69%) and almost half of the articles used VERO cells. Toxicity of most substances was promising. Many TSCs have anti-TB activity superior to many drugs already used in the basic regimens of TB treatment, with low toxicity, both in sensitive and resistant M. tuberculosis. New research should be carried out to obtain new chemical drug prototypes for treating TB.

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.

DEVELOPMENT OF THE PHARMACEUTIC CRYSTALLIZATION PROCESS USING PLASMODIUM FALCIPARUM, A DERIVATIVE OF THIOSEMICARBAZONE

Objective: The current study was designed with the goal of analyzing novel derivatives of organic and semi-organic NLO molecules that are just entering this field as the foundation for future therapeutic development. Methods: Thiosemicarbazones (TSC) are semicarbazide analogs that have sulfur atoms in place of oxygen atoms. The greatest number of therapeutic treatments for various disorders are also being used carbonyl compounds. These two types of organic compounds were combined, and their replacement with crystal growth procedures using solution growth was tested as an antibiotic for a few fastidious and nonfastidious species. The preparation of meta-substituted benzaldehydes using TSC. Tests were conducted with this single component. The following experimental technique was used to determine the antibacterial activity of Plasmodium falciparum. Half-inhibitory maximum (IC50) by calculation technique, cell viability % calculation method, and MTT assay by colorimetric method. Results: Method using agar discs. Using the agar disc diffusion method to measure the inhibition zone width and comparing the minimal inhibitory concentration (MIC) and inhibition zone width of available antibiotics against the aforementioned organism using data from the EUCAST and NCCLS databases, The absolute, relative, and mound slope values of an antibiotic that is currently on the market may be determined using the GraphPad Prism software; the epidemiological cutoff value can be determined using the ECOF Finder software; and the nature of the antibiotic can be determined using the WHONET 5.6 software. The newly developed antibiotics’ size and structure are contrasted with the structures of commercially available antibiotics and living organisms. Conclusion: The design of new drugs using novel derivatives of organic and semiorganic NLO molecules is based on the in vitro method of analysis, which has recently been introduced to this field. P. falciparum has an extremely low MIC value (0.625 μg/mL) against TSCMNB. The MIC break points are always larger than, not equal to, the MIC values and fall within the range of 110 μg/mL–130 μg/mL. We concluded that all of the novel compounds exhibit a susceptible form of inhibition.

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.

Quinoline-based hydrazones for biocide detection: Machine learning-aided design of new TBT chemosensors

Antifouling compounds are used as paint components to mitigate biofouling on ships and submerged structures. One of the most known and used antifouling compounds is tributyltin (TBT). However, TBT is toxic to aquatic living beings, causing problems such as reduction of growth and imposex. The development of a TBT chemosensor could be of utter relevance in the building of an in-situ TBT monitoring device. Therefore, this work reports the synthesis of five new quinoline-based hydrazones (HZ) and two new quinoline-based thiosemicarbazones (TSC), with synthesis yields from 17 to 83 %. The compounds were tested in the presence of TBT, and some compounds of the group showed colorimetric or fluorimetric changes. The interaction between these compounds and TBT was tested by spectrophotometric or spectrofluorimetric titrations, which allowed to calculate the limit of detection (LOD) for each interaction. The fluorimetric interaction between HZ 4a and TBT was shown to be the most sensitive chemosensory method, with a LOD value of 1.7 μM.A Ridge classifier model was developed to correlate the ability for TBT detection and the modification of the structure of each molecule. The validity of the proposed model was tested by assessing the TBT-sensing ability of the two novel TSC 5a and 5b, which were synthesized after the development of the model. These two compounds also showed colorimetric changes in the presence of TBT, with LODs of 13.8 and 3.1 μM, respectively, in good accordance with the model's predictions. Further analysis of the model's decision process provided some insights on the desirable properties of the novel quinoline-derived TBT optical chemosensors.

Solvatochromism, optical and electronic properties of thiosemicarbazone derivatives in solution phase

The electronic structure, solvatochromic and some optoelectronic properties of five different thiosemicarbazone (TSCs) derivatives with different substituents consisted from indole ring, benzyl ring and conjugated thiosemicarbazide have been investigated in detail. UV–vis. absorption spectra of TSC compounds have been analyzed in solvent media with different polarity. The spectral changes are observed to forming of solvent effects and substituents. Spectral behaviors and electronic transitions are interpreted based on the UV-Vis. spectra. Solvatochromic behaviors were defined by linear solvation energy relationships via multiple linear regression analysis by using Kamlet-Abboud-Taft and Catalán parameters. In addition, the correlations of electronic absorption transition energy with Marcus optical dielectric parameter and Reichardt-Dimroth parameter were also determined. Some optoelectronic parameters such as forbidden band gap energy and refractive index have been determined in different solvent medium. Thiosemicarbazone derivatives have a global electronic absorption transition energy of about 3.351 eV. According to LSER calculations, polarizability-induction of electronic transitions of the investigated molecules is effective. The (E)-4-(4-nitrobenzyl)-1-(2-oxo-2H-indol-3(3aH)-ylidene)thiosemicarbazide (TSC-B) compound that does not a methoxy group and contain nitro group substituent and has the highest forbidden energy range.

Synthesis, characterization, and anticancer potency of coumarin-derived thiosemicarbazones and their Copper(II) complexes

A series of 3-acetylcoumarin-based thiosemicarbazones and their copper(II) complexes were synthesized and characterized by elemental analysis, IR, UV–Vis, HR-ESI Mass, NMR, EPR and single crystal XRD. The XRD study revealed thione tautomer for TSCs 3 (AcCmDEtTSC) and 4 (AcCmDPrTSC) whereas Cu(II) complex 8[Cu(AcCmDPrTSC)Cl] has distorted square planar geometry around the metal ion. Compound 1 (AcCmMeHTSC) among the thiosemicarbazones (TSCs) was more effective against both breast cancer cell lines: MCF-7 (IC50; 13.02 µg/mL) and MDA-MB-231 (IC50; 42.71 µg/mL), whereas compounds 7[Cu(AcCmDEtTSC)Cl] (IC50; 32.84 µg/mL) and 8[Cu(AcCmDPrTSC)Cl] (IC50: 34.69 µg/mL) among the Cu(II) complexes were more effective against MDA-MB-231 cell lines. Anticancer activity of the test compounds enhanced in dose dose-dependent manner against both MCF-7 and MDA-MB-231 cells. Molecular docking study showed significant binding affinity of the test compounds, notably compound 2 (AcCmEtHTSC) with −7.1 kcal/mol and −8.0 kcal/mol, compound 3 with −7.3 kcal/mol and −7.8 kcal/mol against target proteins EGFR and HER2 respectively. Although the IC50 value of the synthesized compounds is not very encouraging, their significant binding affinity values (−5.8 kcal/mol to −8.0 kcal/mol) against the target proteins EGFR and HER 2 is encouraging for the further exploration of their anticancer activity in the future.

DNA Interactions and Biological Activity of 2,9-Disubstituted 1,10-Phenanthroline Thiosemicarbazone-Based Ligands and a 4-Phenylthiazole Derivative.

Four 1,10-phenanthroline derivatives (1-4) were synthesized as potential telomeric DNA binders, three substituted in their chains with thiosemicarbazones (TSCs) and one 4-phenylthiazole derivative. The compounds were characterized using NMR, HRMS, FTIR-spectroscopy and combustion elemental analysis. Quadruplex and dsDNA interactions were preliminarily studied, especially for neutral derivative 1, using FRET-based DNA melting assays, equilibrium dialysis (both competitive and non-competitive), circular dichroism and viscosity titrations. The TSC derivatives bind and stabilize the telomeric Tel22 quadruplex more efficiently than dsDNA, with an estimated 24-fold selectivity determined through equilibrium dialysis for compound 1. In addition, cytotoxic activity against various tumor cells (PC-3, DU145, HeLa, MCF-7 and HT29) and two normal cell lines (HFF-1 and RWPE-1) was evaluated. Except for the 4-phenylthiazole derivative, which was inactive, the compounds showed moderate cytotoxic properties, with the salts displaying lower IC50 values (30-80 μM), compared to the neutral TSC, except in PC-3 cells (IC50 (1) = 18 μM). However, the neutral derivative was the only compound that exhibited a modest selectivity in the case of prostate cells (tumor PC-3 versus healthy RWPE-1). Cell cycle analysis and Annexin V/PI assays revealed that the compounds can produce cell death by apoptosis, an effect that has proven to be similar to that demonstrated by other known 1,10-phenanthroline G4 ligands endowed with antitumor properties, such as PhenDC3 and PhenQE8.

Construction of a three-mode sensor based on gold nanoparticles and carbon quantum dots as probes for the detection of thiosemicarbazone.

In this study, ginkgo leaves were used as a carbon source to synthesize carbon quantum dots (CQDs) with uniform particle size, high fluorescence (FL) intensity and strong stability, using a hydrothermal method. FL could be quenched by the FL resonance energy transfer effect between CQDs and gold nanoparticles (AuNPs), an important FL quenching agent. The electrostatic attraction between thiosemicarbazone (TSC) and citrate on the surface of AuNPs and the formation of a stable Au-S bond between TSC and AuNPs led to the aggregation of AuNPs and thus weakened the quenching effect on CQDs and partly recovered the FL. A sensor in FL mode for the detection of TSC was constructed based on the above-mentioned FL "off" and "on" phenomena. The results showed a good linear correlation in the concentration range 0-1.75 μM, and the limit of detection was as low as 0.05 μM. In addition, the aggregation of AuNPs caused by TSC also led to a change in the absorbance curve and color of the solution; colorimetric and chrominance detection modes were also constructed using these two types of changes, with sensitive responses ranging 0-2.25 μM and 0-1.60 μM and the limits of detection of 0.03 μM and 0.08 μM, respectively. More importantly, these three detection modes obtained satisfactory recovery rates in the detection of the TSC content in river water, liquor and wheat samples, and the detection results were mutually verified (95.18% to 104.96%).

Rhenium (I) tricarbonyl complex with thiosemicarbazone ligand derived from Indole-2-carboxaldehyde: Synthesis, crystal structure, computational investigations, antimicrobial activity, and molecular docking studies

Antibiotic resistance is becoming a cause of serious concern to human health causing a significant impact on the global economy. The demand for novel antimicrobial agents is pressing since drug resistance is spreading and making antibiotics less and less effective. There is unrealized antibacterial potential in metal complexes. Among other compounds, rhenium complexes are particularly appealing because of their strong antibacterial activity and minimal in vivo toxicity. In this study, three Re carbonyl thiosemicarbazone (TSC) complexes were synthesized and characterized and their antibacterial potential was evaluated against various types of gram-positive and gram-negative bacteria. The structure of the ligands and their corresponding Re complexes were optimized at the DFT/B3LYP level of theory employing 6–311++G(d,p) and LANL2DZ basis sets for C, H, N, O, S, and Re atoms respectively. The MS studies performed with time show that [fac-[Re(CO)3Br(HL)] was converted into dimer [Re2(CO)6(L)2] in solution and the crystal structure of the dimer [Re2(CO)6(L)2] obtained as the result of dimerization of the complex was solved. Among the three Re TSC complexes, [fac-[Re(CO)3Br(HL1)] exhibits the greatest antibacterial activity against S.aureus with MIC value 0.5 µg/mL. The data obtained showed that the synthesized complexes were ineffective against gram-negative bacteria but showed excellent antibacterial activity against gram-positive S.aureus. The [fac-[Re(CO)3Br(HL2)] complex derived from isatin-β-thiosemicarbazone showed lesser activity than the other two rhenium TSC complexes which were obtained by condensation of indole-2-carboxaldehyde and thiosemicarbazide. Furthermore, the in-silico molecular docking studies revealed that the binding energy of the docked compound [Re(CO)3Br(HL)] with E. Coli and MRSA targets were extremely favorable (-7.18 and -5.67 kcal/mol, respectively which further demonstrates the potential of the synthesized complexes in the development of new antibacterial drugs. The molecular docking studies as well as experimental investigations demonstrate the effect of substituents on the ligand backbone on the antimicrobial activity of the synthesized rhenium carbonyl complexes. The enhanced antibacterial properties of rhenium carbonyl complexes with the TSC ligands in comparison to the ligand alone also suggest a possible synergistic effect of the metal center and the organic ligand.

Synthesis, characterization, anticancer, pharmacokinetics and molecular docking investigation of N (3)-alkyl incorporated-3-acetyl-4-hydroxycoumarin thiosemicarbazones and their copper(II) complexes

Coumarin based thiosemicarbazones (TSC), (E)-2-(1-(4‑hydroxy-2-oxo-2H-chromen-3-yl)ethylidene)-N-methylhydrazine-1-carbothioamide (HACmMeTsc) (3), (E)-N-ethyl-2-(1-(4‑hydroxy-2-oxo-2H-chromen-3-yl)ethylidene)hydrazine-1-carbothioamide (HACmEtTsc) (4) and (E)-N,N‑diethyl-2-(1-(4‑hydroxy-2-oxo-2H-chromen-3-yl)ethylidene)hydrazine-1-carbothioamide (HACmDEtTsc) (5) and their respective copper(II) complexes ([Cu(ACmMeTsc)Cl] (3a), [Cu(ACmEtTsc)Cl] (4a) and [Cu(ACmDEtTsc)Cl] (5a)) are synthesized and characterized by elemental analysis, FTIR, UV–Vis, ESI HRMS, 1H NMR, 13C NMR and single crystal X-ray diffraction analysis. The in vitro anticancer activity of the synthesized compounds by MTT assay against breast cancer cell lines MCF-7 and MDA-MB-231 exhibited strong anti-cancer potential in a dose dependent manner with IC50 value in the range of 12.94 -23.70 μg/mL and 42.18- >100 μg/mL in MCF-7 and MDA-MB-231 cells respectively. Molecular docking study showed that compounds 3, 4 and 5 have significant binding affinity (ΔG = -6.8 to -8.4 kcal/mol) along with interactions including hydrogen bonding with active sites of amino acid residues of both studied proteins, EGFR and HER 2, which may be responsible for the inactiveness of the receptors.

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

BackgroundMultifunctional 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.MethodsThe 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.ResultsFA4 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.ConclusionsOur 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.

Synthesis, crystal structures and antimicrobial activities of 3-methyl and 3-bromo substituted benzo[b]thiophene based thiosemicarbazones

A series of thiosemicarbazones (TSCs) (L1–5 ) containing benzothiophen moiety were prepared via the reaction of 3-methyl/3-bromobenzo[b]thiophene-2-carboxaldehyde with appropriate thiosemicarbazides. The compounds were confirmed by elemental analysis, FT-IR, 1H NMR, MALDI-TOF and single crystal X-Ray diffraction techniques. The compounds exist in the E conformation with respect to the azomethine C = N double bond as confirmed by their C8/C9/N1/N2 torsion angles being 178.4(2)° (L1 ), – 175.2(5)/177.4(5)° (L2 ), 177.5(2)° (L3 ), 179.7(3)° (L4 ), and – 177.4(7)° (L5 ). These compounds were researched for their antibacterial activity against Gram-positive bacteria (E. faecalis and S. aureus), Gram-negative bacteria (E. coli, P. aeruginosa and S. marcescens) and antifungal activity against a yeast species C. albicans. The ligands possessed varying degrees of antimicrobial activity. Generally, the compounds demonstrated higher efficacy against gram-positive bacteria than gram-negative ones. The antifungal activity of the compounds against C. albicans was found to be lower in comparison to their activity against bacteria.

New thiosemicarbazones and their palladium(II) complexes: Synthesis, spectroscopic characterization, X-ray structure and anticancer evaluation

Thiosemicarbazones (TSCs) have proven to be an important group of NS donor Schiff base ligands. Their biological activities, structural and donor diversities are often improved after coordination to a metal ion. In this work, novel thiophene-based thiosemicarbazone ligands; (E)-N,N’-dimethyl-2-((5′-methyl-[2,2′-bithiophen]-5-yl)methylene)hydrazine-1-carbothioamide (L1), (E)-N-ethyl-2-((5-phenylthiophen-2-yl)methylene)hydrazine-1-carbothioamide (L2) and (E)-2-((5′methyl)-[2,2′-bithiophen]-5-yl)methylene)-N-phenylhydrazine-1-carbothioamide (L3) were synthesized via condensation reaction. The corresponding complexes (C1, C2 and C3) were synthesized by reacting the ligands with Pd(cod)Cl2 under inert nitrogen environment. All the prepared ligands and complexes were characterized by using the FTIR, UV–Vis, 1H and 13C NMR, elemental analysis and single crystal X-ray crystallography on ligand L2. The anticancer activities of the complexes were investigated against human the Caco-2, HT-29, HeLa and non-cancerous KMST-6 cell lines. In the preliminary studies, unexpectedly of all ligands and complexes, L1 showed the best anti-tumor activities at 100 µg/mL with cell viabilities < 31% in all the cell lines. In general, cell lines were more susceptible to complexes than free ligands except for C1. Complex C2 had the highest activity among complexes; HeLa (8.4%), HT-29 (8.8%), Caco-2 (16.1%) and KMST-6 (24.5%) cell viabilities at a concentration of 100 µg/mL. The C3 complex demonstrated appreciable selectivity since it had minimal effect on non-cancerous KMST-6 cell line (76%) with relatively reduced cytotoxicity in other cells except in HeLa (0.0%). All the complexes prepared inhibited proliferation of HeLa cells.

Theoretical, antioxidant, antidiabetic and in silico molecular docking and pharmacokinetics studies of heteroleptic oxovanadium(IV) complexes of thiosemicarbazone-based ligands and diclofenac

A series of new heteroleptic oxovanadium(IV) complexes with the general formula [VOL1–6(Dcf)] (1–6), where L1−6 = thiosemicarbazone (TSC)-based ligands and Dcf = diclofenac have been synthesized and characterized. The spectral studies along with the density functional theory calculations evidenced the distorted square-pyramidal geometry around oxovanadium(IV) ion through imine nitrogen and thione sulfur atoms of TSC moiety, and two asymmetric carboxylate oxygen atoms of diclofenac drug. The complexes were evaluated for in vitro antioxidant activity using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2'-diphenyl-1-picrylhydrazyl (DPPH), hydrogen peroxide (H2O2) and superoxide radical scavenging assays with respect to the standard antioxidant drugs butylated hydroxyanisole (BHA) and rutin. The in vitro antidiabetic activity of the complexes was tested with enzymes such as α-amylase, α-glucosidase and glucose-6-phosphatase. The complexes containing methyl substituent showed higher activity than that containing the nitro substituent due to the electron-donating effect of methyl group. The in silico molecular docking studies of the oxovanadium(IV) complexes with α-amylase and α-glucosidase enzymes showed strong interaction via hydrogen bonding and hydrophobic interactions. The dynamic behavior of the proposed complexes was analyzed by molecular dynamics (MDs) simulations, which revealed the stability of docked structures with α-amylase and α-glucosidase enzymes. The in silico physicochemical and pharmacokinetics parameters, such as Lipinski’s ‘rule of five’, Veber’s rule and absorption, distribution, metabolism and excretion (ADME) properties predicted non-toxic, non-carcinogenic and safe oral administration of the synthesized complexes. Communicated by Ramaswamy H. Sarma

Human serum albumin as a copper source for anticancer thiosemicarbazones.

Thiosemicarbazones (TSCs) are a class of biologically active compounds with promising anticancer activity. Their typical mechanism, especially of the clinically far developed representative Triapine, is chelation of iron (Fe), with the Fe-containing enzyme ribonucleotide reductase as primary intracellular target. However, for the subclass of terminally disubstituted, nanomolar-active derivatives like Dp44mT and Me2NNMe2, recent findings suggest that the chelation, stability, and reduction properties of the copper(II) (Cu) complexes are essential for their modes of action. Consequently, it is important to elucidate whether blood serum Cu(II) is a potential metal source for these TSCs. To gain more insights, the interaction of Triapine, Dp44mT or Me2NNMe2 with purified human serum albumin (HSA) as the main pool of labile Cu(II) was investigated by UV-vis and electron paramagnetic resonance measurements. Subsequently, a size-exclusion chromatography inductively coupled plasma mass spectrometry method for the differentiation of Cu species in serum was developed, especially separating the non-labile Cu enzyme ceruloplasmin from HSA. The results indicate that the TSCs specifically chelate copper from the N-terminal Cu-binding site of HSA. Furthermore, the Cu(II)-TSC complexes were shown to form ternary HSA conjugates, most likely via histidine. Noteworthy, Fe-chelation from transferrin was not overserved, even not for Triapine. In summary, the labile Cu pool of HSA is a potential source for Cu-TSC complex formation and, consequently, distinctly influences the anticancer activity and pharmacological behavior of TSCs.

Inhibition of Topoisomerases by Metal Thiosemicarbazone Complexes.

Topoisomerases, common targets for anti-cancer therapeutics, are crucial enzymes for DNA replication, transcription, and many other aspects of DNA metabolism. The potential anti-cancer effects of thiosemicarbazones (TSC) and metal-TSC complexes have been demonstrated to target several biological processes, including DNA metabolism. Human topoisomerases were discovered among the molecular targets for TSCs, and metal-chelated TSCs specifically displayed significant inhibition of topoisomerase II. The processes by which metal-TSCs or TSCs inhibit topoisomerases are still being studied. In this brief review, we summarize the TSCs and metal-TSCs that inhibit various types of human topoisomerases, and we note some of the key unanswered questions regarding this interesting class of diverse compounds.

Evaluating the effects of chemotherapy drugs and thiosemicarbazone complexes on the alteration of SNHG16 expression in Acute Lymphoblastic Leukemia

Background: Acute lymphoblastic leukemia (ALL) is a malignant disease that afflicts both children and adults. It starts from the bone marrow (soft and spongy tissue inside the bone) where immature white blood cells or lymphocytes are formed. This study aims to compare chemotherapy drugs, methotrexate (MTX), cyclophosphamide, cytarabine (Ara-C) and mercaptopurine (6mp) with nickel (Ni) and copper (Cu) complexes of thiosemicarbazone (TSCZ) in terms of their effects on the changes of Small Nucleolar RNA Host Gene 16(SNHG16) long non coding RNA (lncRNA) expression in the ALL cell line.&#x0D; Materials and Methods: this experimental study was conducted on various concentrations of chemotherapy drugs including MTX, CP, Ara-C, 6mp and Ni and Cu complexes of TSCZ. The Jurkat E6.1 cell lines were subjected to passage in different groups and times (24, 48, and 72h) and then treated with the chemotherapy drugs. After RNA extraction and cDNA synthesis, the SNHG16 gene expression was evaluated by Real-Time PCR, and the results were analyzed by the Rest software.&#x0D; Results: As the results indicated, within 24h, MTX (0.77, 0.72), CP (0.61, 0.7), ara-C (0.78, 0.87), Cu (0.91, 0.95) and Ni (0.94, 0.79) complexes as well as complex 1(0.73) and 2 (0.94) decreased the expression of SNHG16 gene significantly (P&lt;0.001). Furthermore within 48h, under the influence of CP (0.86, 0.89) and Ara-C (0.94, 0.97) as well as Cu (0.96) and Ni (0.98) complexes, the gene expression continued to decline(P&lt;0.001).The greatest effect of chemotherapy drugs belonged to the combination of 1μM of ara-C and 5μM of 6mp.(P&lt;0.001). &#x0D; Conclusion: It was found that gene expression analysis is a feasible method to identify the pathways affected by the standard induction chemotherapy in ALL patients. This finding promotes the development of novel targeted drugs and biomarkers to categorize disease aggressiveness and evaluate treatment responses.