Thiosemicarbazone Derivatives Research Articles

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

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

Synthesis, 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 ± 0.02. However, the most powerful inhibitor of NPP3 was 3e with an IC50 value of 0.24 ± 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.

Synthesis, characterization and anticancer screening of novel phenylbenzylidene thiosemicarbazone derivatives

Ten derivatives of phenylbenzylidene thiosemicarbazones (1–10) were synthesized by multicomponent reaction between hydrazine hydrate, isothiocyanate and substituted aldehydes in the presence of the phase transfer reagent Triton-B and subsequently heating the mixture. The synthesized compounds 1, 2, 5, 8 demonstrated to act as highly potent anticancer agents. They showed anticancer activity by mobilizing cellular 59Fe, inhibiting cellular uptake of 59Fe from 59Fe2-Tf, and mediating the ascorbate oxidation. Further, the structure activity relationship revealed that the donor atom and its stabilization resulted in better anticancer activity. The softness of the chelating donor atoms N and S yielded redox active iron complexes, which easily mediated ascorbate oxidation. This study identified the selective and potential chelators, which may act as anticancer agents and require further in vivo screening in future.

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.

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. 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 Aydın Adnan Menderes University in 2021. 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. 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.

Pristine 2-chloroquinoline-based-thiosemicarbazones as multitarget agents against alzheimer's disease: In vitro and in silico studies of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors

Neurodegenerative diseases can be treated more effectively with multitarget approaches. monoamine oxidases (MAOs) acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are promising agents for cognitive decline. Here, a series of novel 2-chloroquinoline-3-carbaldehyd thiosemicarbazone derivatives (3a-r) were synthesized via a single-pot reaction. In-vitro testing results showed four compound 3c, 3o, 3g and 3l having chloro, fluoro, methyl and ethyl functional groups showed high potency against MAO-A, MAO-B, AChE and BChE, with an IC50 value 0.549 ± 0.045, 0.340 ± 0.02, 0.280 ± 0.135 and 2.77 ± 0.62 µM, respectively. Compounds 3g exhibited maximum inhibitory potential against all four targeted enzymes. Density functional theory (DFT) was used to evaluate the reaction profiles of the potent derivatives. We found that compounds 3c, 3o, 3l, and 3g exhibited strong reactivity because their LUMO/HOMO energy gaps were narrow. In addition, the molecular docking studies revealed excellent docking scores, ligands were well accommodated in the active site of targeted enzymes and produced stable protein-ligand complexes. The stability of the protein-ligand complex was confirmed by molecular dynamic (MD) simulations which revealed stable and equilibrated protein-ligand complexes. While compounds 3p, 3q and 3r were less effective than the whole series against the targeted enzymes. This integrated approach enhances the findings' comprehensiveness and reliability. The finding of In-vitro and In-silico studies suggested compound 3g as a promising multi-targeted compound that can be act as a molecule for AD treatment.

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, antimicrobial activity and molecular docking study of transition metal complexes based on azo coumarin and thiosemicarbazone derivative

Synthesis, characterization, antimicrobial activity and molecular docking study of transition metal complexes based on azo coumarin and thiosemicarbazone derivative

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.

Advances in Breast Cancer Drug Discovery: A Review of Therapeutic Strategies and Studies Involving Photosensitizers, Caged Xanthones and Thiosemicarbazones Derivatives

Cancer is one of the major causes of death worldwide, and breast cancer is the most prevalent and deadly type among women. Despite the side effects and the phenomena of chemoresistance associated with the drugs involved, chemotherapy remains the main therapeutic strategy to combat and control breast cancer. Therefore, several new classes of compounds against breast cancer have been explored, in an effort to identify new drug candidates with alternative mechanisms of action. The principal results of such exploration, focusing on caged xanthones, thiosemicarbazones and photosensitizers, are presented in this review, along with the main aspects of the drug discovery process against breast cancer. More specifically, the design, structure-activity relationship investigations and anti-breast cancer properties of these three classes are described and discussed in this work.

GREEN SYNTHESIS AND ANTIMICROBIAL EVALUATION OF SOME THIOSEMICARBAZONE AND SEMICARBAZONE DERIVATIVES

The interaction of substituted pyridine carboxaldehyde with thiosemicarbazide and semicarbazide via a greener approach resulted in the synthesis of thiosemicarbazone and semicarbazone derivatives; respectively. The resultant compounds were synthesized in aqueous media and were characterized by FTIR and 1H-NMR spectral studies. The antimicrobial evaluation of the final compounds has proven that they are active against the strains (S. aureus, P. aeruginosa, A. niger, and C. glabrata) incorporating the microdilution method.

Solid-state photochromic properties of indole thiosemicarbazones with aggregation-induced emission

Four indole thiosemicarbazones have solid-state photochromism and AIE properties. Based on the single crystal structure, FT-IR spectra and theoretical calculations, the structure–activity relationship and the photochromic mechanism were revealed.

Mixed-ligand copper(ii)-diimine complexes of 3-formylchromone-N 4-phenyl thiosemicarbazone: 5,6-dmp co-ligand confers enhanced cytotoxicity.

The promising biological applications of thiosemicarbazone derivatives have inspired the design, synthesis, and study of their Cu(ii) complexes for anticancer therapeutic applications. Herein, we have evaluated the DNA/protein binding, DNA cleaving, and cytotoxic properties of four mixed-ligand Cu(ii) complexes of the type [Cu(L)(diimine)](NO3) 1-4, where HL is 4-oxo-4H-chromene-3-carbaldehyde-4(N)-phenylthiosemicarbazone and diimine is 2,2'-bipyridine (bpy, 1) 1,10-phenanthroline (phen, 2), 5,6-dimethyl-1,10-phenanthroline (5,6-dmp, 3), or dipyrido-[3,2-f:2',3'-h]-quinoxaline (dpq, 4). Interestingly, complex 3 with higher lipophilicity shows stronger DNA binding and oxidative DNA cleavage, higher ROS production, and more reversible redox behaviour, resulting in its remarkable cytotoxicity (IC50, 1.26 μM) against HeLa cervical cancer cells, and rendering it 5 times more potent than the widely used drug cisplatin. The same complex induces enhanced apoptotic cell death on HeLa cells but lower toxicity towards the non-cancerous PBMC cells. Molecular docking studies suggest that all the complexes bind in the minor groove of DNA and subdomain II of HSA, which is in close agreement with the experimental results. Also, 3 shows cytotoxicity higher than the analogous mixed ligand Cu(ii) complexes, reported already, emphasizing the importance of co-ligand in tuning the anticancer activity.

Synthesis of New of 4-Thiazolidinone and Thiazole Derivatives Containing Coumarin Moiety with Antimicrobial Activity.

Synthesizing hybrid molecules is one the best manner to achieve novel promising agents. Consequently, series of new thiazoles having coumarin nucleus were synthesized from 3-acetylcoumarin thiosemicarbazones. Cyclization of thiosemicarbazone derivatives with ethyl 2-chloroacetate, 1-chloropropan-2-one and 2-bromo-1-phenylethanone afforded the corresponding 4-thiazolidinones, 4-methylthiazoles and 4-phenylthiazoles, respectively. The expected antimicrobial propriety for the synthesized thiosemicarbazone and thiazole derivatives were investigated. The thiosemicarbazones and thiazolidin-4-ones showed moderate activities against G +ve and G -ve bacteria.

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, 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.

Synthesis and Caracterizations of New Thiosemicarbazone and Thiazole Derivatives From Polycyclic Chiral 1,5‐Diketones

AbstractThiosemicarbazone derivatives have a wide spectrum of biological activity as well as various application areas such as forming complexes with metals, using as intermediates in the synthesis of heterocyclic bioactive compounds. Thiazole derivatives can be easily synthesized from thiosemicarbazones and are among the important compounds in demand in terms of biological activity. In this study, 14 new thiosemicarbazone derivatives were synthesized starting from polycyclic 1,5‐diketone derivatives with five stereocenters, and 14 thiazole derivatives were synthesized from the reaction of the obtained thiosemicarbazones with 2‐bromoacetophenone and their structure determinations were carried out using spectroscopic methods (1H‐NMR, 13C‐NMR, 2D‐NMR, FT‐IR and Q‐TOF LC/MS). This synthesis route from polycyclic chiral 1,5‐diketones may contribute to the design of new drug‐like molecules, which are important in medicinal chemistry.

Synthesis, Theoretical, in Silico and in Vitro Biological Evaluation Studies of New Thiosemicarbazones as Enzyme Inhibitors.

Eleven new thiosemicarbazone derivatives (1-11) were designed from nine different biologically and pharmacologically important isothiocyanate derivatives containing functional groups such as fluorine, chlorine, methoxy, methyl, and nitro at various positions of the phenyl ring, in addition to the benzyl unit in the molecular skeletal structure. First, their substituted-thiosemicarbazide derivatives were synthesized from the treatment of isothiocyanate with hydrazine to synthesize the designed compounds. Through a one-step easy synthesis and an eco-friendly process, the designed compounds were synthesized with yields of up to 95 % from the treatment of the thiosemicarbazides with aldehyde derivatives having methoxy and hydroxy groups. The structures of the synthesized molecules were elucidated with elemental analysis and FT-IR, 1 H-NMR, and 13 C-NMR spectroscopic methods. The electronic and spectroscopic properties of the compounds were determined by the DFT calculations performed at the B3LYP/6-311++G(2d,2p) level of theory, and the experimental findings were supported. The effects of some global reactivity parameters and nucleophilic-electrophilic attack abilities of the compounds on the enzyme inhibition properties were also investigated. They exhibited a highly potent inhibition effect on acetylcholinesterase (AChE) and carbonic anhydrases (hCAs) (KI values are in the range of 23.54±4.34 to 185.90±26.16 nM, 103.90±23.49 to 325.90±77.99 nM, and 86.15±18.58 to 287.70±43.09 nM for AChE, hCA I, and hCA II, respectively). Furthermore, molecular docking simulations were performed to explain each enzyme-ligand complex's interaction.

Synthesis of new 2‐pyridinone and thiazole derivatives containing coumarin moiety

AbstractCoumarin has shown considerable therapeutic potency because of its versatile biological prosperities. Also, pyridines have been adopted in medicinal chemistry as potent ring. Moreover, several investigations reported the potency of thiazole‐containing compounds. So, during this research, new functionalized 2‐pyridinone and thiazole derivatives bearing coumarin moiety were aimed to synthesize. Many trials to obtain the 6‐amino‐2‐oxo‐pyridine‐3,5‐dicarbonitriles through the condensation of cyanoacetohydrazone of 3‐acetyl coumarin with 2‐(arylidene)malononitriles were carried out using different reaction conditions. In all cases, the reaction gave none of the corresponding 2‐pyridinone derivatives except the reaction with 2‐(benzylidene)‐malononitrile afforded product in few yield. Moreover, the reaction of another cyanoacetanilide with the 2‐(arylidene)‐malononitrile afforded the unexpected arylidene derivatives rather than the expected pyridin‐2‐one derivatives. Finally, new thiazoles bearing coumarin moiety were synthesized using 3‐acetylcoumarin N‐(2,4‐dimethoxyphenyl)‐thiosemicarbazone. Cyclization of thiosemicarbazone derivative with ethyl 2‐chloroacetate, chloroacetone or phenacyl bromide afforded in high yields the corresponding derivatives of thiazolidin‐4‐one, 4‐methylthiazole or 4‐phenylthiazole, respectively.

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.

Transition Metal Catalyst Free and Single‐Step Synthesis of Significant Thiosemicarbazones via Oxidative Coupling Strategy

AbstractThe efficacy and selectivity of the transition metal‐free catalysis have been emphasized in constructing thiosemicarbazone derivatives from the dehydrogenative coupling of alcohols and thiosemicarbazides under aerobic conditions. A broad spectrum of thiosemicarbazones was obtained in good‐to‐excellent yields up to 90 %, with water as the only by‐product. The catalytic synthesis worked in an atom‐economical fashion in the absence of any oxidant with only 1 mmol of the base loading per mmol of the substrates. Further, the impact of different temperatures, solvents, bases, and base loading of the coupling reaction has been explored. A probable pathway that involves the generation of an aldehyde intermediate to thiosemicarbazones, which releases only water has been proposed.