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1.
J Biol Inorg Chem ; 29(1): 3-31, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38148423

RESUMO

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


Assuntos
Antineoplásicos , Complexos de Coordenação , Tiossemicarbazonas , Metais , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Oxirredução , Tiossemicarbazonas/química , Íons , Antineoplásicos/farmacologia , Antineoplásicos/química
2.
Biometals ; 37(1): 247-265, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37938497

RESUMO

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


Assuntos
Antimaláricos , Complexos de Coordenação , Malária , Tiossemicarbazonas , Humanos , Antimaláricos/farmacologia , Antimaláricos/química , Simulação de Acoplamento Molecular , Antioxidantes/farmacologia , Antioxidantes/química , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Ligantes , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Zinco/química , Cobre/química , Quelantes
3.
Bioorg Chem ; 147: 107338, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38583253

RESUMO

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.


Assuntos
Antibacterianos , Escherichia coli , Fluorometria , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Antibacterianos/farmacologia , Antibacterianos/química , Escherichia coli/efeitos dos fármacos , Sítios de Ligação , Estrutura Molecular , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Relação Estrutura-Atividade , Ribossomos/metabolismo , Ribossomos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Animais , Bovinos , Azitromicina/farmacologia , Azitromicina/química , Azitromicina/metabolismo
4.
Bioorg Chem ; 148: 107486, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38788367

RESUMO

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.


Assuntos
Antineoplásicos , Apoptose , Neoplasias da Mama , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Tiossemicarbazonas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Tiossemicarbazonas/síntese química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Apoptose/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Feminino , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Platina/química , Platina/farmacologia , Autofagia/efeitos dos fármacos
5.
An Acad Bras Cienc ; 96(2): e20231247, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38808881

RESUMO

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.


Assuntos
Antineoplásicos , Antioxidantes , Tiossemicarbazonas , Animais , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Camundongos , Humanos , Masculino , Linhagem Celular Tumoral , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Compostos de Benzilideno/farmacologia , Compostos de Benzilideno/química
6.
An Acad Bras Cienc ; 96(3): e20230811, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38865509

RESUMO

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.


Assuntos
Antineoplásicos , Antioxidantes , Indóis , Tiossemicarbazonas , Humanos , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacocinética , Indóis/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacos
7.
Chem Biodivers ; 21(5): e202400363, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38470083

RESUMO

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.


Assuntos
Antineoplásicos , Complexos de Coordenação , Paládio , Tiossemicarbazonas , Humanos , Paládio/química , Paládio/farmacologia , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Ligantes , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Células MCF-7 , Estrutura Molecular , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Relação Estrutura-Atividade , DNA/química , DNA/metabolismo , DNA/efeitos dos fármacos
8.
Arch Pharm (Weinheim) ; 357(8): e2400140, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38687119

RESUMO

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


Assuntos
Cromonas , Diabetes Mellitus Tipo 2 , Desenho de Fármacos , Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes , Simulação de Acoplamento Molecular , Tiossemicarbazonas , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Cromonas/farmacologia , Cromonas/síntese química , Cromonas/química , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Tiossemicarbazonas/síntese química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estrutura Molecular , Humanos , Simulação de Dinâmica Molecular , Simulação por Computador , Relação Dose-Resposta a Droga
9.
Int J Mol Sci ; 25(12)2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38928235

RESUMO

The reaction mechanism of tthe formation of azomethine ylides from isatins and sarcosine is addressed in the literature in a general manner. This computational study aims to explore the mechanistic steps for this reaction in detail and to assess the reactivity of formed ylide in a 1,3-dipolar cycloaddition reaction with 7-oxabenzonorbornadiene. For this purpose, density functional theory (DFT) calculations at the M06-2X(SMD,EtOH)/6-31G(d,p) level were employed. The results indicate that CO2 elimination is the rate-determining step, the activation barrier for 1,3-dipolar cycloaddition is lower, and the formed ylide will readily react with dipolarophiles. The substitution of isatine with electron-withdrawal groups slightly decreases the activation barrier for ylide formation.


Assuntos
Compostos Azo , Reação de Cicloadição , Sarcosina , Tiossemicarbazonas , Tiossemicarbazonas/química , Compostos Azo/química , Sarcosina/química , Sarcosina/análogos & derivados , Isatina/química , Modelos Moleculares , Teoria da Densidade Funcional , Norbornanos/química , Estrutura Molecular
10.
Int J Mol Sci ; 25(13)2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-39000166

RESUMO

Pyridoxal-S-methyl-isothiosemicarbazone (PLITSC) is a member of an important group of ligands characterized by different complexation modes to various transition metals. In this contribution, a new complex containing two differently protonated PLITSC ligands ([Fe(PLITSC-H)(PLITSC)]SO4)∙2.5H2O was obtained. The crystal structure was solved by the X-ray analysis and used further for the optimization at B3LYP/6-311++G(d,p)(H,C,N,O,S)/def2-TZVP(Fe) level of theory. Changes in the interaction strength and bond distance due to protonation were observed upon examination by the Quantum Theory of Atoms in Molecules. The protein binding affinity of [Fe(PLITSC-H)(PLITSC)]SO4 towards transport proteins (Bovine Serum Albumin (BSA) and Human Serum Albumin (HSA)) was investigated by the spectrofluorimetric titration and molecular docking. The interactions with the active pocket containing fluorescent amino acids were examined in detail, which explained the fluorescence quenching. The interactions between complex and DNA were followed by the ethidium-bromide displacement titration and molecular docking. The binding along the minor groove was the dominant process involving complex in the proximity of DNA.


Assuntos
DNA , Simulação de Acoplamento Molecular , Ligação Proteica , Soroalbumina Bovina , Ligantes , DNA/química , DNA/metabolismo , Humanos , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Cristalografia por Raios X , Tiossemicarbazonas/química , Tiossemicarbazonas/metabolismo , Bovinos , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Animais , Prótons , Compostos Férricos/química , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Sítios de Ligação , Ferro/química , Ferro/metabolismo
11.
Molecules ; 29(2)2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38276575

RESUMO

The aim of this work is to explore a new library of coordination compounds for medicinal applications. Gallium is known for its various applications in this field. Presently, indium is not particularly important in medicine, but it shares a lot of chemical traits with its above-mentioned lighter companion, gallium, and is also used in radio imaging. These metals are combined with thiosemicarbazones, ligating compounds increasingly known for their biological and pharmaceutical applications. In particular, the few ligands chosen to interact with these hard metal ions share the ideal affinity for a high charge density. Therefore, in this work we describe the synthesis and the characterization of the resulting coordination compounds. The yields of the reactions vary from a minimum of 21% to a maximum of 82%, using a fast and easy procedure. Nuclear Magnetic Resonance (NMR) and Infra Red (IR) spectroscopy, mass spectrometry, elemental analysis, and X-ray Diffraction (XRD) confirm the formation of stable compounds in all cases and a ligand-to-metal 2:1 stoichiometry with both cations. In addition, we further investigated their chemical and biological characteristics, via UV-visible titrations, stability tests, and cytotoxicity and antibiotic assays. The results confirm a strong stability in all explored conditions, which suggests that these compounds are more suitable for radio imaging applications rather than for antitumoral or antimicrobic ones.


Assuntos
Complexos de Coordenação , Gálio , Tiossemicarbazonas , Gálio/farmacologia , Gálio/química , Índio/química , Tiossemicarbazonas/química , Ligantes , Espectroscopia de Ressonância Magnética , Complexos de Coordenação/química
12.
J Biol Inorg Chem ; 28(1): 17-27, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36459222

RESUMO

The inhibitory effects on mushrooms tyrosinase activity of some semi- and thiosemicarbazones were investigated. While the semicarbazones are inactive, the thiosemicarbazones are, in general, more active than the reference (kojic acid, IC50 = 70 µM), with maximum activity obtained with benzaldehyde thiosemicarbazone (IC50 = 7 µM). These inhibitors probably act by coordination of the copper(II) metal ions in the active site of tyrosinase: effectively, potentiometric studies conducted in water solutions confirm that the most active thiosemicarbazone is a good ligand for copper(II) ions. The tyrosinase CD spectra do not show any significant difference by addition of an inhibitor or an inactive compound. On the contrary, interesting results were obtained by spectrofluorimetric titrations of mushrooms tyrosinase aqueous solutions with some of the investigated compounds, giving helpful information about possible mechanism of action. The thiosemicarbazones here reported are not cytotoxic on human fibroblasts and do not activate cells in a pro-inflammatory way.


Assuntos
Agaricales , Tiossemicarbazonas , Humanos , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Monofenol Mono-Oxigenase/química , Cobre/química , Espectrometria de Fluorescência , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química
13.
J Biol Inorg Chem ; 28(8): 711-723, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37768364

RESUMO

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.


Assuntos
Tiossemicarbazonas , Tripanossomicidas , Trypanosoma cruzi , Animais , Camundongos , Paládio/farmacologia , Paládio/química , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Ligantes , Parasitemia , Platina/química , Tripanossomicidas/farmacologia , Cumarínicos/farmacologia , Mamíferos
14.
J Biol Inorg Chem ; 28(5): 457-472, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37129705

RESUMO

A novel fluorescent ligand (H2LCl⋅1.5CH3OH, 1) was synthesized and metal complexes of 1 with Mn(II), Fe(III), Ni(II), Cu(II), and Zn(II) were obtained as Mn(HL)2Cl2 (2), Fe(HL)2Cl3⋅3H2O (3), Ni(L)(HL)Cl⋅8H2O (4), Cu(HL)Cl2⋅4H2O (5), Zn(H2L)Cl3 (6), respectively. These compounds were identified by spectroscopic methods, elemental analysis, molar conductivity, and single-crystal X-ray crystallography. According to the crystal structure of 4 nickel (II), center is surrounded by two ligands in a distorted octahedral geometry. The ligand and its complexes are soluble in water and have excellent stability. In vitro anti-proliferative activity of these compounds was evaluated against human breast adenocarcinoma (MCF-7) and human lipo-sarcoma (SW-872) as cancer cells and human fibroblasts (HFF-2) as normal cells by MTT assay. Interestingly, complex 5 exhibited excellent activity against both cancer cells with low IC50 value 22.18 ± 0.35 µg/mL (35.66 ± 0.56 µM) for SW-872 and 79.41 ± 3.54 µg/mL (127.6 ± 5.69 µM) for MCF-7 among the compounds and in comparison with paclitaxel (PTX) which acts finely. Morphological changes were evaluated by flow cytometry that revealed apoptosis is the main cause of cell death. Likewise, cell cycle studies indicated the cell cycle arrest in the G1 and S phases for complex 5 against MCF-7 and SW-872 cancer cells, while complex 6 could arrest the MCF-7 and SW-872 cells in G2 and G1 phases, respectively. All of the compounds are fluorescent which enabled us to monitor the uptake and intracellular distribution in living human cancer cells by fluorescence microscopy.


Assuntos
Antineoplásicos , Complexos de Coordenação , Tiossemicarbazonas , Humanos , Ligantes , Tiossemicarbazonas/química , Bases de Schiff/farmacologia , Bases de Schiff/química , Compostos Férricos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Cobre/química
15.
Inorg Chem ; 62(1): 224-237, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36546528

RESUMO

Nine potentially S,N,Npy-tridentate thiosemicarbazones (HL) derived from pyridine-2-carbaldehyde or 1-(2-pyridyl)ethanone have been prepared and fully characterized. The X-ray crystal structures of six of them and two hydrochlorides were determined and analyzed. The reaction of the [ReX(CH3CN)2(CO)3]/[ReX(CO)5] (X = Cl and Br) precursors with these ligands yielded different kinds of compounds: the adducts [ReX(HL)(CO)3], in which the ligands were S,N-bidentate; the trinuclear species [Re3Cl2(L23)(HL23)(CO)9]; and the thiosemicarbazonate compounds [Re(L)(CO)3], where the ligand is S,N,Npy-tridentate. Besides, the reaction in methanol or ethanol of the thiosemicarbazones derived from aldehydes yielded S,N,Npy-tridentate hemiaminal cationic [Re(HLOR)(CO)3]X and neutral [Re(LOMe)(CO)3] complexes after the coordinated ligand underwent addition of the alcohol group to the imine bond. The reactivity of the complex [ReX(HL)(CO)3] in MeOH and NEt3 led to the formation of dinuclear [Re2(L)2(CO)6], where the thiosemicarbazonate is again S,N-bidentate. The influence that the substituents on the thiosemicarbazone ligands have on the stability of the complexes and the effect of the reaction medium on the resulting compounds have been analyzed.


Assuntos
Tiossemicarbazonas , Ligantes , Tiossemicarbazonas/química , Aldeídos , Cristalografia por Raios X
16.
Inorg Chem ; 62(50): 20791-20805, 2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-37855107

RESUMO

Bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators have demonstrated utility in nuclear medicine. In particular, the 64Cu2+ complexes have been extensively developed for hypoxia imaging and molecular imaging of peptide and protein markers of disease. However, the chemistry and application of bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators in combination with 99mTc, the most widely used radionuclide in nuclear medicine, is underexplored. Herein, a series of bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators were radiolabeled with nitrido-technetium-99m in an optimized one-pot synthesis from [99mTc]TcO4-. Optimization of the radiochemical syntheses allowed for production of the complexes in >90% radiochemical conversion with apparent molar activities of 3.3-5 GBq/µmol. Competition experiments demonstrated the excellent stability of the complexes. The nitrido-technetium-99 complexes were synthesized, and the chemical identities were investigated using mass spectrometry, spectroscopy, and density functional theory calculations. Complexation of nitrido-rhenium(V) was achieved with the N4-dialkylated bis(thiosemicarbazones). Planar imaging and ex vivo biodistribution studies of the five 99mTc complexes were conducted on healthy BALB/c mice to determine in vivo behavior. The lipophilic nature of the complexes resulted in uptake of 1.6-5.7% ID g-1 in the brain at 2 min postinjection and retention of 0.4-1.7% ID g-1 at 15 min postinjection. The stability of the complexes and the biodistribution data demonstrate that these chelators are ideal platforms for future production of radiopharmaceutical candidates.


Assuntos
Tecnécio , Tiossemicarbazonas , Camundongos , Animais , Tecnécio/química , Tiossemicarbazonas/química , Distribuição Tecidual , Radioisótopos , Compostos Radiofarmacêuticos/química , Quelantes/química
17.
J Chem Inf Model ; 63(5): 1506-1520, 2023 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-36802548

RESUMO

Trypanosoma cruzi is a parasite that infects about 6-7 million people worldwide, mostly in Latin America, causing Chagas disease. Cruzain, the main cysteine protease of T. cruzi, is a validated target for developing drug candidates for Chagas disease. Thiosemicarbazones are one of the most relevant warheads used in covalent inhibitors targeting cruzain. Despite its relevance, the mechanism of inhibition of cruzain by thiosemicarbazones is unknown. Here, we combined experiments and simulations to unveil the covalent inhibition mechanism of cruzain by a thiosemicarbazone-based inhibitor (compound 1). Additionally, we studied a semicarbazone (compound 2), which is structurally similar to compound 1 but does not inhibit cruzain. Assays confirmed the reversibility of inhibition by compound 1 and suggested a two-step mechanism of inhibition. The Ki was estimated to be 36.3 µM and Ki* to be 11.5 µM, suggesting the pre-covalent complex to be relevant for inhibition. Molecular dynamics simulations of compounds 1 and 2 with cruzain were used to propose putative binding modes for the ligands. One-dimensional (1D) quantum mechanics/molecular mechanics (QM/MM) potential of mean force (PMF) and gas-phase energies showed that the attack of Cys25-S- on the C═S or C═O bond yields a more stable intermediate than the attack on the C═N bond of the thiosemicarbazone/semicarbazone. Two-dimensional (2D) QM/MM PMF revealed a putative reaction mechanism for compound 1, involving the proton transfer to the ligand, followed by the Cys25-S- attack at C═S. The ΔG and energy barrier were estimated to be -1.4 and 11.7 kcal/mol, respectively. Overall, our results shed light on the inhibition mechanism of cruzain by thiosemicarbazones.


Assuntos
Doença de Chagas , Semicarbazonas , Tiossemicarbazonas , Trypanosoma cruzi , Humanos , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Cisteína Endopeptidases/química , Proteínas de Protozoários/química , Inibidores de Cisteína Proteinase/química
18.
Exp Parasitol ; 248: 108498, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36907541

RESUMO

In this work, 13 thiosemicarbazones (1a - m) and 16 thiazoles (2a - p) were obtained, which were properly characterized by spectroscopic and spectrometric techniques. The pharmacokinetic properties obtained in silico revealed that the derivatives are in accordance with the parameters established by lipinski and veber, showing that such compounds have good bioavailability or permeability when administered orally. In assays of antioxidant activity, thiosemicarbazones showed moderate to high antioxidant potential when compared to thiazoles. In addition, they were able to interact with albumin and DNA. Screening assays to assess the toxicity of compounds to mammalian cells revealed that thiosemicarbazones were less toxic when compared to thiazoles. In relation to in vitro antiparasitic activity, thiosemicarbazones and thiazoles showed cytotoxic potential against the parasites Leishmania amazonensis and Trypanosoma cruzi. Among the compounds, 1b, 1j and 2l stood out, showing inhibition potential for the amastigote forms of the two parasites. As for the in vitro antimalarial activity, thiosemicarbazones did not inhibit Plasmodium falciparum growth. In contrast, thiazoles promoted growth inhibition. This study shows in a preliminary way that the synthesized compounds have antiparasitic potential in vitro.


Assuntos
Tiossemicarbazonas , Trypanosoma cruzi , Animais , Antioxidantes/farmacologia , Antiparasitários/toxicidade , Relação Estrutura-Atividade , Tiazóis/farmacologia , Tiazóis/química , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Mamíferos
19.
J Enzyme Inhib Med Chem ; 38(1): 2193676, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37146256

RESUMO

The development of skin-care products is recently growing. Cosmetic formulas containing active ingredients with proven efficacy, namely cosmeceuticals, are based on various compounds, including peptides. Different whitening agents featuring anti-tyrosinase activity have been applied in the cosmeceutical field. Despite their availability, their applicability is often limited due to several drawbacks including toxicity, lack of stability, and other factors. In this work, we present the inhibitory effect on diphenolase activity of thiosemicarbazone (TSC)-peptide conjugates. Tripeptides FFY, FWY, and FYY were conjugated with three TSCs bearing one or two aromatic rings via amide bond formation in a solid phase. Compounds were then examined as tyrosinase and melanogenesis inhibitors in murine melanoma B16F0 cell line, followed by the cytotoxicity assays of these cells. In silico investigations explained the differences in the activity, observed among tested compounds. Mushroom tyrosinase was inhibited by TSC1-conjugates at micromolar level, with IC50 lower than this for kojic acid, a widely used reference compound. Up to now, this is the first report regarding thiosemicarbazones conjugated with tripeptides, synthesised for the purpose of tyrosinase inhibition.


Assuntos
Agaricales , Cosmecêuticos , Tiossemicarbazonas , Animais , Camundongos , Monofenol Mono-Oxigenase , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Melaninas
20.
Chem Biodivers ; 20(11): e202301063, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37769192

RESUMO

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.


Assuntos
Tiossemicarbazonas , Tiossemicarbazonas/química , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Inibidores da Colinesterase/química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/química , Acetilcolinesterase/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Anidrase Carbônica I , Inibidores Enzimáticos/química , Estrutura Molecular , Isotiocianatos
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