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1.
Eur J Pharmacol ; 983: 176963, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39260813

RESUMO

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options. This study explores the potential of novel 5-nitro-thiophene-thiosemicarbazone derivatives as therapeutic agents for PDAC. METHODS: We evaluated the cytotoxicity of seven derivatives in peripheral blood mononuclear cells (PBMCs) and PDAC cell lines. Promising candidates (PR12 and PR17) were further analyzed for their effects on colony formation, cell cycle progression, and reactive oxygen species (ROS) production. PR17, the most promising derivative, was subjected to additional investigation, including analysis of autophagy-related genes and protein kinase inhibition. RESULTS: Three derivatives (PR16, PR19, and PR20) displayed cytotoxicity towards PBMCs. PR12 reduced colony formation and G0/G1 cell cycle arrest in PDAC cells. Notably, PR17 exhibited potent activity in MIA PaCa-2 cells, inducing S-phase cell cycle arrest, downregulating autophagy genes, and inhibiting key protein kinases. CONCLUSION: PR17, a 5-nitro-thiophene-thiosemicarbazone derivative, demonstrates promising antineoplastic activity against PDAC cells by potentially modulating cell cycle progression, autophagy, and protein kinase signaling. Further studies are warranted to elucidate the detailed mechanism of action and explore its efficacy in vivo.


Assuntos
Antineoplásicos , Autofagia , Carcinoma Ductal Pancreático , Pontos de Checagem do Ciclo Celular , Neoplasias Pancreáticas , Tiofenos , Tiossemicarbazonas , Humanos , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Tiofenos/farmacologia , Tiofenos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Autofagia/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Morte Celular/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Proliferação de Células/efeitos dos fármacos
2.
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
3.
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
4.
Gene ; 897: 148082, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38101710

RESUMO

Transforming growth factor-ß (TGF-ß) and bone morphogenetic protein (BMP) signaling has fundamental roles in the regulation of the stem cell niche for both embryonic and adult stem cells. In zebrafish, male germ stem cell niche is regulated by follicle-stimulating hormone (Fsh) through different members of the TGF-ß superfamily. On the other hand, the specific roles of TGF-ß and BMP signaling pathways are unknown in the zebrafish male germ stem cell niche. Considering this lack of information, the present study aimed to investigate the pharmacological inhibition of TGF-ß (A83-01) and BMP (DMH1) signaling pathways in the presence of recombinant zebrafish Fsh using testicular explants. We also reanalyzed single cell-RNA sequencing (sc-RNA-seq) dataset from adult zebrafish testes to identify the testicular cellular sites of smad expression, and to understand the physiological significance of the changes in smad transcript levels after inhibition of TGF-ß or BMP pathways. Our results showed that A83-01 potentiated the pro-stimulatory effects of Fsh on spermatogonial differentiation leading to an increase in the proportion area occupied by differentiated spermatogonia with concomitant reduction of type A undifferentiated (Aund) spermatogonia. In agreement, expression analysis showed lower mRNA levels for the pluripotency gene pou5f3, and increased expression of dazl (marker of type B spermatogonia and spermatocyte) and igf3 (pro-stimulatory growth factor) following the co-treatment with TGF-ß inhibitor and Fsh. Contrariwise, the inhibition of BMP signaling nullified the pro-stimulatory effects of Fsh, resulting in a reduction of differentiated spermatogonia and increased proportion area occupied by type Aund spermatogonia. Supporting this evidence, BMP signaling inhibition increased the mRNA levels of pluripotency genes nanog and pou5f3, and decreased dazl levels when compared to control. The sc-RNA-seq data unveiled a distinctive pattern of smad expression among testicular cells, primarily observed in spermatogonia (smad 2, 3a, 3b, 8), spermatocytes (smad 2, 3a, 8), Sertoli cells (smad 1, 3a, 3b), and Leydig cells (smad 1, 2). This finding supports the notion that inhibition of TGF-ß and BMP signaling pathways may predominantly impact cellular components within the spermatogonial niche, namely spermatogonia, Sertoli, and Leydig cells. In conclusion, our study demonstrated that TGF-ß and BMP signaling pathways exert antagonistic roles in the zebrafish germ stem cell niche. The members of the TGF-ß subfamily are mainly involved in maintaining the undifferentiated state of spermatogonia, while the BMP subfamily promotes spermatogonial differentiation. Therefore, in the complex regulation of the germ stem cell niche by Fsh, members of the BMP subfamily (pro-differentiation) should be more predominant in the niche than those belonging to the TGF-ß (anti-differentiation). Overall, these findings are not only relevant for understanding the regulation of germ stem cell niche but may also be useful for expanding in vitro the number of undifferentiated spermatogonia more efficiently than using recombinant hormones or growth factors.


Assuntos
Pirazóis , Espermatogônias , Tiossemicarbazonas , Peixe-Zebra , Animais , Masculino , Espermatogônias/metabolismo , Peixe-Zebra/genética , Hormônio Foliculoestimulante/farmacologia , Hormônio Foliculoestimulante/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Testículo/metabolismo , Diferenciação Celular/genética , RNA Mensageiro/genética , Espermatogênese/genética
5.
PLoS One ; 18(11): e0295012, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38032914

RESUMO

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.


Assuntos
Antineoplásicos , Melanoma , Tiossemicarbazonas , Humanos , Limoneno/farmacologia , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Simulação de Acoplamento Molecular , Proliferação de Células , Melanoma/tratamento farmacológico , Melanoma/patologia , Apoptose , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais
6.
Sci Rep ; 13(1): 19735, 2023 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-37957227

RESUMO

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


Assuntos
Esquistossomose mansoni , Esquistossomose , Esquistossomicidas , Tiossemicarbazonas , Animais , Chlorocebus aethiops , Schistosoma mansoni , Células Vero , Esquistossomicidas/farmacologia , Tiossemicarbazonas/farmacologia , Hidrazonas/farmacologia , Hemoglobinas/farmacologia , Esquistossomose mansoni/tratamento farmacológico
7.
Future Microbiol ; 18: 1225-1233, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37882752

RESUMO

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


Assuntos
Sporothrix , Tiazolidinedionas , Tiossemicarbazonas , Animais , Camundongos , Antifúngicos/farmacologia , Itraconazol/farmacologia , Tiossemicarbazonas/farmacologia , Testes de Sensibilidade Microbiana
8.
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
9.
Chempluschem ; 88(12): e202300500, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37726222

RESUMO

Invited for this month's cover are the collaborating groups of Esteban Rodríguez-Arce from the University of Chile and María Contel from The City University of New York Brooklyn College. The cover picture shows "Supergold" a very powerful gender neutral warrior with superpowers who fights against cancer! The warrior's golden armor and sword represent the pharmacological power of the gold atom. Engraved on the shield, the gold-thiosemicarbazone molecules are the warrior's coat of arms. Supergold selectively destroys different cancer cells. More information can be found in the Research Article by Esteban Rodríguez-Arce, María Contel, and co-workers.


Assuntos
Ouro , Tiossemicarbazonas , Humanos , Ouro/farmacologia , Tiossemicarbazonas/farmacologia , Masculino , Feminino , Antineoplásicos/farmacologia
10.
Future Med Chem ; 15(11): 959-985, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37435731

RESUMO

Aim: Discovery of novel SARS-CoV-2 main protease (Mpro) inhibitors using a structure-based drug discovery strategy. Materials & methods: Virtual screening employing covalent and noncovalent docking was performed to discover Mpro inhibitors, which were subsequently evaluated in biochemical and cellular assays. Results: 91 virtual hits were selected for biochemical assays, and four were confirmed as reversible inhibitors of SARS CoV-2 Mpro with IC50 values of 0.4-3 µM. They were also shown to inhibit SARS-CoV-1 Mpro and human cathepsin L. Molecular dynamics simulations indicated the stability of the Mpro inhibitor complexes and the interaction of ligands at the subsites. Conclusion: This approach led to the discovery of novel thiosemicarbazones as potent SARS-CoV-2 Mpro inhibitors.


Assuntos
COVID-19 , Tiossemicarbazonas , Humanos , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/química , Tiossemicarbazonas/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Proteínas não Estruturais Virais
11.
Int J Mol Sci ; 24(14)2023 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-37511201

RESUMO

The current research describes the synthesis and characterization of 2-acetylpyridine N(4)-cyclohexyl-thiosemicarbazone ligand (HL) and their two metal complexes, [Au(L)Cl][AuCl2] (1) and [Pd(L)Cl]·DMF (2). The molecular structures of the compounds were determined by physicochemical and spectroscopic methods. Single crystal X-ray diffraction was employed in the structural elucidation of the new complexes. The complexes showed a square planar geometry to the metal center Au(III) and Pd(II), coordinated with a thiosemicarbazone molecule by the NNS-donor system and a chloride ion. Complex (1) also shows the [AuCl2]- counter-ion in the asymmetric unit, and complex (2) has one DMF solvent molecule. These molecules play a key role in the formation of supramolecular structures due to different interactions. Noncovalent interactions were investigated through the 3D Hirshfeld surface by the dnorm function and the 2D fingerprint plots. The biological activity of the compounds was evaluated in vitro against the human glioma U251 cells. The cytotoxicity results revealed great antitumor activity in complex (1) compared with complex (2) and the free ligand. Molecular docking simulations were used to predict interactions and properties with selected proteins and DNA of the synthesized compounds.


Assuntos
Antineoplásicos , Complexos de Coordenação , Tiossemicarbazonas , Humanos , Simulação de Acoplamento Molecular , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Paládio/farmacologia , Paládio/química , Ouro/química , Ligantes , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Estrutura Molecular , Cristalografia por Raios X , Antineoplásicos/química
12.
Chempluschem ; 88(12): e202300115, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37191319

RESUMO

This work describes the synthesis of four gold(I) [AuClL] compounds containing chloro and biologically active protonated thiosemicarbazones based on 5-nitrofuryl (L=HSTC). The stability of the compounds in dichloromethane, DMSO, and DMSO/culture media solutions was investigated by spectroscopy, cyclic voltammetry, and conductimetry, indicating the formation overtime of cationic monometallic [Au(HTSC)(DMSO)]± or [Au(HTSC)2 ]± , and/or dimeric species. Neutral [{Au(TSC)}2 ] species were obtained from one of the compounds in dichlomethane/n-hexane solution and characterized by X-ray crystallography revealing a Au-Au bond, and deprotonated thiosemicarbazone (TSC). The cytotoxicity of the gold compounds and thiosemicarbazone ligands was evaluated against selected cancer cell lines and compared to that of Auranofin. Studies of the most stable, cytotoxic, and selective compound on a renal cancer cell line (Caki-1) demonstrated its relevant antimigratory and anti-angiogenic properties, and preferential accumulation in the cell nuclei. Its mode of action seems to involve interaction with DNA, and subsequent cell death via apoptosis.


Assuntos
Antineoplásicos , Tiossemicarbazonas , Ouro , Linhagem Celular Tumoral , Dimetil Sulfóxido , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química
13.
J Inorg Biochem ; 245: 112239, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37148641

RESUMO

Chalcone and thiosemicarbazone have attracted attention due to their easy synthetic procedure and high success in the development of antiviral and antitumor, however, there are few biological data on the evaluation of chalcone-thiosemicarbazone hybrids and their complexation with metal ions. In this sense, the present work reports the synthesis and characterization of the hybrid (Z)-2-((E)-3-(4-chlorophenyl)-1-phenylallylidene)hydrazine-1-carbothioamide (CTCl) and its Zn(II)-complex (CTCl-Zn). The compounds were cell-based evaluated in terms of cytotoxicity against human T-cell lymphotropic virus type 1 (HTLV-1) infected leukemia cells (MT-2) and the experimental data were correlated with molecular docking calculations. The ligand and Zn(II)-complex were easily synthesized with a good yield - 57% and 79%, respectively. The dynamic of E/Z isomers with respect to the imine bond configuration of CTCl was evidenced by 1H NMR experiments in DMSO­d6, while the X-ray diffraction of CTCl-Zn showed that Zn(II) ion is tetracoordinated to two ligands in a bidentate mode and the metal ion lies on an intermediate geometry between the see-saw and trigonal pyramid. The ligand and complex exhibited low toxicity and the Zn(II)-complex is more cytotoxic than the ligand, with the corresponding IC50 value of 30.01 and 47.06 µM. Both compounds had a pro-apoptotic effect without the release of reactive oxygen species (ROS) and they can interact with DNA via minor grooves driven by van der Waals forces.


Assuntos
Antineoplásicos , Chalcona , Chalconas , Vírus Linfotrópico T Tipo 1 Humano , Tiossemicarbazonas , Humanos , Tiossemicarbazonas/química , Ligantes , Simulação de Acoplamento Molecular , Vírus Linfotrópico T Tipo 2 Humano , Zinco/química , Antineoplásicos/química
14.
Eur J Med Chem ; 254: 115345, 2023 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-37054562

RESUMO

Based on the activity of 23 TSCs on CZ taken from the literature, we have developed a QSAR model for predicting the activity of TSCs. New TSCs were designed and then tested against CZP, resulting in inhibitors with IC50 values in the nanomolar range. The modelling of the corresponding TSC-CZ complexes by molecular docking and QM/QM ONIOM refinement indicates a binding mode compatible with what was expected for active TSCs, according to a geometry-based theoretical model previously developed by our research group. Kinetic experiments on CZP suggest that the new TSCs act by a mechanism that involves the formation of a reversible covalent adduct with slow association and dissociation kinetics. These results demonstrate the strong inhibitory effect of the new TSCs and the benefit of the combined use of QSAR and molecular modelling techniques in the design of new and potent CZ/CZP inhibitors.


Assuntos
Tiossemicarbazonas , Tiossemicarbazonas/química , Simulação de Acoplamento Molecular , Cisteína Endopeptidases , Proteínas de Protozoários
15.
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
16.
Int J Biol Macromol ; 234: 123606, 2023 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-36773880

RESUMO

In this work we will discuss the antiproliferative evaluation and the possible mechanisms of action of indole-thiosemicarbazone compounds LTs with anti-inflammatory activity, previously described in the literature. In this perspective, some analyzes were carried out, such as the study of binding to human serum albumin (HSA) and to biological targets: DNA and human topoisomerase IIα (topo). Antiproliferative study was performed with DU-145, Jukart, MCF-7 and T-47D tumor lines and J774A.1, besides HepG2 macrophages and hemolytic activity. In the HSA interaction tests, the highest binding constant was 3.70 × 106 M-1, referring to LT89 and in the fluorescence, most compounds, except for LT76 and LT87, promoted fluorescent suppression with the largest Stern-Volmer constant for the LT88 3.55 × 104. In the antiproliferative assay with DU-145 and Jurkat strains, compounds LT76 (0.98 ± 0.10/1.23 ± 0.32 µM), LT77 (0.94 ± 0.05/1.18 ± 0.08 µM) and LT87 (0.94 ± 0.12/0.84 ± 0.09 µM) stood out, due to their IC50 values mentioned above. With the MCF-7 and T-47D cell lines, the lowest IC50 was presented by LT81 with values of 0.74 ± 0.12 µM and 0.68 ± 0.10 µM, respectively, followed by the compounds LT76 and LT87. As well as the positive control amsacrine, the compounds LT76, LT81 and LT87 were able to inhibit the enzymatic action of human Topoisomerase IIα.


Assuntos
Antineoplásicos , Tiossemicarbazonas , Humanos , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Antineoplásicos/química , Relação Estrutura-Atividade , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Linhagem Celular Tumoral , Inibidores da Topoisomerase II/farmacologia , DNA/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Indóis/farmacologia , Indóis/química , Proliferação de Células
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.
Curr Top Med Chem ; 23(6): 426-439, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36567284

RESUMO

BACKGROUND: Zika virus (ZIKV) remains an important cause of congenital infection, fetal microcephaly, and Guillain-Barré syndrome in the population. In 2016, WHO declared a cluster of microcephaly cases and other neurological disorders reported as a global public health emergency in Brazil. There is still no specific treatment for Zika virus fever, only palliative care. Therefore, there is a need for new therapies against this disease. According to the literature, thiosemicarbazone, phthalimide and thiazole are privileged structures with several biological activities, including antiviral activity against various viruses. OBJECTIVE: Based on this, this work presents an antiviral screening using previously synthesized compounds derived from thiosemicarbazone, phthalimide, and thiazole as new hits active against ZIKV. METHODS: After synthesis and characterization, all compounds were submitted to Cytotoxicity by MTT and Antiviral activity against ZIKV assays. RESULTS: Compounds 63, 64, 65, and 73 exhibited major reductions in the ZIKV title from this evaluation. Compounds 63 (99.74%), 64 (99.77%), 65 (99.92%), and 73 (99.21%) showed a higher inhibition than the standard 6MMPr (98.74%) at the CC20 dose. These results revealed new chemical entities with anti-ZIKV activity. CONCLUSION: These derivatives are promising candidates for further assays. In addition, the current approach brings a new privileged scaffolding, which may drive future drug discovery for ZIKV.


Assuntos
Microcefalia , Tiossemicarbazonas , Infecção por Zika virus , Zika virus , Humanos , Microcefalia/tratamento farmacológico , Tiossemicarbazonas/farmacologia , Infecção por Zika virus/epidemiologia , Antivirais/farmacologia , Antivirais/uso terapêutico
19.
Curr Med Chem ; 30(5): 558-572, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-34951353

RESUMO

The discovery of the anticancer activity of cisplatin has marked the emergence of modern Inorganic Medicinal Chemistry. This field of research is concerned with the application of inorganic compounds to therapy or diagnosis of disease. In particular, metal coordination of bioactive ligands has gained recognition in drug design. The interaction between transition metal ions and the organic drugs could enhance their diagnostic and therapeutic potentials by improving the stability and/or bioavailability or by achieving a metal-drug synergism through a dual or multiple mechanisms of action. The isosteric replacement of sulfur by selenium in thiosemicarbazones leads to selenosemicarbazones. This class of compounds exhibits numerous biological activities like antitumor, antimicrobial, antiviral, etc. and, in most cases, they were more pronounced in comparison to the sulfur analogues. On the other hand, while the effect of transition metal complexation on the biological activity of thiosemicarbazones has been widely studied, the pharmacological activity of the corresponding metal-selenosemicarbazone compounds has been less explored. In this work, the most relevant results related to the selenosemicarbazone metal complexes as potential metal-based drugs have been reviewed.


Assuntos
Complexos de Coordenação , Tiossemicarbazonas , Elementos de Transição , Humanos , Complexos de Coordenação/farmacologia , Metais/química , Enxofre , Tiossemicarbazonas/farmacologia , Compostos de Selênio/química , Compostos de Selênio/farmacologia , Semicarbazonas/química , Semicarbazonas/farmacologia
20.
J Inorg Biochem ; 237: 111995, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36152470

RESUMO

In the present work, the synthesis, characterization, antifungal activity, molecular docking study and in silico approach of five thiosemicarbazone derivatives and their corresponding zinc(II) complexes are described. The compounds were characterized by elemental analysis, IR, UV-Vis and NMR spectroscopic measurements, molar conductivity measurements, emission spectra, high-resolution mass spectrometry and X ray study. The antifungal activity of the free ligands and synthesized compounds was preliminarily evaluated against Candida albicans (ATCC 90028), Candida tropicalis (ATCC 13803) and Candida glabrata (ATCC 2001), by the minimum inhibitory concentration (MIC) assay. Two complexes, 4 (MIC = 3.18 to 6.37 µM) and 5 (MIC = 25.95 µM for all) showed promising results, being highly active against all strains evaluated. The X-ray analyses shown that the complex 2 crystallizes in the centrosymmetric space group P21/c of the monoclinic system and the coordination sphere around zinc(II) atom is better described as slightly distorted octahedral. The Hirshfeld surface (HS) analysis showed that non-classical H···H and C···H/H···C contacts contribute with 65.9% while the S···H and N···H (21%) and Cl···H and O···H interactions (12%) complete the HS area. The molecular docking results, performed against CYP51 enzyme (sterol 14α-demethylase) of C. albicans and C. glabrata shows that the complexes 4 (ΔG = -10.75 and - 12.90 kcal/ mol) and 5 (ΔG = -11.12 and - 14.53 kcal/ mol) showed the highest binding free energies of all compounds. The ADME-Tox (absorption, distribution, metabolism, excretion and toxicity) in silico parameters evaluated showed promising results for all compounds.


Assuntos
Complexos de Coordenação , Tiossemicarbazonas , Simulação de Acoplamento Molecular , Antifúngicos/química , Zinco/química , Ligantes , Tiossemicarbazonas/química , Testes de Sensibilidade Microbiana , Candida albicans , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Estrutura Molecular
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