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1.
Int J Mol Sci ; 23(15)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35955683

RESUMO

Anticancer therapy by anthracyclines often leads to the development of multidrug resistance (MDR), with subsequent treatment failure. Thiosemicarbazones have been previously suggested as suitable anthracycline partners due to their ability to overcome drug resistance through dual Pgp-dependent cytotoxicity-inducing effects. Here, we focused on combining anthracyclines (doxorubicin, daunorubicin, and mitoxantrone) and two thiosemicarbazones (DpC and Dp44mT) for treating cell types derived from the most frequent pediatric solid tumors. Our results showed synergistic effects for all combinations of treatments in all tested cell types. Nevertheless, further experiments revealed that this synergism was independent of Pgp expression but rather resulted from impaired DNA repair control leading to cell death via mitotic catastrophe. The downregulation of checkpoint kinase 1 (CHEK1) expression by thiosemicarbazones and the ability of both types of agents to induce double-strand breaks in DNA may explain the Pgp-independent synergism between anthracyclines and thiosemicarbazones. Moreover, the concomitant application of these agents was found to be the most efficient approach, achieving the strongest synergistic effect with lower concentrations of these drugs. Overall, our study identified a new mechanism that offers an avenue for combining thiosemicarbazones with anthracyclines to treat tumors regardless the Pgp status.


Assuntos
Antraciclinas , Tiossemicarbazonas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antraciclinas/farmacologia , Antibióticos Antineoplásicos , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/metabolismo , Criança , Dano ao DNA , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Humanos , Tiossemicarbazonas/farmacologia , Inibidores da Topoisomerase II
2.
Med Oncol ; 39(10): 157, 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35861942

RESUMO

In this study, firstly, 22 thiosemicarbazone derivatives (3a-y) were synthesized. Then, ADME parameters, pharmacokinetic properties, drug-like structures, and suitability for medicinal chemistry of these molecules were studied theoretically by using SwissADME and admetSAR programs. According to the results of these theoretical studies, it can be said that the bioavailability and bioactivity of these compounds may be high. In silico molecular docking between ligands (thiosemicarbazone derivatives) and targeted proteins (protein-78 (GRP78) for C6 and quinone reductase-2 (4ZVM for MCF 7) was analyzed using Hex 8.0.0 docking software. According to the docking data, almost all molecules had higher negative E values than Imatinib (already used as a drug). For this, in vitro anticancer studies of these molecules were done. The cytotoxic activities of thiosemicarbazone derivatives (3a-y) were evaluated on C6 glioma and MCF7 breast cancer cell lines at 24 h, and Imatinib was used as the positive control. According to the results of the cytotoxicity assay, it can be said that the five compounds (3b, c, f, g, and m with IC50 = 10.59-9.08 µg/mL; Imatinib IC50 = 11.68 µg/mL) showed more potent cytotoxic activity than Imatinib on C6 cell line. Together with to these results ten compounds (3b, d, f, g, I, k, l, m, n, and r with IC50 = 7.02-9.08 µg/mL; Imatinib IC50 = 9.24 µg/mL) had a more effective cytotoxic activity against MCF7 cell line than Imatinib. Compound 3 m showed the highest antiproliferative effect against C6 and MCF7 cell lines.


Assuntos
Antineoplásicos , Tiossemicarbazonas , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Mesilato de Imatinib/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia
3.
Sci Rep ; 12(1): 12878, 2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35896584

RESUMO

To develop innovative mesoporous crosslinked poly(azomethine- sulfone)s with environmental applications, a simple Schiff base condensation technique based on barbituric acid BA or condensed terephthaldehyde barbituric acid TBA in their structures as monomeric units are applied. Different analysis methodologies and viscosity measurements identify them as having stronger heat stability and an amorphous structure. The photophysical features of the multi stimuli response MSR phenomenon are observable, with white light emission at higher concentrations and blue light emission at lower concentrations. Their emission characteristics make them an excellent metal ions sensor through diverse charge transfer methods. They can have a better inhibition efficiency and be employed as both mixed-type and active corrosion inhibitors according to their fluorescence emission with metals, demonstrating their capacity to bind with diverse metals. The adsorption of two distinct dye molecules, Methylene blue MB cationic and sunset yellow SY anionic, on the mesoporous structures of the polymers is investigated, revealing their selectivity for MB dye adsorption. Quantum studies support these amazing discoveries, demonstrating a crab-like monomeric unit structure for the one that is heavily crosslinked.


Assuntos
Corantes , Azul de Metileno , Adsorção , Compostos Azo , Corantes/química , Azul de Metileno/química , Porosidade , Sulfonas , Tiossemicarbazonas
4.
Carbohydr Polym ; 294: 119839, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-35868782

RESUMO

Personal protective equipment (PPE) is vital in battling bacteria crisis, but conventional PPE materials lack antimicrobial activities and environmental friendliness. Our work focused on developing biodegradable and antibacterial fibers as promising bioprotective materials. Here, we grafted highly effective antibacterial copper-thiosemicarbazone complexes (CT1-4) on cellulose fibers via covalent linkages. Multiple methods were used to characterize the chemical composition or morphology of CT1-4 conjugated-fibers. Conjugation of CT1-4 maintains the mechanical properties (Breaking strength: 2.35-2.45 cN/dtex, Breaking elongation: 7.19 %-7.42 %) and thermal stability of fibers. CT1 can endow cellulose fibers with the excellent growth inhibition towards Escherichia coli (E. coli) (GIR: 61.5 % ± 1.28 %), Staphylococcus aureus (S. aureus) (GIR: 85.7 % ± 1.93 %), and Bacillus subtilis (B. subtilis) (GIR: 87.6 % ± 1.44 %). We believe that the application of CT1 conjugated-cellulose fibers is not limited to the high-performance PPE, and also can be extended to various types of protective equipment for food and medicine safety.


Assuntos
Celulose , Tiossemicarbazonas , Antibacterianos/química , Antibacterianos/farmacologia , Bacillus subtilis , Celulose/química , Celulose/farmacologia , Cobre/química , Cobre/farmacologia , Escherichia coli , Staphylococcus aureus , Tiossemicarbazonas/farmacologia
5.
Int J Mol Sci ; 23(15)2022 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-35897736

RESUMO

A new series of thiophene-based azomethines differing in the core structure was synthesized. The effect of the central core structure in azomethines on the thermal, optical and electrochemical properties was investigated. The obtained compounds exhibited the ability to form a stable amorphous phase with a high glass transition temperature above 100 °C. They were electrochemically active and undergo oxidation and reduction processes. The highest occupied (HOMO) and the lowest unoccupied molecular (LUMO) orbitals were in the range of -3.86--3.60 eV and -5.46--5.17 eV, respectively, resulting in a very low energy band gap below 1.7 eV. Optical investigations were performed in the solvents with various polarity and in the solid state as a thin film deposited on a glass substrate. The synthesized imines absorbed radiation from 350 to 600 nm, depending on its structure and showed weak emission with a photoluminescence quantum yield below 2.5%. The photophysical investigations were supported by theoretical calculations using the density functional theory. The synthesized imines doped with lithium bis-(trifluoromethanesulfonyl)imide were examined as hole transporting materials (HTM) in hybrid inorganic-organic perovskite solar cells. It was found that both a volume of lithium salt and core imine structure significantly impact device performance. The best power conversion efficiency (PCE), being about 35-63% higher compared to other devices, exhibited cells based on the imine containing a core tiphenylamine unit.


Assuntos
Ésteres , Tiofenos , Compostos Azo , Iminas , Lítio , Tiofenos/química , Tiossemicarbazonas
6.
Spectrochim Acta A Mol Biomol Spectrosc ; 281: 121590, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-35850043

RESUMO

A group of 5-methylsalicylaldehyde thiosemicarbazone derivatives (HMTs) bearing different lipophilic and steric substituents attached at the 3-position of cresol ring were synthesized and investigated as mushroom tyrosinase (TYR) inhibitors. The ability of HMTs to inhibit the diphenolase activity of TYR was evaluated with L-DOPA as substrate by determining IC50 values in relation to their structure modifications. HMTs displayed distinct inhibitory competencies towards TYR activity with IC50 values in the range of 1.02-143.56 µM. A close correlation between their inhibition potency and both lipophilicity and molecular size was observed. The inhibitory effect of the hydroxyethyl-containing derivatives was much higher than the hydroxyethyl-free ones overall. Among them, HMT-NBO exhibited the most potent effect with IC50 of 5.85 µM, which was nearly 25-fold and 3.8-fold lower than its parent HMT-NBE and the control kojic acid, respectively. The hydroxyethyl clearly benefited the improvement of the inhibitory competences and acted as a regulating group of lipophilicity of the inhibitors. The kinetic analyses showed that HMTs were reversible and mixed type inhibitors against mushroom TYR. The inhibition mechanism was studied by means of fluorescence spectroscopy, FT-IR, ESI-MS and molecular docking analysis. The results indicated that the observed inhibitory effect of HMTs was accomplished by acting on the amino acid residues rather than by chelating the centre copper ions of TYR. Each of HMTs can insert the hydrophobic pocket and interact with the residues of TYR through Van der Waals forces and hydrogen bonds, with additional electrostatic interactions for HMT-NEE and HMT-NEO further strengthening the affinity. Meanwhile, the inhibitors were observed to bind with L-DOPA or/and L-DOPAquinone forming 1:1 stoichiometric complexes, probably exerting indirect inhibition against TYR activity.


Assuntos
Agaricales , Tiossemicarbazonas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Levodopa , Simulação de Acoplamento Molecular , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade , Tiossemicarbazonas/farmacologia
7.
Molecules ; 27(14)2022 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-35889421

RESUMO

The structure assignment and conformational analysis of the thiosemicarbazones, DKI21 and DKI24, were performed through homonuclear and heteronuclear 2D Nuclear Magnetic Resonance (NMR) spectroscopy (2D-COSY, 2D-NOESY, 2D-ROESY, 2D-HSQC, and 2D-HMBC) and quantum mechanics (QM) calculations, using Functional Density Theory (DFT). In addition, utilizing a combination of 2D-NOESY and 2D-ROESY spectra an exo structure was established for both of the analogs. This experimental results were confirmed by theoretical mechanistic studies, as the lowest minima conformations derived through DFT calculations were compatible with the spatial correlations observed in the 2D-NOESY and 2D-ROESY spectra. Finally, molecular binding experiments were performed to detect the potential targets for DKI21 and DKI24, derived from SwissAdme. In silico molecular binding experiments showed favorable binding energy values for the most of the enzymes studied. The ADMET calculations, using the preADMET and pKCSm software, showed that the two molecules appear as possible drug leads.


Assuntos
Tiossemicarbazonas , Espectroscopia de Ressonância Magnética , Conformação Molecular , Ressonância Magnética Nuclear Biomolecular/métodos , Software
8.
J Mol Model ; 28(8): 234, 2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35895241

RESUMO

The mechanism of host-guest interaction of receptors towards fluoride ion has been investigated using computational methods. To distinguish the effect of aromaticity in host-guest interaction, we investigated unsubstituted (ATSC) and phenyl-substituted (APTSC) anthracene thiosemicarbazones towards different ions. In the ground state of receptor-fluoride complex, the added fluoride ion made hydrogen bond through N - H…F…H - N, whereas the intramolecular hydrogen bonding was through F - H…N in the excited state of receptor-fluoride complex. Experimental absorption and emission spectra were well reproduced by the calculated vertical excitation energies. The transition state (TS) calculations were performed to understand the thermodynamic features and mechanism of host-guest interaction. The natural bond orbital analyses show that the second perturbation energy for donor-acceptor interaction of F- with hydrogen is more than 300 kcal/mol-1 at the excited state of receptor-fluoride complex, which indicates the strong single bond between fluoride and hydrogen atom. The PES scan confirms that deprotonation took place at the excited state of receptor-fluoride complex. The results indicate the excited-state proton transfer (ESPT) process from N-H group nearby the anthracene moiety. The APTSC is a better chemosensor than ATSC. This infers that the aromaticity will increase the efficiency of fluorescence receptor towards fluoride ion. A schematic representation of sensing mode of anthracene-based thiosemicarbazones toward fluoride ion. The fluoride ion first makes a hydrogen bond with NH proton nearby anthracene moiety. The excited state proton transfer mechanism was confirmed by PES and NBO studies.


Assuntos
Prótons , Tiossemicarbazonas , Ânions/química , Antracenos , Teoria da Densidade Funcional , Fluoretos/química , Teoria Quântica , Espectrometria de Fluorescência
9.
Drug Deliv ; 29(1): 2206-2216, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35815732

RESUMO

Cancer is a leading cause of death worldwide and affects society in terms of the number of lives lost. Current cancer treatments are based on conventional chemotherapy which is nonspecific in targeting cancer. Therefore, intensive efforts are underway to better target cancer-specific cells while minimizing the side effects on healthy tissues by using LDL particles as active drug delivery vehicles. The goal is to encapsulate anticancer agents thiosemicarbazone metal-ligand complexes into LDL particles to increase the cytotoxic effect of the agent by internalization through LDL receptors into MCF7, A549, and C42 cancer cell lines as segregate models for biological evaluations targeting tubulin. Zeta potential data of LDL-particles encapsulated anticancer agents showed an acceptable diameter range between 66-91 nm and uniform particle morphology. The results showed cell proliferation reduction in all tested cell lines. The IC50 values of LDL encapsulated thiosemicarbazone metal-ligand complexes treated with MCF7, A549, and C42 ranged between 1.18-6.61 µM, 1.17-9.66 µM, and 1.01-6.62 µM, respectively. Western blot analysis showed a potent decrease in tubulin expression when the cell lines were treated with LDL particles encapsulated with thiosemicarbazone metal-ligand complexes as anticancer agents. In conclusion, the data provide strong evidence that LDL particles are used as an active drug delivery strategy for cancer therapy.


Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias da Próstata , Tiossemicarbazonas , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Humanos , Ligantes , Lipoproteínas LDL , Pulmão , Masculino , Tiossemicarbazonas/farmacologia , Tubulina (Proteína)
10.
Bioorg Chem ; 127: 105928, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35717802

RESUMO

The superbug infection mediated by metallo-ß-lactamases (MßLs) has grown into anemergent health threat, and development of MßL inhibitors is an ideal strategy to combat the infection. In this work, twenty-five thiosemicarbazones 1a-e, 2a-e, 3a-e, 4a-d, 5a-d and 6a-b were synthesized and assayed against MßLs ImiS, NDM-1 and L1. The gained molecules specifically inhibited NDM-1 and ImiS, exhibiting an IC50 value in the range of 0.37-21.35 and 0.45-8.76 µM, and 2a was found to be the best inhibitor, with an IC50 of 0.37 and 0.45 µM, respectively, using meropenem (MER) as substrate. Enzyme kinetics and dialysis tests revealed and confirmed by ITC that 2a is a time-and dose-dependent inhibitor of ImiS and NDM-1, it competitively and reversibly inhibited ImiS with a Ki value of 0.29 µM, but irreversibly inhibited NDM-1. Structure-activity relationship disclosed that the substitute dihydroxylbenzene significantly enhanced inhibitory activity of thiosemicarbazones on ImiS and NDM-1. Most importantly, 1a-e, 2a-e and 3a-b alone more strongly sterilized E. coli-ImiS and E. coli-NDM-1 than the MER, displaying a MIC value in the range of 8-128 µg/mL, and 2a was found to be the best reagent with a MIC of 8 and 32 µg/mL. Also, 2a alone strongly sterilized the clinical isolates EC01, EC06-EC08, EC24 and K. pneumonia-KPC-NDM, showing a MIC value in the range of 16-128 µg/mL, and exhibited synergistic inhibition with MER on these bacteria tested, resulting in 8-32-fold reduction in MIC of MER. SEM images shown that the bacteria E. coli-ImiS, E. coli-NDM-1, EC24, K. pneumonia-KPC and K. pneumonia-KPC-NDM treated with 2a (64 µg/mL) suffered from distortion, emerging adhesion between individual cells and crumpled membranes. Mice tests shown that monotherapy of 2a evidently limited growth of EC24 cells, and in combination with MER, it significantly reduced the bacterial load in liver and spleen. Docking studies suggest that the 2,4-dihydroxylbenzene of 2a acts as zinc-binding group with the Zn(II) and the residual amino acids in CphA active center, tightly anchoring the inhibitor at active site. This work offered a promising scaffold for the development of MßLs inhibitors, specifically the antimicrobial for clinically drug-resistant isolates.


Assuntos
Tiossemicarbazonas , Inibidores de beta-Lactamases , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/metabolismo , Escherichia coli , Camundongos , Testes de Sensibilidade Microbiana , Tiossemicarbazonas/farmacologia , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo
11.
Bioorg Chem ; 127: 105968, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35728289

RESUMO

Vascular Endothelial Growth Factor II (VEGFR-2) has been proved as a rational target in cancer therapy. Although currently prescribed VEGFR-2 inhibitors are showing potent antitumor activity, they are often causing serious unwanted effects, restricting their extensive use as chemotherapeutics. Herein, after analyzing the structures of the effective VEGFR-2 inhibitor molecules, we report the synthesis of a new set of semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles with expected potency of inhibiting the VEGFR-2 signaling. The design of new compounds considered maintaining the essential pharmacophoric features of sorafenib for effective binding with the receptor target. All compounds have been evaluated for their growth inhibition effect against a panel of sixty cancer cells at the National Cancer Institute. Leukemia cancer cells, especially HL-60 and SR, were shown to be the most sensitive to the cytotoxic effect of new compounds. Thiosemicarbazones 21, 26, and 30 exhibited the best activity against almost all tested cancer cells. Therefore, a set of subsequent in vitro biological evaluations has been performed to understand the mechanistic effect of these compounds further. They inhibited the VEGFR-2 with IC50 values of 0.128, 0.413, and 0.067 µM respectively compared with 0.048 µM of Sorafenib. The probable mechanistic effect of 30 has been further evaluated on a number of apoptotic and antiapoptotic markers including BAX, BCL2, caspase-3, and caspase-9. Results revealed the potential of the thiosemicarbazone-linked triazole 30 to induce both the early and the late apoptosis, elevate BAX/BCL2 ratio, induce caspase-3 & caspase-9, and arrest the HL-60 cell cycle at the G2/M and G0-G1 phases. Molecular docking of new semicarbazones and thiosemicarbazones into the proposed biological target receptor has also been performed. Results of docking studies proved the potential of new semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles to effectively bind with crucial residues of the VEGFR-2 binding pocket.


Assuntos
Antineoplásicos , Leucemia Mieloide , Semicarbazonas , Tiossemicarbazonas , Antineoplásicos/química , Caspase 3/metabolismo , Caspase 9/metabolismo , Ciclo Celular , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Sorafenibe/farmacologia , Relação Estrutura-Atividade , Tiossemicarbazonas/química , Triazóis/química , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Proteína X Associada a bcl-2/metabolismo
12.
Chem Biol Interact ; 363: 109997, 2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-35654126

RESUMO

In order to examine the anticancer potential of oxovanadium(IV) complexes with thiosemicarbazone, two new complexes were prepared starting from 2-thenoyltrifluoroacetone-S-methylthiosemicarbazone. The complexes with tetradentate thiosemicarbazone ligand were characterized by elemental analysis, IR, ESI MS, and single-crystal X-ray diffraction analysis. Cytotoxicity on breast cancer cells, MDA-MB-231 and MCF-7, was determined by MTT assay. Cisplatin was positive control and the results were compared with those of the normal cells, HUVEC and 3T3. The complexes exhibited greater activity on cancer cells than cisplatin, but they were cytotoxic at several times higher concentrations in the healthy cells. In our study, the presence of thiophene and fluoro groups in the oxovanadium(IV) complexes with thiosemicarbazone increased greatly the cytotoxic activity of the complexes on breast cancer cells. Moreover, the complexes induced apoptosis-mediated cell death and also reduced the expression of MDR-1 or P-glycoprotein and ABCG2. As a result, the findings indicated that the complexes have selective cytotoxicity on breast cancer cells and can overcome multidrug resistance. These properties of the complexes make it possible to be a potential anticancer drug candidate for breast cancer treatment.


Assuntos
Antineoplásicos , Neoplasias da Mama , Complexos de Coordenação , Tiossemicarbazonas , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose , Neoplasias da Mama/tratamento farmacológico , Cisplatino/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Resistência a Medicamentos , Feminino , Humanos , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia
13.
Chem Commun (Camb) ; 58(56): 7805-7808, 2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35735739

RESUMO

An enantioselective synthesis of polycyclic fluorinated pyrrolidines has been achieved by Cu-catalyzed intramolecular 1,3-dipolar cycloaddition of azomethine ylides with fluorinated dipolarophiles. The method displays a wide scope and afforded the desired cycloadducts in high yields with up to 99% ee. These results demonstrate that fluoroalkyl substituents are excellent activating groups in this transformation.


Assuntos
Tiossemicarbazonas , Compostos Azo , Catálise , Reação de Cicloadição , Estereoisomerismo
14.
J Inorg Biochem ; 234: 111887, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35690039

RESUMO

Resistant bacteria represent an urgent worldwide threat. NDM-1-producing strains are rendering the last line antibiotics less effective. Six bismuth complexes of general formula BiLCl2, where L is a thiosemicarbazone bearing a quinoline moiety, have been synthesized and fully characterized, including their X-ray crystal structures. The synergistic relationship between the compounds and meropenem have been tested in a combination therapy in carbapenem-resistant Klebsiella pneumoniae (NTCT14331) carrying the NDM-1 gene. Quinoline-2-carboxaldehyde-N4-phenyl-3-thiosemicarbazone bismuth dichloride and carbapenem showed synergism in a dose dependent manner with negligible antibacterial activity when used in a monotherapy and could restore antibiotic sensitivity in the strain producing NDM-1 enzyme. The minimum inhibitory concentration (MIC) of meropenem lowered down 128 folds up to 2 µgmL-1, a concentration lower to the sensitivity level. The IC50 of the compound against A549 human lung carcinoma cells and HuDe human epithelial tissue was 46.96 ± 16.66 µM and 54.26 ± 9.89 µM respectively. The cytotoxicity against human cells was higher than the effective concentration needed for the synergistic effect in bacterial cells, indicating that a structural optimization of the compounds is needed.


Assuntos
Quinolinas , Tiossemicarbazonas , Antibacterianos/química , Antibacterianos/farmacologia , Bismuto/farmacologia , Carbapenêmicos/farmacologia , Humanos , Klebsiella pneumoniae , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Quinolinas/farmacologia , Tiossemicarbazonas/farmacologia , beta-Lactamases/genética
15.
Anal Chim Acta ; 1218: 340029, 2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35701038

RESUMO

We have designed and synthesised a novel fluorescent probe with a tetraphenylethylene (TPE) scaffold as an active fluorescent unit and thiosemicarbazide (TSC) group as a recognition unit. The probe, TPE-TSC, exhibited superior selectivity towards hypochlorite (ClO-) with a low limit of detection (2.0 nM). It also demonstrated a turn-off response for a brief period (<30 s) via an oxidation reaction. Furthermore, high-resolution mass spectrometry (HRMS) revealed that TPE-TSC reacted with ClO- by forming a carboxylic acid moiety in nearly 100% aqueous environments. More significantly, the probe detected ClO- in disinfectant, spiked milk samples, and spiked water samples. In all, TPE-TSC proposes an optimistic approach precisely for the determining the quality of milk and water contaminated with ClO- and trace amounts of ClO- in disinfectants.


Assuntos
Desinfetantes , Tiossemicarbazonas , Laticínios/análise , Desinfetantes/análise , Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Espectrometria de Fluorescência , Estilbenos , Tiossemicarbazonas/análise , Água/química
16.
Future Med Chem ; 14(13): 1005-1017, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35670251

RESUMO

Standard treatments have shown dismal activity against pancreatic cancer (PC), due in part to the development of a dense stroma (desmoplasia). This perspective discusses the development of the di-2-pyridylketone thiosemicarbazones that overcomes bidirectional oncogenic signaling between PC cells and pancreatic stellate cells (PSCs), which is critical for desmoplasia development. This activity is induced by the up-regulation of the metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1), which inhibits oncogenic signaling via HGF, IGF-1 and Sonic Hedgehog pathway. More recent studies have deciphered additional pathways including those mediated by Wnt and tenascin C that are secreted by PSCs to activate ß-catenin and YAP/TAZ signaling in PC cells. Suppression of bidirectional signaling between cell types presents a unique therapeutic opportunity.


Assuntos
Neoplasias Pancreáticas , Tiossemicarbazonas , Carcinogênese , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proteínas Hedgehog , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Tiossemicarbazonas/farmacologia
17.
Arch Pharm (Weinheim) ; 355(8): e2200023, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35500156

RESUMO

1-Methyl/ethyl/benzyl-5-(un)substituted 1H-indole-2,3-diones (2, 3, and 4) were synthesized by reaction of 5-(un)substituted 1H-indole-2,3-diones (1) with methyl iodide, ethyl chloride, and benzyl bromide. (3-Sulfamoylphenyl)isothiocyanate (6) was obtained by the treatment of 3-aminobenzenesulfonamide (5) with thiophosgene. Compound 6 was reacted with hydrazine to yield 4-(3-sulfamoylphenyl)thiosemicarbazide (7). Novel 1-(un)substituted/methyl/ethyl/benzyl-5-(un)substituted 1H-indole-2,3-dione 3-[4-(3-sulfamoylphenyl)thiosemicarbazone] derivatives (8-11) were prepared by condensation of 7 and 1-4. The structures of the synthesized compounds were confirmed by elemental analysis and spectral data. Inhibition of the widely distributed cytosolic off-targets human carbonic anhydrases (hCAs) I and II, and two tumor-associated membrane-bound isoforms (hCAs IX and XII), by 8-11 was investigated. The hCA II inhibitory effects of all tested compounds were in the subnanomolar to low nanomolar levels (Ki = 0.32-83.3 nM), and generally high selectivity for hCA II isoenzyme over hCA I, IX, and XII isoenzymes was observed. The strongest inhibitors of hCA II, 1-benzyl-5-(trifluoromethoxy)-substituted 11c (Ki = 0.32 nM) and 1-ethyl-5-chloro-substituted 10e (Ki = 0.35 nM), were docked within the enzyme active site. Molecular modeling studies with the most effective hCA IX and XII inhibitors were also carried out.


Assuntos
Anidrases Carbônicas , Tiossemicarbazonas , Anidrase Carbônica I , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Humanos , Indóis/farmacologia , Isoenzimas , Estrutura Molecular , Relação Estrutura-Atividade , Tiossemicarbazonas/farmacologia
18.
Chem Commun (Camb) ; 58(41): 6100-6103, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35503100

RESUMO

Thanks to metal- and catalyst-free electrochemical conditions in an undivided cell, a series of readily available redox-active N-(acyloxy)phthalimide esters led to an efficient and highly stereoselective addition (85 : 15 to 95 : 5 dr) of putative radical species to chiral (racemic and enantioenriched) C5-substituted azomethine imines to provide an array of 31 polyaminated hydrazine derivatives as a single diastereoisomer.


Assuntos
Ésteres , Iminas , Compostos Azo , Oxirredução , Estereoisomerismo , Tiossemicarbazonas
19.
Chem Commun (Camb) ; 58(45): 6510-6513, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35575428

RESUMO

A 1,3-cycloaddition reaction of 2-(tert-butyl)-8H-isoquinolino[4,3,2-de]phenanthridin-9-ium chloride to NiII norcorrole in the presence of base is shown to produce a family of chiral derivatives of polycyclic system(s) fused with pyrrole subunit(s) of the macrocycle. Dehydrogenation of the cycloaddition products gave rise to dibenzoullazine ortho-fused antiaromatic porphyrinoids.


Assuntos
Tiossemicarbazonas , Compostos Azo , Reação de Cicloadição , Estereoisomerismo
20.
Bioorg Chem ; 124: 105799, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35462235

RESUMO

The emerging COVID-19 pandemic generated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has severely threatened human health. The main protease (Mpro) of SARS-CoV-2 is promising target for antiviral drugs, which plays a vital role for viral duplication. Development of the inhibitor against Mpro is an ideal strategy to combat COVID-19. In this work, twenty-three hydroxamates 1a-i and thiosemicarbazones 2a-n were identified by FRET screening to be the potent inhibitors of Mpro, which exhibited more than 94% (except 1c) and more than 69% inhibition, and an IC50 value in the range of 0.12-31.51 and 2.43-34.22 µM, respectively. 1a and 2b were found to be the most effective inhibitors in the hydroxamates and thiosemicarbazones, with an IC50 of 0.12 and 2.43 µM, respectively. Enzyme kinetics, jump dilution and thermal shift assays revealed that 2b is a competitive inhibitor of Mpro, while 1a is a time-dependently inhibitor; 2b reversibly but 1a irreversibly bound to the target; the binding of 2b increased but 1a decreased stability of the target, and DTT assays indicate that 1a is the promiscuous cysteine protease inhibitor. Cytotoxicity assays showed that 1a has low, but 2b has certain cytotoxicity on the mouse fibroblast cells (L929). Docking studies revealed that the benzyloxycarbonyl carbon of 1a formed thioester with Cys145, while the phenolic hydroxyl oxygen of 2b formed H-bonds with Cys145 and Asn142. This work provided two promising scaffolds for the development of Mpro inhibitors to combat COVID-19.


Assuntos
COVID-19 , Tiossemicarbazonas , Animais , Antivirais/química , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus , Humanos , Camundongos , Simulação de Acoplamento Molecular , Pandemias , Inibidores de Proteases/química , SARS-CoV-2 , Tiossemicarbazonas/farmacologia
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