RESUMEN
A new complex of copper(II) with methyl-5-(trifluoromethyl)pyrazol-3-yl-ketazine (H2L) was synthesized with the composition [Cu2L2]âC2H5OH (1). Recrystallization of the sample from DMSO yielded a single crystal of the composition [Cu2L2((CH3)2SO)] (2). The coordination compounds were studied by single-crystal X-ray diffraction analysis, IR spectroscopy, and static magnetic susceptibility method. The data obtained indicate that the polydentate ligand is coordinated by both acyclic nitrogen and heterocyclic nitrogen atoms. The cytotoxic activity of the ligand and complex 1 was investigated on human cell lines MCF7 (breast adenocarcinoma), Hep2 (laryngeal carcinoma), A549 (lung carcinoma), HepG2 (hepatocellular carcinoma), and MRC5 (non-tumor lung fibroblasts). The complex was shown to have a pronounced dose-dependent cytotoxicity towards these cell lines with LC50 values in the range of 0.18-4.03 µM.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Cobre , Hidrazonas , Humanos , Cobre/química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Cristalografía por Rayos X , Estructura Molecular , Ligandos , Células MCF-7 , Células Hep G2RESUMEN
Six organotin(IV) complexes, viz., [Me2Sn(L)] (1), [n-Bu2Sn(L)] (2), [n-Oct2Sn(L)] (3), [Bz2Sn(L)]·0.5C7H8 (4), [n-BuSn(L)Cl] (5), and [PhSn(L)Cl] (6), were synthesized using a 2,6-diacetylpyridine bis(2-hydroxybenzoylhydrazone), H2L. Compounds were characterized by Fourier transform infrared (FT-IR), High-resolution mass spectrometry (HRMS), and solutions Fourier transform nuclear magnetic resonance (FT-NMR) spectroscopies. The structures 1-6 were established by single-crystal X-ray diffraction (SC-XRD) analysis. Diffraction results evidenced that complexes 1-6 were seven-coordinated mononuclear species with the equatorial plane comprising the pentagonal N3O2 chelate ring of the doubly deprotonated L and two axial ligands, either R (R = Me, n-Bu, n-Oct, Bz) or R (n-Bu or Ph) and Cl ligands. Additionally, the photophysical properties were examined due to the enhanced conjugation and rigidity of the molecules while thermogravimetric analysis was carried out to evaluate the thermal stabilities of compounds. The anti-proliferative activity of the complexes 1-6 was tested against prostate cancer cells (DU-145) and normal human embryonic kidney cells (HEK-293). Among the compounds, dibutyltin compound 2 exhibited increased anti-proliferative activity, with an IC50 value of 6.16 ± 1.56 µM. The investigation of its mechanism of action involves using AO/EB (acridine orange/ethidium bromide) and ROS (reactive oxygen species) generation assays. This likely detects apoptotic morphological alterations in the nucleus of the cells, with ROS generation ultimately leading to apoptosis and cell death. The superior activity of 2 may be attributed to the C···H contacts and respective higher de outside and di inside distances from the Hirshfeld surface. Thus, these compounds could be a promising alternative to classical chemotherapy agents.
Asunto(s)
Antineoplásicos , Proliferación Celular , Compuestos Orgánicos de Estaño , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos Orgánicos de Estaño/química , Compuestos Orgánicos de Estaño/farmacología , Compuestos Orgánicos de Estaño/síntesis química , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Cristalografía por Rayos X , Estructura Molecular , Piridinas/química , Piridinas/farmacologíaRESUMEN
Nowadays, searching for novel antimicrobial agents is crucial due to the increasing number of resistant bacterial strains. Moreover, cancer therapy is a major challenge for modern medicine. Currently used cytostatics have a large number of side effects and insufficient therapeutic effects. Due to the above-mentioned facts, we undertook research to synthesize novel compounds from the acylhydrazone group aimed at obtaining potential antimicrobial and anticancer agents. As a starting material, we employed hydrazides of 2-, 3- or 4-iodobenzoic acid, which gave three series of acylhydrazones in the condensation reaction with various aldehydes. The chemical structure of all obtained compounds was confirmed by IR, 1H NMR, and 13C NMR. The structure of selected compounds was determined by single-crystal X-ray diffraction analysis. Additionally, all samples were characterized using powder X-ray diffraction. The other issue in this research was to examine the possibility of the solvent-free synthesis of compounds using mechanochemical methods. The biological screening results revealed that some of the newly synthesized compounds indicated a beneficial antimicrobial effect even against MRSA-the methicillin-resistant Staphylococcus aureus ATCC 43300 strain. In many cases, the antibacterial activity of synthesized acylhydrazones was equal to or better than that of commercially available antibacterial agents that were used as reference substances in this research. Significantly, the tested compounds do not show toxicity to normal cell lines either.
Asunto(s)
Antibacterianos , Hidrazonas , Pruebas de Sensibilidad Microbiana , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Humanos , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Yodobenzoatos/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Estructura Molecular , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Cristalografía por Rayos X , Relación Estructura-Actividad , Antiinfecciosos/farmacología , Antiinfecciosos/química , Antiinfecciosos/síntesis químicaRESUMEN
3-Cyanopyridine derivatives are known for exhibiting excellent anticancer activity due to their strong capability to inhibit various biological targets, including Pim-1 kinase, survivin, and tubulin polymerization. On the other hand, N-acylhydrazones (NAH) are known to be a very versatile motif in medicinal chemistry and drug design. Based on these data, we report in this paper, the synthesis of novel 3-cyanopyridines incorporating N-acyl hydrazine scaffold, the evaluation of their cytotoxicity on the breast (MCF-7) and ovarian (A-2780) cancer cell lines and their antioxidant properties. Excluding 4a and 4d, all tested molecules exhibited high cytotoxicity against A-2780, with IC50 values ranging from 1.14 to 1.76 µM. Conversely, only four molecules 3d, 4b, 4c, and 4d demonstrated cytotoxicity against MCF-7, with IC50 values ranging from 1.14 to 3.38 µM. On the other hand, all the tested molecules exhibited a moderate antioxidant capacity in both the DPPH and metal chelation assays. Docking and molecular dynamics studies revealed that 2d, 3d, and 4d are potential inhibitors of tubulin and the Åstrogen receptor, which may explain their high cytotoxicity. These results are promising to study these newly synthesized 3-cyanopyridine-N-acylhydrazones in depth for use as potential anticancer candidates.
Asunto(s)
Antineoplásicos , Antioxidantes , Hidrazonas , Piridinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Piridinas/química , Piridinas/farmacología , Piridinas/síntesis química , Antioxidantes/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Células MCF-7 , Simulación del Acoplamiento Molecular , Línea Celular Tumoral , Teoría Funcional de la Densidad , Modelos MolecularesRESUMEN
In an effort to develop new and effective therapeutic agents for Alzheimer's disease, a series of hydrazone derivatives bearing piperidine rings have been designed and synthesized. The chemical structures of the compounds were characterized by various spectroscopic techniques. In vitro antioxidant and cholinesterase activities of the compounds were evaluated. Among the compounds, N12 exhibited the most antioxidant activity in all methods (CUPRAC, FRAP, DPPH, ABTS). In vitro acetylcholinesterase (AChE) activity results of the compounds showed good IC50 values between 14.124 ± 0.084 and 49.680 ± 0.110 µM were obtained (IC50 = 38.842 ± 0.053 µM for Donepezil). Among the compounds, N7 and N6 are much more effective derivatives than the standard compound donepezil with IC50 values of 14.124 ± 0.084 and 17.968 ± 0.072 µM, respectively. In vitro, butyrylcholinesterase (BChE) inhibition values of the compounds were between 13.505 ± 0.025 and 52.230 ± 0.027 µm. Among the compounds, N6 has the highest BChE inhibition with an IC50 value of 13.505 µm in the series. The cytotoxicity and AChE inhibitory activity of the compounds on SH-SY5Y cell lines were also evaluated. Kinetic studies were also performed to determine the behavior of the compounds as competitive or noncompetitive inhibitors. The binding modes of N6, which was determined to be highly effective according to in vitro analyses, with AChE and BChE were investigated using molecular docking studies, and the stability of the complexes was determined by molecular dynamics simulations. These findings indicated that AChE and BChE enzymes maintained their overall structural stability and compactness during interactions with compound N6.
Asunto(s)
Acetilcolinesterasa , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Diseño de Fármacos , Hidrazonas , Simulación del Acoplamiento Molecular , Piperidinas , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Hidrazonas/química , Piperidinas/farmacología , Piperidinas/química , Piperidinas/síntesis química , Butirilcolinesterasa/metabolismo , Acetilcolinesterasa/metabolismo , Humanos , Antioxidantes/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Relación Estructura-Actividad , Modelos MolecularesRESUMEN
In this paper, we present the synthesis and characterization of two known sulfonyl hydrazides (1 and 2) and their new sulfonyl hydrazone derivatives (9-20), as well as in vitro and in silico investigations of their cytotoxic properties against human lung (A549) and human breast (MCF-7) cancer cell lines. The target compounds (9-20) obtained in high yields were synthesized for the first time by a multi-step reaction, and their structures were confirmed by elemental analysis and various spectral techniques, including FT-IR, 1H-, and 13C-NMR. The antiproliferative profiles of these compounds (1, 2, and 9-20) in this study were determined at concentrations of 200, 100, 50, and 25 µM against selected cancer cell lines for 72 h using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. Except for compounds 1 and 2, other compounds (9-20) demonstrated cytotoxic activity at concentrations lower than 200 µM. The newly synthesized compounds (9-20) demonstrated antiproliferative activities at a micromolar level, with IC50 values in the range of 29.59-176.70 µM for the A549 cell line and 27.70-170.30 µM for the MCF-7 cell line. Among these compounds, compound 15 (IC50 = 29.59 µM against A549 cell line and IC50 = 27.70 µM against MCF-7 cell line) showed the highest cytotoxic activity against these two cancer cell lines compared to the reference drug cisplatin (IC50 = 22.42 µM against A549 cell line and IC50 = 18.01 µM against MCF-7 cell line). From docking simulations, to establish a plausible binding mode of compounds, we noticed that compound 15 demonstrated the highest affinity (-6.8508 kcal/mol) for estrogen receptor-beta (ERbeta) compared to others, suggesting promising ERbeta binding potential. Most compounds followed Lipinski's rule of five, with acceptable logP values. Additionally, all had mixed gastrointestinal absorption and limited blood-brain barrier permeability. Overall, our study proposed new sulfonyl hydrazones as a potential class of anticancer agents.
Asunto(s)
Antineoplásicos , Proliferación Celular , Diseño de Fármacos , Hidrazonas , Simulación del Acoplamiento Molecular , Humanos , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Células MCF-7 , Células A549 , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Línea Celular Tumoral , Ésteres/química , Ésteres/farmacologíaRESUMEN
In our ongoing work to create potential antifungal agents, we synthesized and tested a group of C1-substituted acylhydrazone ß-carboline analogues 9a-o and 10a-o for their effectiveness against Valsa mali, Fusarium solani, Fusarium oxysporum, and Fusarium graminearum. Their compositions were analyzed using different spectral techniques, such as 1H/13C NMR and HRMS, with the structure of 9l being additionally confirmed through X-ray diffraction. The antifungal evaluation showed that, among all the target ß-carboline analogues, compounds 9n and 9o exhibited more promising and broad-spectrum antifungal activity than the commercial pesticide hymexazol. Several intriguing findings regarding structure-activity relationships (SARs) were examined. In addition, the cytotoxicity test showed that these acylhydrazone ß-carboline analogues with C1 substitutions exhibit a preference for fungi, with minimal harm to healthy cells (LO2). The reported findings provide insights into the development of ß-carboline analogues as new potential antifungal agents.
Asunto(s)
Antifúngicos , Carbolinas , Fusarium , Hidrazonas , Pruebas de Sensibilidad Microbiana , Carbolinas/química , Carbolinas/farmacología , Carbolinas/síntesis química , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Relación Estructura-Actividad , Fusarium/efectos de los fármacos , Hidrazonas/farmacología , Hidrazonas/química , Hidrazonas/síntesis química , Estructura Molecular , HumanosRESUMEN
The data on the synthesis of N-aminomorpholine hydrazones are presented. It is shown that the interaction of N-aminomorpholine with functionally substituted benzaldehydes and 4-pyridinaldehyde in isopropyl alcohol leads to the formation of corresponding hydrazones. The structure of the synthesized compounds was studied by 1H and 13C NMR spectroscopy methods, including the COSY (1H-1H), HMQC (1H-13C) and HMBC (1H-13C) methodologies. The values of chemical shifts, multiplicity, and integral intensity of 1H and 13C signals in one-dimensional NMR spectra were determined. The COSY (1H-1H), HMQC (1H-13C), and HMBC (1H-13C) results revealed homo- and heteronuclear interactions, confirming the structure of the studied compounds. The antiviral, cytotoxic, and antimicrobial activity of some synthesized hydrazones were investigated. It is shown that 2-((morpholinoimino)methyl)benzoic acid has a pronounced viral inhibitory property, comparable in its activity to commercial drugs Tamiflu and Remantadine. A docking study was performed using the influenza virus protein models (1930 Swine H1 Hemagglutinin and Neuraminidase of 1918 H1N1 strain). The potential binding sites that are complementary with 2-((morpholinoimino)methyl)benzoic acid were found.
Asunto(s)
Hidrazonas , Simulación del Acoplamiento Molecular , Morfolinas , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Morfolinas/química , Morfolinas/farmacología , Morfolinas/síntesis química , Humanos , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Animales , Relación Estructura-Actividad , Pruebas de Sensibilidad Microbiana , Estructura MolecularRESUMEN
In search of small molecules for targeted therapy of non-small cell lung carcinoma (NSCLC), an efficient four-step synthetic route was followed for the synthesis of new imidazothiazole-hydrazone hybrids, which were assessed for their cytotoxic effects on human lung adenocarcinoma (A549) and human lung fibroblast (CCD-19Lu) cells. Among them, compounds 4, 6, 13, 16, 17 and 21 exhibited selective cytotoxic activity against A549 cell line. In vitro mechanistic studies were performed to assess their effects on apoptosis, caspase-3, cell cycle, EGFR and Akt in A549 cells. Compounds 6, 16, 17 and 21 promoted apoptotic cell death more than erlotinib. According to the in vitro data, it is quite clear that compound 6 promotes apoptosis through caspase-3 activation and arrests the cell cycle at the G0/G1 phase in A549 cells. Compounds 16 and 17 arrested the cell cycle at the S phase, whereas compounds 4, 13 and 21 caused the cell cycle arrest at the G2/M phase. The most effective EGFR inhibitor in this series was found as compound 13, followed by compounds 17 and 16. Furthermore, Akt inhibitory effects of compounds 16 and 17 in A549 cells were close to that of GSK690693. In particular, it can be concluded that the cytotoxic and apoptotic effects of compounds 16 and 17 are associated with their inhibitory effects on both EGFR and Akt. Molecular docking studies suggest that compounds 16 and 17 interact with crucial amino acid residues in the binding sites of human EGFR (PDB ID: 1M17) and Akt2 (PDB ID: 3D0E). Based on the in silico data, both compounds are predicted to possess favorable oral bioavailability and drug-likeness. Further studies are required to benefit from these compounds as anticancer agents for targeted therapy of NSCLC.
Asunto(s)
Antineoplásicos , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB , Hidrazonas , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas c-akt , Humanos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Hidrazonas/farmacología , Hidrazonas/química , Hidrazonas/síntesis química , Relación Estructura-Actividad , Apoptosis/efectos de los fármacos , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Tiazoles/química , Tiazoles/farmacología , Tiazoles/síntesis química , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Simulación del Acoplamiento Molecular , Relación Dosis-Respuesta a Droga , Ciclo Celular/efectos de los fármacosRESUMEN
In this paper, three different Zn(II) complexes with (E)-2-(2-(1-(6-bromopyridin-2-yl)ethylidene)hydrazinyl)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride (HLCl) have been synthesized and characterized by single crystal X-ray diffraction, elemental analysis, IR and NMR spectroscopy. All complexes are mononuclear, with the ligand (L) coordinated in a deprotonated formally neutral zwitterionic form via NNO donor set atoms. Complex 1 forms an octahedral geometry with the composition [ZnL2](BF4)2, while complexes 2 [ZnL(NCO)2] and 3 [ZnL(N3)2] form penta-coordinated geometry. Density functional theory (DFT) calculations were performed to enhance our understanding of the structures of the synthesized complexes and the cytotoxic activity of the complexes was tested against five human cancer cell lines (HeLa, A549, MDA-MB-231, K562, LS 174T) and normal human fibroblasts MRC-5. Additionally, antibacterial and antifungal activity of these complexes was tested against a panel of Gram-negative and Gram-positive bacteria, two fungal strains, and a yeast strain. It is noteworthy that all three complexes show selective antifungal activity comparable to that of amphotericin B. Molecular docking analysis predicted that geranylgeranyl pyrophosphate synthase, an enzyme essential for sterol biosynthesis, is the most likely target for inhibition by the tested complexes.
Asunto(s)
Antibacterianos , Antifúngicos , Antineoplásicos , Complejos de Coordinación , Teoría Funcional de la Densidad , Hidrazonas , Pruebas de Sensibilidad Microbiana , Zinc , Humanos , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Zinc/química , Zinc/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Estructura Molecular , Simulación del Acoplamiento Molecular , Ensayos de Selección de Medicamentos Antitumorales , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Modelos Moleculares , Hongos/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
PURPOSE: This study target the synthesis of 22 salicylhydrazones derivatives to apply in vitro screening to explore their potential in the search for new anti-TB prototypes drugs. METHODS: The minimum inhibitory concentration (MIC) were evaluated against Mycobacterium tuberculosis (Mtb) H37Rv and clinical isolates. Drug combination assay, cytotoxicity assay, ethidium bromide accumulation assay (EtBr) and in silico analysis regarding the absorption, distribution, metabolism, excretion and toxicity (ADMET) and pharmacological properties were also performed. RESULTS: Three most promising compounds were selected (10, 11 and 18) to proceed with screening tests. Compound 18 presented the lowest MIC value (0.49 µg/mL) against Mtb H37Rv strain, followed by compounds 11 (3.9 µg/mL) and 10 (7.8 µg/mL). All compounds showed activity against drug susceptible and resistant clinical isolates. Cytotoxicity results were promising for all salicylhydrazones, with SI values up to 4,205 for compound 18. The derivative 10 was the only one that demonstrated a non-promising cytotoxicity scenario for a single cell line. All derivatives showed an additive effect (FICI >0.5 to 4.0) in combination with isoniazid, ethambutol and rifampicin. CONCLUSION: All salicylhydrazones showed potential in the screening tests performed in this study and compound 18 stood out due to its activity against susceptible and resistant bacilli at low concentrations and low cytotoxicity.
Asunto(s)
Antituberculosos , Hidrazonas , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis , Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Hidrazonas/farmacología , Hidrazonas/síntesis química , Humanos , Evaluación Preclínica de Medicamentos/métodos , Relación Estructura-Actividad , AnimalesRESUMEN
A bisalicylhydrazone based fluorescence probe, bisalicyladehyde benzoylhydrazone (BS-BH), has been designed to detect Al3+. It exhibited high sensitivity and selectivity towards Al3+ in methanol-water media in physiological condition. Large stokes shifts (â¼122 nm) and over â¼1000-fold enhanced fluorescence intensity were observed, which was ascribed to the formation of the two relatively independent rigid extended π conjugated systems bridged by biphenyl group when binding with Al3+. A 1:2 binding ratio between BS-BH and Al3+ was shown by Job's plot. Based on the fluorescence titration data, the detection limit was down to 3.50 nM and the association constant was evaluated to be 1.12 × 109 M-2. The plausible fluorescence sensing mechanism of suppressed ESIPT, inhibited PET, activated CHEF and restricted C = N isomerization was confirmed by a variety of spectral experiments and DFT / TD-DFT calculations. The reversibility of recognition of Al3+ for probe BS-BH was validated by adding Na2-EDTA. In addition, the MTT assay showed the good biocompatibility of BS-BH and BS-BH could be used for imaging Al3+ in living cells.
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Aluminio , Colorantes Fluorescentes , Hidrazonas , Espectrometría de Fluorescencia , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Aluminio/análisis , Hidrazonas/química , Hidrazonas/síntesis química , Humanos , Límite de Detección , Células HeLaRESUMEN
Leishmaniasis is a disease caused by protozoa Leishmania spp., considered as a significant and urgent public health problem mainly in developing countries. In the absence of an effective vaccine, the treatment of infected people is one of the most commonly prophylactic measures used to control this disease. However, the therapeutic arsenal is reduced to a few drugs, with serious side effects and variability in efficacy. Attempting to this problem, in this work, a series of benzothiazole derivatives was synthetized and assayed against promastigotes and intracellular amastigotes of L. amazonensis, as well as the toxicity on macrophages. In addition, studies about the mechanism of action were also performed. Among the synthesized molecules, the substitution at position 4 of the aromatic ring appears to be critical for activity. The best compound exhibited IC50 values of 28.86 and 7.70 µM, against promastigotes and amastigotes of L. amazonensis, respectively, being more active than miltefosine, used as reference drug. The in silico analysis of physicochemical and pharmacokinetic (ADMET) properties of this compound suggested a good profile of oral bioavailability and safety. In conclusion, the strategy of using benzothiazole nucleous in the search for new antileishmanial agents was advantageous and preliminar data provide information about the mechanism of action as well as in silico parameters suggest a good profile for preclinical studies.
Asunto(s)
Antiprotozoarios , Benzotiazoles , Hidrazonas , Leishmania , Benzotiazoles/química , Benzotiazoles/farmacología , Benzotiazoles/síntesis química , Antiprotozoarios/farmacología , Antiprotozoarios/química , Antiprotozoarios/síntesis química , Animales , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Ratones , Leishmania/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Relación Estructura-Actividad , HumanosRESUMEN
Heterocyclic compounds, particularly those containing azole rings, have shown extensive biological activity, including anticancer, antibacterial, and antifungal properties. Among these, the imidazole ring stands out due to its diverse therapeutic potential. In the presented study, we designed and synthesized a series of imidazole derivatives to identify compounds with high biological potential. We focused on two groups: thiosemicarbazide derivatives and hydrazone derivatives. We synthesized these compounds using conventional methods and confirmed their structures via nuclear magnetic resonance spectroscopy (NMR), MS, and elemental analysis, and then assessed their antibacterial and antifungal activities in vitro using the broth microdilution method against Gram-positive and Gram-negative bacteria, as well as Candida spp. strains. Our results showed that thiosemicarbazide derivatives exhibited varied activity against Gram-positive bacteria, with MIC values ranging from 31.25 to 1000 µg/mL. The hydrazone derivatives, however, did not display significant antibacterial activity. These findings suggest that structural modifications can significantly influence the antimicrobial efficacy of imidazole derivatives, highlighting the potential of thiosemicarbazide derivatives as promising candidates for further development in antibacterial therapies. Additionally, the cytotoxic activity against four cancer cell lines was evaluated. Two derivatives of hydrazide-hydrazone showed moderate anticancer activity.
Asunto(s)
Antibacterianos , Antifúngicos , Antineoplásicos , Bacterias Grampositivas , Pruebas de Sensibilidad Microbiana , Humanos , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Bacterias Grampositivas/efectos de los fármacos , Nitroimidazoles/farmacología , Nitroimidazoles/química , Nitroimidazoles/síntesis química , Línea Celular Tumoral , Bacterias Gramnegativas/efectos de los fármacos , Relación Estructura-Actividad , Semicarbacidas/química , Semicarbacidas/farmacología , Semicarbacidas/síntesis química , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Candida/efectos de los fármacos , Estructura MolecularRESUMEN
Hydrazones display an interesting profile of biological activities, which includes mainly antimicrobial and antiproliferative properties. Hydrazones also play an important role in the synthesis of heterocyclic rings and in coordination chemistry. Currently, the synthesis of complexes of hydrazones with transition metals is quite frequently reported in the scientific literature. The interest in this topic is largely due to diverse biological activities of the metal complexes of hydrazones that in some cases are much more effective than hydrazones themselves. This review focuses on the complexes of hydrazones with transition metals which display antibacterial, antitubercular, antifungal and anticancer activities. In the following subchapters devoted to a given activity, an attempt has been made to present the most active complexes of hydrazones, their trends in their activity and application in medicinal chemistry. The paper presents the literature data from 2009 to 2023. This review constitutes a useful guide for the researchers who intend to synthesize and investigate complexes of hydrazones in terms of their antimicrobial and anticancer activities.
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Antiinfecciosos , Antineoplásicos , Complejos de Coordinación , Hidrazonas , Elementos de Transición , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Elementos de Transición/química , Elementos de Transición/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Humanos , Antiinfecciosos/farmacología , Antiinfecciosos/química , Antiinfecciosos/síntesis química , Neoplasias/tratamiento farmacológicoRESUMEN
In this study, we present the design, synthesis, and cytotoxic evaluation of a series of benzimidazole N-acylhydrazones against strains of T. cruzi (Y and Tulahuen) and Leishmania species (L. amazonensis and L. infantum). Compound (E)-N'-((5-Nitrofuran-2-yl)methylene)-1H-benzo[d]imidazole-2-carbohydrazide demonstrated significant activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 0.033 µM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC50/120 h = 1.520 µM, SI = 1390). Another compound (E)-N'-(2-Hydroxybenzylidene)-1H-benzo[d]imidazole-2-carbohydrazide showed promising activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 3.600 µM and an SI of 14.70. However, its efficacy against L. infantum and L. amazonensis was comparatively lower. These findings provide valuable insights for the development of more effective treatments against Trypanosoma cruzi.
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Bencimidazoles , Hidrazonas , Leishmania infantum , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Hidrazonas/farmacología , Hidrazonas/química , Hidrazonas/síntesis química , Relación Estructura-Actividad , Leishmania infantum/efectos de los fármacos , Bencimidazoles/farmacología , Bencimidazoles/química , Bencimidazoles/síntesis química , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Dosis-Respuesta a Droga , Leishmania/efectos de los fármacos , Tripanocidas/farmacología , Tripanocidas/síntesis química , Tripanocidas/química , Antiprotozoarios/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , AnimalesRESUMEN
The discovery of effective and safe antiobesity agents remains a challenging yet promising field. Our previous studies identified Bouchardatine derivatives as potential antiobesity agents. However, the 8a-aldehyde moiety rendered them unsuitable for drug development. In this study, we designed two series of novel derivatives to modify this structural feature. Through a structure-activity relationship study, we elucidated the role of the 8a-aldehyde group in toxicity induction. We identified compound 14d, featuring an 8a-N-acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound 14d shares a similar lipid-lowering mechanism with our lead compound 3, but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of 14d significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify 14d as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an N-acylhydrazone to enhance drug-like properties.
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Aldehídos , Fármacos Antiobesidad , Hidrazonas , Obesidad , Animales , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/uso terapéutico , Fármacos Antiobesidad/química , Hidrazonas/farmacología , Hidrazonas/química , Hidrazonas/síntesis química , Hidrazonas/farmacocinética , Hidrazonas/uso terapéutico , Ratones , Relación Estructura-Actividad , Aldehídos/química , Masculino , Obesidad/tratamiento farmacológico , Ratones Endogámicos C57BL , Dieta Alta en Grasa/efectos adversos , Humanos , Ratones Obesos , Estructura MolecularAsunto(s)
Antineoplásicos , Hidrazonas , Quinolinas , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Quinolinas/química , Quinolinas/farmacología , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Hidrazinas/química , Hidrazinas/farmacología , Hidrazinas/síntesis químicaRESUMEN
Aim: A new series of 1,2,3-triazole-hydrazone derivatives were developed to evaluate their anti-Alzheimer's activity. Materials & methods: All compounds were screened toward cholinesterases via the modified Ellman's method. The toxicity assay on SH-SY5Y cells was performed using the MTT assay, and the expression levels of GSK-3α, GSK-3ß, DYRK1 and CDK5 were assessed in the presence of compounds 6m and 6p.Results:6m and 6p; acting as mixed-type inhibitors, exhibited promising acetylcholinesterase and butyrylcholinesterase inhibitory activity, respectively. 6m demonstrated no toxicity under tested concentrations on the SH-SY5Y cells and positively impacted neurodegenerative pathways. Notably, 6m displayed a significant downregulation in mRNA levels of GSK-3α, GSK-3ß and CDK5.Conclusion: The target compounds could be considered in developing anti-Alzheimer's disease agents.
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Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Quinasa 5 Dependiente de la Ciclina , Hidrazonas , Triazoles , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/síntesis química , Quinasa 5 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 5 Dependiente de la Ciclina/metabolismo , Acetilcolinesterasa/metabolismo , Relación Estructura-Actividad , Butirilcolinesterasa/metabolismo , Estructura Molecular , Línea Celular Tumoral , Simulación del Acoplamiento MolecularRESUMEN
Wet synthesis approach afforded four new heteroleptic mononuclear neutral diamagnetic oxidovanadium(V) complexes, comprising salicylaldehyde-based 2-furoic acid hydrazones and a flavonol coligand of the general composition [VO(fla)(L-ONO)]. The complexes were comprehensively characterized, including chemical analysis, conductometry, infrared, electronic, and mass spectroscopy, as well as 1D 1H and proton-decoupled 13C(1H) NMR spectroscopy, alongside extensive 2D 1H1H COSY, 1H13C HMQC, and 1H13C HMBC NMR analyses. Additionally, the quantum chemical properties of the complexes were studied using Gaussian at the B3LYP, HF, and M062X levels on the 6-31++g(d,p) basis sets. The interaction of these hydrolytically inert vanadium complexes and the BSA was investigated through spectrofluorimetric titration, synchronous fluorimetry, and FRET analysis in a temperature-dependent manner, providing valuable thermodynamic insights into van der Waals interactions and hydrogen bonding. Molecular docking was conducted to gain further understanding of the specific binding sites of the complexes to BSA. Complex 2, featuring a 5-chloro-substituted salicylaldehyde component of the hydrazone, was extensively examined for its biological activity in vivo. The effects of complex administration on biochemical and hematological parameters were evaluated in both healthy and diabetic Wistar rats, revealing antihyperglycemic activity at millimolar concentration. Furthermore, histopathological analysis and bioaccumulation studies of the complex in the brain, kidneys, and livers of healthy and diabetic rats revealed the potential for further development of vanadium(V) hydrazone complexes as antidiabetic and insulin-mimetic agents.