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1.
Arch Pharm (Weinheim) ; 356(2): e2200374, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36372522

RESUMEN

Fourteen novel quinoline-4-carboxylic acid-chalcone hybrids were obtained via Claisen-Schmidt condensation and evaluated as potential human dihydroorotate dehydrogenase (hDHODH) inhibitors. The ketone precursor 2 was synthesized by the Pfitzinger reaction and used for further derivatization at position 3 of the quinoline ring for the first time. Six compounds showed better hDHODH inhibitory activity than the reference drug leflunomide, with IC50 values ranging from 0.12 to 0.58 µM. The bioactive conformations of the compounds within hDHODH were resolved by means of molecular docking, revealing their tendency to occupy the narrow tunnel of hDHODH within the N-terminus and to prevent ubiquinone as the second cofactor from easily approaching the flavin mononucleotide as a cofactor for the redox reaction within the redox site. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that 4d and 4h demonstrated the highest cytotoxic activity against the A375 cell line, with IC50 values of 5.0 and 6.8 µM, respectively. The lipophilicity of the synthesized hybrids was obtained experimentally and expressed as logD7.4 values at physiologicalpH while the solubility assay was conducted to define physicochemical characteristics influencing the ADMET properties.


Asunto(s)
Chalconas , Dihidroorotato Deshidrogenasa , Quinolinas , Humanos , Chalconas/farmacología , Dihidroorotato Deshidrogenasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Simulación del Acoplamiento Molecular , Quinolinas/farmacología , Quinolinas/química , Relación Estructura-Actividad
2.
Molecules ; 28(17)2023 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-37687065

RESUMEN

Commercially available cathinones are drugs of long-term abuse drugs whose pharmacology is fairly well understood. While their psychedelic effects are associated with 5-HT2AR, the enclosed study summarizes efforts to shed light on the pharmacodynamic profiles, not yet known at the receptor level, using molecular docking and three-dimensional quantitative structure-activity relationship (3-D QSAR) studies. The bioactive conformations of cathinones were modeled by AutoDock Vina and were used to build structure-based (SB) 3-D QSAR models using the Open3DQSAR engine. Graphical inspection of the results led to the depiction of a 3-D structure analysis-activity relationship (SAR) scheme that could be used as a guideline for molecular determinants by which any untested cathinone molecule can be predicted as a potential 5-HT2AR binder prior to experimental evaluation. The obtained models, which showed a good agreement with the chemical properties of co-crystallized 5-HT2AR ligands, proved to be valuable for future virtual screening campaigns to recognize unused cathinones and similar compounds, such as 5-HT2AR ligands, minimizing both time and financial resources for the characterization of their psychedelic effects.


Asunto(s)
Alucinógenos , Drogas Ilícitas , Simulación del Acoplamiento Molecular , Serotonina , Alucinógenos/farmacología , Ligandos , Relación Estructura-Actividad Cuantitativa
3.
Molecules ; 28(19)2023 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-37836777

RESUMEN

A comparative study on essential oils extracted from Mentha suaveolens Ehrh. from Italy is reported. Two extraction procedures were investigated: hydrodistillation and steam distillation, carried out as a continuous and fractionated procedure. Fresh and dried plant material from two harvests was used. The hydrodistillation method yielded a higher amount of essential oil. The dried plant was significantly richer in essential oil per kg of starting plant material. Gas chromatography-mass spectrometry analysis of 112 samples showed that the essential oils belong to the piperitenone oxide-rich chemotype. In addition, piperitenone, p-cymen-8-ol, and limonene were among the most abundant compounds in the different samples. A higher amount of piperitenone oxide was obtained by hydrodistillation, while steam distillation gave a higher percentage of piperitenone and limonene. The essential oils were characterized for their anti-Candida albicans activity; higher potency was observed for the samples rich in piperitenone oxide, with MIC values ranging from 0.39 to 0.78 mg·mL-1 (0.039% and 0.078% p/v). The results of this work provide a deep insight into the methodology of essential oil extraction and the associated chemical variability of M. suaveolens Ehrh. Some of the essential oils are potent against C. albicans and could be considered for potential use in therapy.


Asunto(s)
Mentha , Aceites Volátiles , Aceites Volátiles/farmacología , Aceites Volátiles/química , Candida , Limoneno , Mentha/química , Destilación , Vapor , Candida albicans
4.
J Comput Aided Mol Des ; 36(7): 483-505, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35716228

RESUMEN

The main protease (Mpro) of SARS-Cov-2 is the essential enzyme for maturation of functional proteins implicated in viral replication and transcription. The peculiarity of its specific cleavage site joint with its high degree of conservation among all coronaviruses promote it as an attractive target to develop broad-spectrum inhibitors, with high selectivity and tolerable safety profile. Herein is reported a combination of three-dimensional quantitative structure-activity relationships (3-D QSAR) and comparative molecular binding energy (COMBINE) analysis to build robust and predictive ligand-based and structure-based statistical models, respectively. Models were trained on experimental binding poses of co-crystallized Mpro-inhibitors and validated on available literature data. By means of deep optimization both models' goodness and robustness reached final statistical values of r2/q2 values of 0.97/0.79 and 0.93/0.79 for the 3-D QSAR and COMBINE approaches respectively, and an overall predictiveness values of 0.68 and 0.57 for the SDEPPRED and AAEP metrics after application to a test set of 60 compounds covered by the training set applicability domain. Despite the different nature (ligand-based and structure-based) of the employed methods, their outcome fully converged. Furthermore, joint ligand- and structure-based structure-activity relationships were found in good agreement with nirmatrelvir chemical features properties, a novel oral Mpro-inhibitor that has recently received U.S. FDA emergency use authorization (EUA) for the oral treatment of mild-to-moderate COVID-19 infected patients. The obtained results will guide future rational design and/or virtual screening campaigns with the aim of discovering new potential anti-coronavirus lead candidates, minimizing both time and financial resources. Moreover, as most of calculation were performed through the well-established web portal 3d-qsar.com the results confirm the portal as a useful tool for drug design.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Relación Estructura-Actividad Cuantitativa , Antivirales/química , Antivirales/farmacología , Proteasas 3C de Coronavirus , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , SARS-CoV-2
5.
Molecules ; 27(9)2022 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-35566172

RESUMEN

The estrogen receptor α (ERα) is an important biological target mediating 17ß-estradiol driven breast cancer (BC) development. Aiming to develop innovative drugs against BC, either wild-type or mutated ligand-ERα complexes were used as source data to build structure-based 3-D pharmacophore and 3-D QSAR models, afterward used as tools for the virtual screening of National Cancer Institute datasets and hit-to-lead optimization. The procedure identified Brefeldin A (BFA) as hit, then structurally optimized toward twelve new derivatives whose anticancer activity was confirmed both in vitro and in vivo. Compounds as SERMs showed picomolar to low nanomolar potencies against ERα and were then investigated as antiproliferative agents against BC cell lines, as stimulators of p53 expression, as well as BC cell cycle arrest agents. Most active leads were finally profiled upon administration to female Wistar rats with pre-induced BC, after which 3DPQ-12, 3DPQ-3, 3DPQ-9, 3DPQ-4, 3DPQ-2, and 3DPQ-1 represent potential candidates for BC therapy.


Asunto(s)
Neoplasias de la Mama , Receptor alfa de Estrógeno , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Brefeldino A/farmacología , Brefeldino A/uso terapéutico , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Relación Estructura-Actividad Cuantitativa , Ratas , Ratas Wistar
6.
Bioorg Med Chem Lett ; 46: 128194, 2021 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-34116160

RESUMEN

Twenty novel 2-substituted quinoline-4-carboxylic acids bearing amide moiety were designed and synthesized by Doebner reaction. Human dihydroorotate dehydrogenase (hDHODH) was recognized as a biological target and all compounds were screened as potential hDHODH inhibitors in an enzyme inhibition assay. The prepared heterocycles were also evaluated for their cytotoxic effects on the healthy HaCaT cell line while lipophilic properties were considered on the basis of experimentally determined logD values at physiological pH. The most promising compound 5j, with chlorine at para-position of terminal phenyl ring, showed good hDHODH inhibitory activity, low cytotoxicity, and optimal lipophilicity. The bioactive conformation of 5j on the hDHODH, determined by means of molecular docking, revealed the compound's pharmacology and provide guidelines for further lead optimization.


Asunto(s)
Antineoplásicos/farmacología , Benzaldehídos/química , Dihidroorotato Deshidrogenasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Quinolinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Dihidroorotato Deshidrogenasa/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Quinolinas/química , Relación Estructura-Actividad
7.
J Chem Inf Model ; 61(10): 5028-5053, 2021 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-34648283

RESUMEN

The estrogen receptor α (ERα) represents a 17ß-estradiol-inducible transcriptional regulator that initiates the RNA polymerase II-dependent transcriptional machinery, pointed for breast cancer (BC) development via either genomic direct or genomic indirect (i.e., tethered) pathway. To develop innovative ligands, structure-based (SB) three-dimensional (3-D) quantitative structure-activity relationship (QSAR) studies have been undertaken from structural data taken from partial agonists, mixed agonists/antagonists (selective estrogen receptor modulators (SERMs)), and full antagonists (selective ERα downregulators (SERDs)) correlated with either wild-type or mutated ERα receptors. SB and ligand-based (LB) alignments allow us to rule out guidelines for the SB/LB alignment of untested compounds. 3-D QSAR models for ERα ligands, coupled with SB/LB alignment, were revealed to be useful tools to dissect the chemical determinants for ERα-based anticancer activity as well as to predict their potency. The herein developed protocol procedure was verified through the design and potency prediction of 12 new coumarin-based SERMs, namely, 3DQ-1a to 3DQ-1e, that upon synthesis turned to be potent ERα antagonists by means of either in vitro or in vivo assays (described in the second part of this study).


Asunto(s)
Neoplasias de la Mama , Receptor alfa de Estrógeno , Neoplasias de la Mama/tratamiento farmacológico , Cumarinas , Estradiol , Moduladores de los Receptores de Estrógeno , Femenino , Humanos , Ligandos , Relación Estructura-Actividad Cuantitativa
8.
Bioorg Chem ; 105: 104373, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33074120

RESUMEN

A series of novel 2-substituted quinoline-4-carboxylic acids was synthesized by Doebner reaction starting from freely available protocatechuic aldehyde and vanillin precursors. Human dihydroorotate dehydrogenase (hDHODH) was recognised as a clear molecular target for these heterocycles. All compounds were also tested for their antiproliferative potential against three cancer cells (MCF-7, A549, A375) and one normal cell line (HaCaT) to evaluate the selective cytotoxicity. Quinoline derivatives 3f and 3g were identified as potent hDHODH inhibitors while 3k and 3l demonstrated high cytotoxic activity against MCF-7 and A375 cells and good selectivity. In addition, the logD7.4 values obtained by the experimental method were found to be in the range from -1.15 to 1.69. The chemical structures of all compounds were confirmed by IR, NMR and elemental analysis. The compounds pharmacology on the molecular level was revealed by means of molecular docking, highlighting the structural differences that distinguish highly active from medium and low active hDHODH inhibitors.


Asunto(s)
Aldehídos/farmacología , Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Simulación del Acoplamiento Molecular , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Fenoles/farmacología , Quinolinas/farmacología , Aldehídos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dihidroorotato Deshidrogenasa , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Estructura Molecular , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Fenoles/química , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-Actividad
9.
Bioorg Med Chem Lett ; 28(15): 2593-2598, 2018 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-29970309

RESUMEN

A series of 23 novel anthraquinone-chalcone hybrids containing amide function was synthesized and structurally characterized. Sixteen compounds exerted strong cytotoxic activities against K562, Jurkat and HL-60 leukemia cell lines and significantly lower cytotoxic effects against normal MRC-5 cells, indicating very high selectivity in their anticancer action. The compounds 6g, 6u and 6v activate apoptosis in K562 cells through the extrinsic and intrinsic apoptotic pathway. The compound 6e triggered apoptosis in K562 cells only through the extrinsic apoptotic pathway. Treatment of K562 cells with each of these four compounds caused decrease in the expression levels of MMP2, MMP9, and VEGF, suggesting their anti-invasive, antimetastatic and antiangiogenic properties. The compounds 6g and 6v downregulated expression levels of miR-155 in K562 cells, while compounds 6e and 6u upregulated miR-155 levels in treated cells, in comparison with control cells. The structure-based 3-D QSAR models for 6f, 6e, 6i and 6l describe pro-apoptotic activity against caspase-3.


Asunto(s)
Antraquinonas/química , Antineoplásicos/uso terapéutico , Chalconas/química , Leucemia/tratamiento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Espectroscopía de Resonancia Magnética con Carbono-13 , Caspasa 3/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Humanos , Células Jurkat , Células K562 , Leucemia/enzimología , Leucemia/patología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , MicroARNs/metabolismo , Invasividad Neoplásica/prevención & control , Metástasis de la Neoplasia/prevención & control , Neovascularización Patológica/prevención & control , Espectroscopía de Protones por Resonancia Magnética , Relación Estructura-Actividad Cuantitativa , Factor A de Crecimiento Endotelial Vascular/metabolismo
10.
Bioorg Chem ; 80: 741-752, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30077781

RESUMEN

Dicoumarol derivatives were synthesized in the InCl3 catalyzed pseudo three-component reactions of 4-hydroxycoumarin with aromatic aldehydes in excellent yields. The reactions were performed in water under microwave irradiation. All synthesized compounds were characterized using NMR, IR, and UV-Vis spectroscopy, as well as with TD-DFT. Obtained dicoumarols were subjected to evaluation of their in vitro lipid peroxidation and soybean lipoxygenase inhibition activities. It was shown that five of ten examined compounds (3e, 3h, 3b, 3d, 3f) possess significant potential of antilipid peroxidation (84-97%), and that compounds 3b, 3e, 3h provided the highest soybean lipoxygenase (LOX-Ib) inhibition (IC50 = 52.5 µM) and 3i somewhat lower activity (IC50 = 55.5 µM). The bioactive conformations of the best LOX-Ib inhibitors were obtained by means of molecular docking and molecular dynamics. It was shown that, within the bioactive conformations interior to LOX-Ib active site, the most active compounds form the pyramidal structure made of two 4-hydroxycoumarin cores and a central phenyl substituent. This form serves as a spatial barrier which prevents LOX-Ib Fe2+/Fe3+ ion activity to generate the coordinative bond with the C13 hydroxyl group of the α-linoleate. It is worth pointing out that the most active compounds 3b, 3e, 3h and 3i can be candidates for further examination of their in vitro and in vivo anti-inflammatory activity and that molecular modeling study results provide possibility to screen bioactive conformations and elucidate the mechanism of dicoumarols anti-LOX activity.


Asunto(s)
Dicumarol/análogos & derivados , Dicumarol/farmacología , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/farmacología , Dicumarol/síntesis química , Diseño de Fármacos , Tecnología Química Verde , Peroxidación de Lípido/efectos de los fármacos , Lipooxigenasa/metabolismo , Inhibidores de la Lipooxigenasa/síntesis química , Simulación del Acoplamiento Molecular , Glycine max/enzimología , Relación Estructura-Actividad
11.
Molecules ; 23(9)2018 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-30200244

RESUMEN

Commercially available pesticides were examined as Mus musculus and Homo sapiens acetylcholinesterase (mAChE and hAChE) inhibitors by means of ligand-based (LB) and structure-based (SB) in silico approaches. Initially, the crystal structures of simazine, monocrotophos, dimethoate, and acetamiprid were reproduced using various force fields. Subsequently, LB alignment rules were assessed and applied to determine the inter synaptic conformations of atrazine, propazine, carbofuran, carbaryl, tebufenozide, imidacloprid, diuron, monuron, and linuron. Afterwards, molecular docking and dynamics SB studies were performed on either mAChE or hAChE, to predict the listed pesticides' binding modes. Calculated energies of global minima (Eglob_min) and free energies of binding (∆Gbinding) were correlated with the pesticides' acute toxicities (i.e., the LD50 values) against mice, as well to generate the model that could predict the LD50s against humans. Although for most of the pesticides the low Eglob_min correlates with the high acute toxicity, it is the ∆Gbinding that conditions the LD50 values for all the evaluated pesticides. Derived pLD50 = f(∆Gbinding) mAChE model may predict the pLD50 against hAChE, too. The hAChE inhibition by atrazine, propazine, and simazine (the most toxic pesticides) was elucidated by SB quantum mechanics (QM) DFT mechanistic and concentration-dependent kinetic studies, enriching the knowledge for design of less toxic pesticides.


Asunto(s)
Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Plaguicidas/química , Plaguicidas/farmacología , Acetilcolinesterasa/química , Animales , Humanos , Cinética , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Relación Estructura-Actividad Cuantitativa , Soluciones , Relación Estructura-Actividad
12.
J Chem Inf Model ; 57(4): 787-814, 2017 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-28291352

RESUMEN

Monoamine oxidase B (MAO B) catalyzes the oxidative deamination of aryalkylamines neurotransmitters with concomitant reduction of oxygen to hydrogen peroxide. Consequently, the enzyme's malfunction can induce oxidative damage to mitochondrial DNA and mediates development of Parkinson's disease. Thus, MAO B emerges as a promising target for developing pharmaceuticals potentially useful to treat this vicious neurodegenerative condition. Aiming to contribute to the development of drugs with the reversible mechanism of MAO B inhibition only, herein, an extended in silico-in vitro procedure for the selection of novel MAO B inhibitors is demonstrated, including the following: (1) definition of optimized and validated structure-based three-dimensional (3-D) quantitative structure-activity relationships (QSAR) models derived from available cocrystallized inhibitor-MAO B complexes; (2) elaboration of SAR features for either irreversible or reversible MAO B inhibitors to characterize and improve coumarin-based inhibitor activity (Protein Data Bank ID: 2V61 ) as the most potent reversible lead compound; (3) definition of structure-based (SB) and ligand-based (LB) alignment rule assessments by which virtually any untested potential MAO B inhibitor might be evaluated; (4) predictive ability validation of the best 3-D QSAR model through SB/LB modeling of four coumarin-based external test sets (267 compounds); (5) design and SB/LB alignment of novel coumarin-based scaffolds experimentally validated through synthesis and biological evaluation in vitro. Due to the wide range of molecular diversity within the 3-D QSAR training set and derived features, the selected N probe-derived 3-D QSAR model proves to be a valuable tool for virtual screening (VS) of novel MAO B inhibitors and a platform for design, synthesis and evaluation of novel active structures. Accordingly, six highly active and selective MAO B inhibitors (picomolar to low nanomolar range of activity) were disclosed as a result of rational SB/LB 3D QSAR design; therefore, D123 (IC50 = 0.83 nM, Ki = 0.25 nM) and D124 (IC50 = 0.97 nM, Ki = 0.29 nM) are potential lead candidates as anti-Parkinson's drugs.


Asunto(s)
Benzopiranos/química , Benzopiranos/farmacología , Diseño de Fármacos , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Relación Estructura-Actividad Cuantitativa , Benzopiranos/metabolismo , Humanos , Ligandos , Membranas Artificiales , Simulación del Acoplamiento Molecular , Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/metabolismo , Permeabilidad , Conformación Proteica
13.
ACS Infect Dis ; 10(6): 2127-2150, 2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38771206

RESUMEN

Antibiotic resistance is one of the most serious global health threats. Therefore, there is a need to develop antimicrobial agents with new mechanisms of action. Targeting of bacterial cystathionine γ-lyase (bCSE), an enzyme essential for bacterial survival, is a promising approach to overcome antibiotic resistance. Here, we described a series of (heteroarylmethyl)benzoic acid derivatives and evaluated their ability to inhibit bCSE or its human ortholog hCSE using known bCSE inhibitor NL2 as a lead compound. Derivatives bearing the 6-bromoindole group proved to be the most active, with IC50 values in the midmicromolar range, and highly selective for bCSE over hCSE. Furthermore, none of these compounds showed significant toxicity to HEK293T cells. The obtained data were rationalized by ligand-based and structure-based molecular modeling analyses. The most active compounds were also found to be an effective adjunct to several widely used antibacterial agents against clinically relevant antibiotic-resistant strains of such bacteria as Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The most potent compounds, 3h and 3i, also showed a promising in vitro absorption, distribution, metabolism, and excretion (ADME) profile. Finally, compound 3i manifested potentiating activity in pneumonia, sepsis, and infected-wound in vivo models.


Asunto(s)
Antibacterianos , Cistationina gamma-Liasa , Inhibidores Enzimáticos , Humanos , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Cistationina gamma-Liasa/antagonistas & inhibidores , Cistationina gamma-Liasa/metabolismo , Animales , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Células HEK293 , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Benzoatos/farmacología , Benzoatos/química , Benzoatos/síntesis química , Ratones , Staphylococcus aureus/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacos , Relación Estructura-Actividad
14.
Mutat Res ; 755(2): 81-9, 2013 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-23830930

RESUMEN

The present study was undertaken to investigate the hepatoprotective effect of the methanol extract of Cotinus coggygria Scop. in rats exposed to the hepatotoxic compound pyrogallol. Assessed with the alkaline version of the comet assay, 1000 and 2000mg/kg body weight (bw) of the extract showed a low level of genotoxicity, while 500mg/kg bw of the extract showed no genotoxic potential. Quantitative HPLC analysis of phenolic acids and flavonoids in the methanol extract of C. coggygria showed that myricetin was a major component. To test the hepatoprotective effect, a non-genotoxic dose of the C. coggygria extract and an equivalent amount of synthetic myricetin, as present in the extract, were applied either 2 or 12h prior to administration of 100mg/kg bw of pyrogallol. The extract and myricetin promoted restoration of hepatic function by significantly reducing pyrogallol-induced elevation in the serum enzymes AST, ALT, ALP and in total bilirubin. As measured by the decrease in total score and tail moment, the DNA damage in liver was also reduced by the extract and by myricetin. Our results suggest that pro-surviving Akt activity and STAT3 protein expression play important roles in decreasing DNA damage and in mediating hepatic protection by the extract. These results suggest that myricetin, as a major component in the extract, is responsible for the antigenotoxic and hepatoprotective properties of the methanol extract of C. coggygria against pyrogallol-induced toxicity.


Asunto(s)
Anacardiaceae/química , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Daño del ADN/efectos de los fármacos , Flavonoides/farmacología , Hígado/efectos de los fármacos , Extractos Vegetales/farmacología , Pirogalol/toxicidad , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Animales , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Ensayo Cometa , Flavonoides/aislamiento & purificación , Depuradores de Radicales Libres/aislamiento & purificación , Depuradores de Radicales Libres/farmacología , Hidroxibenzoatos/aislamiento & purificación , Hidroxibenzoatos/farmacología , Masculino , Metanol , Tallos de la Planta/química , Plantas Medicinales/química , Ratas , Ratas Wistar , Solventes
15.
Antioxidants (Basel) ; 12(10)2023 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-37891894

RESUMEN

The antioxidant activity of essential oils (EOs) is an important and frequently studied property, yet it is not sufficiently understood in terms of the contribution of EOs mixtures' constituents and biological properties. In this study, a series of 61 commercial EOs were first evaluated as antioxidants in vitro, following as closely as possible the cellular pathways of reactive oxygen species (ROS) generation. Hence, EOs were assessed for the ability either to chelate metal ions, thus interfering with ROS generation within the respiratory chain, or to neutralize 2,2-diphenyl-1-picrylhydrazyl (DPPH•) and lipid peroxide radicals (LOO•), thereby halting lipid peroxidation, as well as to neutralize 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid cation radicals (ABTS•+) and hydroxyl radicals (OH•), thereby preventing the ROS species from damaging DNA nucleotides. Showing noteworthy potencies to neutralize all of the radicals at the ng/mL level, the active EOs were also characterized as protectors of DNA double strands from damage induced by peroxyl radicals (ROO•), emerging from 2,2'-azobis-2-methyl-propanimidamide (AAPH) as a source, and OH•, indicating some genome protectivity and antigenotoxicity effectiveness in vitro. The chemical compositions of the EOs associated with the obtained activities were then analyzed by means of machine learning (ML) classification algorithms to generate quantitative composition-activity relationships (QCARs) models (models published in the AI4EssOil database available online). The QCARs models enabled us to highlight the key features (EOSs' chemical compounds) for exerting the redox potencies and to define the partial dependencies of the features, viz. percentages in the mixture required to exert a given potency. The ML-based models explained either the positive or negative contribution of the most important chemical components: limonene, linalool, carvacrol, eucalyptol, α-pinene, thymol, caryophyllene, p-cymene, eugenol, and chrysanthone. Finally, the most potent EOs in vitro, Ylang-ylang (Cananga odorata (Lam.)) and Ceylon cinnamon peel (Cinnamomum verum J. Presl), were promptly administered in vivo to evaluate the rescue ability against redox damage caused by CCl4, thereby verifying their antioxidant and antigenotoxic properties either in the liver or in the kidney.

16.
Eur J Med Chem ; 245(Pt 2): 114902, 2023 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-36403514

RESUMEN

A series of new pyrimidine thioethers, recognized as the key intermediates in the synthesis of S-DABO antivirals, were prepared and evaluated both in vivo and in silico. The purpose of this evaluation was to find novel structural analogues of the known antihypoxic drug Isothiobarbamine endowed with improved pharmacological profile. The in vivo studies led to the identification of compounds 5c, 5e, and 5f endowed with antidepressant/anxiolytic, performance enhancing, and nootropic properties. Compounds 5c and 5f were further tested in mice affected by social depression and were able to increase motor and tentative search activity compared to control groups, along with higher interaction frequency and better results in a sucrose preference test. Overall, these data suggested a better psychoemotional state of the animals, treated with compounds 5c, and 5f. Moreover, 5c and 5f exhibited minimal acute toxicity, lower than Fluoxetine hydrochloride. Molecular modelling studies finally indicated the plausible biomolecular mechanism of action of compounds 5c, 5e, and 5f, which seem to bind GABA-A, melatonin, and sigma-1 receptors. Moreover, three-dimensional structure-activity relationships enabled to define a SAR model that will be of great utility for the design of further structurally optimized compounds of the above mentioned chemotype.


Asunto(s)
Ansiolíticos , Nootrópicos , Animales , Ratones , Ansiolíticos/farmacología , Sulfuros , Antidepresivos/farmacología , Pirimidinas
17.
J Biochem Mol Toxicol ; 26(8): 322-30, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22777752

RESUMEN

The in vivo sex-linked recessive lethal test was carried out in Drosophila melanogaster to investigate whether or not five substituted 4-hydroxy-2H-chromen-2-ones can modulate the genotoxicity of the well-established mutagenic agent ethyl methanesulfonate (EMS). For this purpose, 3 days old Canton S males were treated with the potent mutagen EMS alone in concentration of 0.75 ppm, as well as in combination with one of the five 4-hydroxycoumarins, namely diethyl 2-(1-(4-hydroxy-2-oxo-2H-chromen-3-yl)ethylidene)malonate (2b), 3-(1-(4-hydroxy-2-oxo-2H-chromen-3-yl)ethylidene)pentane-2,4-dione (6b), 4-(4-(4-hydroxy-2-oxo-2H-chromen-3-yl)thiazol-2-ylamino) benzenesulfonic acid (4c), 4-hydroxy-3-(2-(2-nitropheny lamino)thiazol-4-yl)-2H-chromen-2-one (9c), and (E)-4-hydroxy-3-(1-(m-tolylimino)ethyl)-2H-chromen-2-one (5d), in concentration of 70 ppm. The frequency of germinative mutations increased significantly after the treatment with EMS and decreased after treatments with coumarins. The maximum reduction was observed after treatments with 2b, 6b, 4c, and 5d. By the formation of hydrogen bonds or electrostatic interactions with O(6) of DNA guanine, tested coumarins prevent EMS-induced alkylation. The results indicate a protective role of five 4-hydroxycoumarins under the action of a strong mutagen.


Asunto(s)
Antimutagênicos/farmacología , Benzopiranos/farmacología , ADN/química , Drosophila melanogaster/genética , Animales , Simulación por Computador , Drosophila melanogaster/efectos de los fármacos , Metanosulfonato de Etilo/química , Metanosulfonato de Etilo/toxicidad , Femenino , Genes Recesivos , Masculino , Modelos Moleculares , Método de Montecarlo , Mutágenos/química , Mutágenos/toxicidad , Mutación/efectos de los fármacos , Conformación de Ácido Nucleico , Cromosomas Sexuales/genética
18.
Eur J Med Chem ; 227: 113869, 2022 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-34710747

RESUMEN

New twelve in silico designed coumarin-based ERα antagonists, namely 3DQ-1a to 3DQ-1е, were synthesized and confirmed as selective ERα antagonists, showing potencies ranging from single-digit nanomolar to picomolar. The hits were confirmed as selective estrogen receptor modulators and validated as antiproliferative agents using MCF-7 breast cancer cell lines exerting from picomolar to low nanomolar potency, at the same time showing no agonistic activity within endometrial cell lines. Their mechanism of action was inspected and revealed to be through the inhibition of the Raf-1/MAPK/ERK signal transduction pathway, preventing hormone-mediated gene expression on either genomic direct or genomic indirect level, and stopping the MCF-7 cells proliferation at G0/G1 phase. In vivo experiments, by means of the per os administration to female Wistar rats with pre-induced breast cancer, distinguished six derivatives, 3DQ-4a, 3DQ-2a, 3DQ-1a, 3DQ-1b, 3DQ-2b, and 3DQ-3b, showing remarkable potency as tumor suppressors endowed with optimal pharmacokinetic profiles and no significant histopathological profiles. The presented data indicate the new compounds as potential candidates to be submitted in clinical trials for breast cancer therapy.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Cumarinas/farmacología , Diseño de Fármacos , Antagonistas del Receptor de Estrógeno/farmacología , Receptor alfa de Estrógeno/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Cumarinas/síntesis química , Cumarinas/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Antagonistas del Receptor de Estrógeno/síntesis química , Antagonistas del Receptor de Estrógeno/química , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Estructura Molecular , Ratas , Ratas Wistar , Relación Estructura-Actividad
19.
Plants (Basel) ; 11(16)2022 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-36015417

RESUMEN

This report summarizes the chemical composition analysis of Nepeta cataria L. flower, leaf, and stem methanol extracts (FME, LME, SME, respectively) as well as their hepatoprotective and antigenotoxic features in vivo and in silico. Herein, Wistar rat liver intoxication with CCl4 resulted in the generation of trichloromethyl and trichloromethylperoxy radicals, causing lipid peroxidation within the hepatocyte membranes (viz. hepatotoxicity), as well as the subsequent formation of aberrant rDNA adducts and consequent double-strand break (namely genotoxicity). Examined FME, LME, and SME administered orally to Wistar rats before the injection of CCl4 exerted the most notable pharmacological properties in the concentrations of 200, 100, and 50 mg/kg of body weight, respectively. Thus, the extracts' hepatoprotective features were determined by monitoring the catalytic activities of enzymes and the concentrations of reactive oxidative species, modulating the liver redox status. Furthermore, the necrosis of hepatocytes was assessed by means of catalytic activities of liver toxicity markers. The extracts' antigenotoxic features were quantified using the comet assay. Distinct pharmacological property features may be attributed to quercitrin (8406.31 µg/g), chlorogenic acid (1647.32 µg/g), and quinic acid (536.11 µg/g), found within the FME, rosmarinic acid (1056.14 µg/g), and chlorogenic acid (648.52 µg/g), occurring within the LME, and chlorogenic acid (1408.43 µg/g), the most abundant in SME. Hence, the plant's secondary metabolites were individually administered similar to extracts, upon which their pharmacology in vivo was elucidated in silico by means of the structure-based studies within rat catalase, as a redox marker, and rat topoisomerase IIα, an enzyme catalyzing the rat DNA double-strand break. Conclusively, the examined N. cataria extracts in specified concentrations could be used in clinical therapy for the prevention of toxin-induced liver diseases.

20.
Eur J Med Chem ; 237: 114410, 2022 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-35525212

RESUMEN

LSD1 is a histone lysine demethylase proposed as therapeutic target in cancer. Chemical modifications applied at C2, C4 and/or C7 positions of the quinazoline core of the previously reported dual LSD1/G9a inhibitor 1 led to a series of non-covalent, highly active, and selective LSD1 inhibitors (2-4 and 6-30) and to the dual LSD1/G9a inhibitor 5 that was more potent than 1 against LSD1. In THP-1 and MV4-11 leukemic cells, the most potent compounds (7, 8, and 29) showed antiproliferative effects at sub-micromolar level without significant toxicity at 1 µM in non-cancer AHH-1 cells. In MV4-11 cells, the new derivatives increased the levels of the LSD1 histone mark H3K4me2 and induced the re-expression of the CD86 gene silenced by LSD1, thereby confirming the inhibition of LSD1 at cellular level. In breast MDA-MB-231 as well as in rhabdomyosarcoma RD and RH30 cells, taken as examples of solid tumors, the same compounds displayed cell growth arrest in the same IC50 range, highlighting a crucial anticancer role for LSD1 inhibition and suggesting no added value for the simultaneous G9a inhibition in these tumor cell lines.


Asunto(s)
Inhibidores Enzimáticos , Leucemia , Línea Celular Tumoral , Proliferación Celular , Inhibidores Enzimáticos/química , Histona Demetilasas , Humanos , Leucemia/tratamiento farmacológico , Leucemia/metabolismo
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