RESUMEN
New imidazol-5-one derivatives 12a,b and 12e, f, 14a,b and 16a,b were synthesized and screened for their in vivo anti-inflammatory activity using a standard acute carrageenan-induced rat paw oedema method. All the tested compounds exhibited good anti-inflammatory activity; especially compound 12f which produced the maximum effect of 49.0% compared to the standard drug, celecoxib, (43.1%). The most active anti-inflammatory agents 12a, 12e, and 12f were studied for their interactions with enzyme COX-2 compared to celecoxib. The study showed that, compound 12e exhibited a high selectivity towards COX-2 inhibition with IC50â¯=â¯0.087⯵M. Moreover, the antibacterial screening indicated that some synthesized compounds showed good antibacterial activity toward the Gram-negative bacteria Escherichia coli. Additionally, compounds 7, 12a, 12f, and 12 showed a good binding affinity with enzyme dihydrofolate reductase (DHFR) whereas compound 12f has a higher inhibitory effect on DHFR than the tested compounds 7, 12a and 12â¯h. On the other hand, the combination between these tested compounds and sulfadiazine as a reference drug (10⯵M compoundâ¯+â¯1⯵M reference), showed that compound 12â¯h has higher potency (0.078⯱â¯0.002) than sulfadiazine (0.135⯱â¯0.004). In addition, docking analysis was performed and it confirmed the presented results.
Asunto(s)
Antibacterianos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Escherichia coli/efectos de los fármacos , Antagonistas del Ácido Fólico/farmacología , Imidazoles/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Benzoatos/química , Benzoatos/farmacología , Carragenina , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Edema/metabolismo , Antagonistas del Ácido Fólico/síntesis química , Antagonistas del Ácido Fólico/química , Humanos , Imidazoles/síntesis química , Imidazoles/química , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Tetrahidrofolato Deshidrogenasa/metabolismoRESUMEN
A novel, quick, environmentally safe, and one-pot synthesis of a series of N,N-bis(cyanoacetyl)hydrazine derivatives, bis-imino-2H-chromenes and bis-2-oxo-2H-chromene derivatives have been designed. Some selected newly synthesized compounds were investigated in vitro for their antibacterial activity. Compound 5j is the most toxic compound against Staphylococcus aureus with activity index 171%, followed by compound 15b with activity index 136% compared to standard drug ampicillin. Moreover, compound 15a is the most toxic compound against Escherichia coli with activity index 111% compared to standard drug gentamicin. Minimum inhibitory concentration (MIC) was carried out for compounds with high antibacterial activity. Compound 5j has good MIC (7.8 µg/ml) against Staphylococcus aureus while 15a has good MIC (31.25 µg/ml) against Streptococcus mutans which is better than MIC of the standard drug ampicillin (MIC = 62.5 µg/ml). Compounds 5j, 5k, 15a, 15b and 15e which have good MIC values were introduced to enzyme assay against DNA gyrase and topoisomerase IV. The results showed that compound 15a can strongly inhibit DNA gyrase and topoisomerase IV (IC50 = 27.30 and 25.52 µM respectively), compared to methotrexate as the standard drug (IC50 = 29.01 and 23.55 µM respectively). Structure-activity relationships were also discussed based on the biological and docking simulation results.
Asunto(s)
Antibacterianos/farmacología , Bacterias/enzimología , Cumarinas/farmacología , Hidrazinas/farmacología , Inhibidores de Topoisomerasa/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiología , Técnicas Químicas Combinatorias , Cumarinas/síntesis química , Cumarinas/química , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , Topoisomerasa de ADN IV/metabolismo , Diseño de Fármacos , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Tecnología Química Verde , Humanos , Hidrazinas/síntesis química , Hidrazinas/química , Simulación del Acoplamiento Molecular , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Streptococcus mutans/efectos de los fármacos , Streptococcus mutans/enzimología , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa/síntesis química , Inhibidores de Topoisomerasa/químicaRESUMEN
A novel series of pyrazolo[1,5-a]pyrimidines were synthesized and proved by their spectral and elemental analysis, some elected of the newly synthesized compounds were examined for their cytotoxic activity employing MTT assay on two cancer cell lines (Breast and Hela cancers). Compounds 5, 7e and 7i showed the higher cytotoxicity against two cancer cell lines with (IC50â¯=â¯13.91⯱â¯1.4 and 22.37⯱â¯1.8⯵M/L), (IC50â¯=â¯6.56⯱â¯0.5 and 8.72⯱â¯0.9⯵M/L) and (IC50â¯=â¯4.17⯱â¯0.2 and 5.57⯱â¯0.4⯵M/L) for two cancer cell lines breast and hela respectively, using doxorubicin as a reference drug. The most potent cytotoxic active compounds 5, 7e and 7i presented inhibitory activity against KDM (histone lysine demethylases) with IC50â¯=â¯4.05, 1.91 and 2.31⯵M, respectively. The most potent KDM inhibitor 7e (IC50â¯=â¯1.91⯵M) showed to cause cell cycle arrest at G2/M phase by 4 folds than control and induce total apoptotic effect by 10 folds more than control. In silico studies performed on the more potent cytotoxic active compounds 5, 7e and 7i included lipinisk's rule of five. Moreover, molecular docking study was utilized to explore the binding mode of the most active compounds to the target enzyme (PDB-ID: 5IVE). Also, some bioinformatics studies were carried out for compounds 7e and 7i using Swiss ADME (Swiss Institute of bioinformatics 2018).
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Diseño de Fármacos , Histona Demetilasas/antagonistas & inhibidores , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Histona Demetilasas/metabolismo , Humanos , Células MCF-7 , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
A series of novel 2-imino-4-thiazolidinone derivatives 4a,b was synthesized through reaction of unsymmetrical thioureas 3a,b with chloroacetic acid. Condensation of 4a,b with aromatic aldehydes 5a-eyielded the corresponding 5-arylidene derivatives 6a-j. In addition, the reaction of 4a,b with 4-arylazo-3-hydroxybenzaldehydes 8a-c furnished the respective mono-arylazo-4-thiazolidinones10a-f. All the newly synthesized compounds were confirmed by their elemental analysis and spectral data. The antifungal activity of the newly synthesized compounds was assessed and the compounds 6d, 6e, 6i, 6j, 9a,b and 10a-frevealedhigher antifungal activity towards Alternaria solani than to the standard Ridomil gold plus. Moreover, the DNA toxicity of 4-thiazolidinone derivatives 6d, 9a, 10b, 10c and 10f on the nucleic acid of Alternaria solani (KT354939) was performed and the results showed qualitatively more than 70% cleavage. Also, compounds 6i, 6j, 9b, 10c and 10f were docked inside the active site of 1ZOYenzyme and suitable binding with the active site of amino acids, were displayed according to their bond lengths, angles and conformational energy.
Asunto(s)
Antifúngicos/síntesis química , Diseño de Fármacos , Tiazolidinedionas/química , Antifúngicos/metabolismo , Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Sitios de Unión , ADN/química , ADN/metabolismo , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Conformación de Ácido Nucleico , Relación Estructura-Actividad , Tiazolidinedionas/metabolismo , Tiazolidinedionas/farmacologíaRESUMEN
The key intermediate 3-aminopyrazolo[4,3-c]pyridine-4,6-dione (2) is considered as a precursor for some novel pyrazolo[4,3-c]pyridines 4a-c, arylhydrazopyrazolo[4,3-c]pyridines 8a-e, pyrazolo[4,5,1-ij][1,6]naphthyridines 11a-e and pyrido[4',3':3,4]pyrazolo[1,5-a]-pyrimidines 15a-d through Knovenegal condensation, coupling reaction and Michael addition. Some of the newly synthesized pyrazolo[4,3-c]pyridine derivatives were investigated for anticancer activity. The results of the cytotoxic activity revealed that compound 6b was the most active compound against the breast and liver carcinoma cell lines which gives IC50 values of 1.937 and 3.695⯵g/mL, respectively compared to reference drug (doxorubicin) with IC50 values of 2.527 and 4.749⯵g/ml, respectively. Moreover, compound 6c was potent compound against the colon carcinoma cell line which gives the value of IC50â¯=â¯2.914⯵g/ml compared to doxorubicin with IC50 value of 3.641⯵g/ml. Some selected of the novel synthesized compounds were docked inside the active site of ERK2 enzyme and were found display a suitable binding with the active site amino acids according to their bond lengths, angles and conformational energy.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Pirazoles/farmacología , Piridinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Neoplasias Hepáticas/patología , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
The knöevenagel condensation of 3-phenyl-4-thioxo-2-thiazolidinone (1) with 1-phenyl-3-aryl-1H-pyrazole-4-carbaldehydes 2a-d in refluxing glacial acetic acid or in polyethylene glycol-400 (PEG-400) at room temperature without catalyst, afforded the corresponding 5-hetarylmethylene derivatives 3a-d. [4+2]Cycloaddition reaction of compounds 3 with N-arylmaleimides, acrylonitrile and ethyl acrylate afforded thiopyrano[2,3-d]thiazole derivatives 5a-p. The anticancer activity of some of the newly synthesized compounds was investigated against different human cancer cell lines (MCF7 and HEPG2) and confirmed by molecular docking. Moreover, the structure for one representative example of the new products was confirmed by X-ray crystallography. The structure of all the newly synthesized compounds was established by elemental and spectral data.
Asunto(s)
Antineoplásicos/síntesis química , Piranos/química , Pirazoles/química , Tiazoles/química , Ácido Acético/química , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Reacción de Cicloadición , Células Hep G2 , Humanos , Células MCF-7 , Conformación Molecular , Simulación del Acoplamiento Molecular , Polietilenglicoles/química , Estructura Terciaria de Proteína , Piranos/síntesis química , Piranos/farmacología , Temperatura , Tiazoles/síntesis química , Tiazoles/farmacología , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismoRESUMEN
The starting compound 3-amino-1,7-dihydro-4H-pyrazolo[4,3-c]pyridine-4,6(5H)-dione (1) is reacted with each of diketone and ß-ketoester, forming pyridopyrazolo[1,5-a]pyrimidines 4a,b and 14a,b, respectively. The compounds 4 and 14 reacted with each of aromatic aldehyde and arenediazonium salt to give the respective arylidenes and arylhydrazo derivatives, respectively. The structure of the new products was established using spectroscopic techniques. The cytotoxic activity of selected targets was tested in vitro against three cancer cell lines MCF7, HepG2 and HCT116. The data obtained from enzymatic assays of TrKA indicated that compounds 7b and 16c have the strongest inhibitory effects on TrKA with IC50 = 0.064 ± 0.0037 µg/ml and IC50 = 0.047 ± 0.0027 µg/ml, respectively, compared to the standard drug Larotrectinib with IC50 = 0.034 ± 0.0021 µg/ml for the HepG2 cancer cell line. In cell cycle analysis, compounds 7b, 15b, 16a and 16c caused the greatest arrest in cell cycle at the G2/M phase. In addition, compound 15b has a higher apoptosis-inducing effect (36.72%) than compounds 7b (34.70%), 16a (21.14) and 16c (26.54%). Compounds 7b, 16a and 16c were shown fit tightly into the active site of the TrKA kinase crystal structure (PDB: 5H3Q). Also, ADME study was performed on some selected potent anticancer compounds described in this study.
RESUMEN
Frequent and variant infections are caused by the virtue of opportunistic fungi pathogens. Candidiasis, aspergillosis, and mucormycosis are pathogenic microorganisms that give rise to vast fungal diseases that alternate between moderate to fatal in severity. The use of fluconazole as an antifungal drug was limited due to the acquired resistance in some types of Candida and other fungal species. This study aims to consolidate fluconazole's biological effectiveness against several pathogenic fungi. Six active monoterpenes (MTs) of carvacrol, linalool, geraniol, α-terpinene, citronellal, and nerolidol were selected and encapsulated in nanostructure lipid carrier (NLC) with (NLC-Flu-MTs) and/without (NLC-MTs) fluconazole in one nanoformulation to determine if they will act synergistically or not? The synthesized nanoformulation NLC-Flu-MTs and NLC-MTs exhibited very good particle size of 144.5 nm and 138.6 nm for size and zeta potential values of (- 23.5 mV) and (- 20.3 mV), respectively. Transmission electron microscope investigation confirmed that the synthesized NLCs have regular and spherical shape. The abundance and concentration of the six released monoterpenes were determined, as a novel approach, using GC-MS with very good results and validity. In-vitro antifungal screening was done before and after nano co-delivery against seven pathogenic, and aggressive fungi of Candida tropicalis, Candida krusei, Candida glabrata, Geotrichum Candidum, Candidaalbicans, Aspergillus Niger, and mucor circinelloides. Inhibition Zone diameter (IZD) and the minimum inhibitory concentration (MIC) were measured. Nanoformulations NLC-Flu-MTs and NLC-MTs manifested potential and unique biological susceptibility against all the tested microorganisms with reduced (MIC) values, especially against Candida Tropicalis (MIC = 0.97 µg/ml) which represents 16-fold of the value shown by NLC-MTs (MIC = 15.6 µg/ml) and 64-fold of fluconazole free before nanoformulation (MIC = 62.5 µg/ml). The efficiency of nanomaterials, particularly NLC-Flu-MTs, has become evident in the diminishing value of MIC which affirmed the synergism between fluconazole and the other six monoterpenes.
Asunto(s)
Antifúngicos , Fluconazol , Pruebas de Sensibilidad Microbiana , Monoterpenos , Nanoestructuras , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/administración & dosificación , Fluconazol/farmacología , Fluconazol/química , Monoterpenos/farmacología , Monoterpenos/química , Nanoestructuras/química , Lípidos/química , Sinergismo Farmacológico , Portadores de Fármacos/química , Tamaño de la Partícula , Candida/efectos de los fármacosRESUMEN
A novel series of benzothiazolyl-pyridine hybrids 8a-h and 14a-e were produced from the reaction of enamine derivative 4 with each of the arylcyanoacetamides 5a-h and cyanoacetohydrazides 9a-e. The new products were characterized by spectral techniques (IR, 1H NMR, 13C NMR, and MS). Biological evaluation of 8a-h and 14a-e in vitro against H5N1 and SARS-COV-2 viruses showed that several compounds had significant activity. Compounds 8f-h, which contain fluorine atoms, have better activity against H5N1 and anti-SARS-CoV-2 viruses than the other compounds included in this study. Compound 8h has a trifluoromethyl group at position-3 of the phenyl ring and exhibits a high activity against H5N1 virus with 93 and 60% inhibition at concentrations of 0.5 and 0.25 µmol/µL, respectively, among the tested compounds, and it also showed anti-SARS-CoV-2 virus with a half-maximum inhibition rate of 3.669 µM, among the remaining compounds. The mechanism of action of 8f-h, which is expected to be repurposed against COVID-19, was investigated. The results showed that the compounds have virucidal effects at different stages of the three mechanisms of action. Furthermore, compounds 8f-h were found to possess CoV-3CL protease inhibitory activities with IC50 values of 544.6, 868.2, and 240.6 µg/mL, respectively, compared to IC50 = 129.8 µg/mL of the standard drug lopinavir. Interestingly, compounds 8f-h also showed high inhibitory activity against the H5N1 virus as well as the SARS-CoV-2 virus. Moreover, compounds 8f-h fit admirably into the active site of the SARS-CoV-2 main protease (PDB ID: 6LU7) using the molecular docking Moe software 2015.10.
RESUMEN
In recent years, molecular hybridization strategies have developed into a potent strategy for drug discovery. A series of novel thiopyrano[2,3-d]thiazoles linked to the pyrazole moiety was designed and developed as anticancer agents by a molecular hybridization. Target compounds were synthesized and characterized by spectroscopic tools as well as X-ray crystallography analysis as in the case of thiopyrano[2,3-d]thiazole derivative 5a. The MTT assay was used to demonstrate the in vitro efficacy of compounds 5a-g and 7a-j on MCF-7 and HePG-2. The results showed that some cycloadducts such as bromophenyl-4-thioxo-2-thiazolidinone 3e, 4-methylphenyl derivative of thiopyrano[2,3-d]thiazole 5d, and 6-substituted-thiopyrano[2,3-d]thiazoles 7e-j displayed good to excellent IC50 in the range of 10.08 ± 1.5 to 25.95 ± 2.8 µg/mL against the MCF-7 cell line and from 7.83 ±2.1 to 13.37 ± 1.2 µg/mL against the HePG-2 cell line. To explore the enzymatic tests for isozymes hCAIX and hCAXII, the most promising eight compounds 3e, 5d, and 7e-j with IC50 ranging from 7.83 ± 2.1 to 25.95 ± 2.8 µM were chosen. Compound 7e exhibited an IC50 (0.067 ± 0.003 µM) similar to that of the standard drug AZA against CAIX (0.059 ± 0.003 µM)). For CAXII, the compound 7i had an IC50 equal to 0.123 ± 0.007 µM compared to that of AZA (0.083 ± 0.005 µM). In addition, using flow cytometry, cell cycle analysis and apoptosis studies in HePG-2 were performed for the two potent anticancer and selective carbonic anhydrase agents (7e and 7i). An enzymatic assay of these two compounds against caspase-9 was also examined. Interestingly, the molecular docking studies revealed that compounds 7e and 7i successfully embedded themselves in the active pockets of the CAIX and CAXII enzymes through different interactions. Overall, the novel thiopyrano[2,3-d]thiazole-pyrazole hybrids (7e and 7i) were suggested to be potent and selective inhibitors of CAIX and CAXII.
RESUMEN
INTRODUCTION: It is well known that the grafted multiwalled carbon nanotubes (MWCNTs) have antibacterial activity and lower cytotoxicity. Moreover, pyrazole derivatives have a broad spectrum of biological activity due to their fertile template for many medicinal drugs. On view of these findings we report herein the hybridization between MWCNTs and some pyrazole derivatives as antibacterial agents. MATERIALS AND METHODS: Pyrazole and pyrazolone derivatives were grafted onto the surface of carboxylated MWCNTs via the reaction of carboxylated MWCNTs and the diazonium salts of pyrazoles and pyrazolones using mixed acid treatment. The insertion of the pyrazole and pyrazolone moieties was characterized by Fourier transform infrared (FTIR) spectroscopy, energy dispersion spectroscopy, transmission electron microscopy, X-ray diffraction and thermogravimetric (TGA). RESULTS: The results indicate that pyrazole and pyrazolone moieties successfully attached on carboxylated MWCNTs surface. The neat pyrazole and pyrazolone derivatives and their corresponding carbon nanotubes were tested against Staphylococcus aureus, Bacillus subtilus, Escherichia coli, and Candida albicans bacteria, and Aspergillusniger fungi. The results showed that the grafted carbon nanotubes of pyrazole and pyrazolone derivatives have better antimicrobial activity than the neat pyrazole and pyrazolone derivatives. The molecular docking studies were performed on the most potent antimicrobial compounds to investigate the existence of the interactions between the most active inhibitors and Farnesyl pyrophosphate synthase (FPPS). CONCLUSION: The surface of the carboxylated MWCNTs was successfully grafted with some pyrazole derivatives. The antibacterial activity was investigated for the newly synthesized compounds and indicated that the grafted MWCNTs have good antibacterial activity toward some pathogenic types of bacteria.
Asunto(s)
Antibacterianos/farmacología , Simulación del Acoplamiento Molecular , Nanotubos de Carbono/química , Pirazoles/química , Pirazoles/farmacología , Bacterias/efectos de los fármacos , Dominio Catalítico , Hongos/efectos de los fármacos , Ligandos , Pruebas de Sensibilidad Microbiana , Nanotubos de Carbono/ultraestructura , Pirazoles/síntesis química , Espectroscopía Infrarroja por Transformada de Fourier , Termogravimetría , Difracción de Rayos XRESUMEN
5-Arylidene-2-thioxo-4-thiazolidinones 3a-f react with each of 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl and alpha-D-galactopyranosyl bromides 4a,b in acetone in the presence of aqueous potassium hydroxide at room temperature to afford N-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl) or N-(2,3,4,6-tetra-O-acetyl-beta-d-galactopyranosyl) 2-thioxo-4-thiazolidinone derivatives 5a-f. Similarly, the reaction of 5-cycloalkylidene-2-thioxo-4-thiazolidinones 7a,b with 4a gave the corresponding N-glucosides 8a,b. Also, 5-pyrazolidene rhodanines 10a-e react with 4a to afford the new N-glucosides 11a-e. Treatment of compounds 15 and 16 with 4a in the presence of few drops of triethylamine or in KOH solution accomplished the mono- and bis-nucleosides 17 and 18, respectively. Some selected products were tested for their antimicrobial activities.