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1.
BMC Complement Altern Med ; 19(1): 154, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269948

RESUMO

BACKGROUND: Of over 35 Saudi plants traditionally used to treat liver disorders, majority still lack scientific validations. We therefore, evaluated the anti-oxidative, anti-apoptotic and hepatoprotective potential of Solanum surattense leaves total ethanol-extract (SSEE). METHODS: The cytoprotective (4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide/ MTT assay) and anti-apoptotic (caspase-3/7) potential of SSEE (25-200 µg/mL) were assessed in cultured HepG2 cells against dichlorofluorescein (DCFH)-induced toxicity. The hepatoprotective salutation of SSEE (100 and 200 mg/kg.bw/day) in carbon tetrachloride (CCl4)-intoxicated rats was evaluated by serum biochemistry and histopathology. The anti-oxidative activity of SSEE (31.25-500 µg/mL) was tested by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging and linoleic acid bleaching assays. Also, SSEE was subjected to qualitative phytochemical analysis, and standardized by validated high-performance liquid chromatography (HPTLC). RESULTS: SSEE at doses 50, 100 and 200 µg/mL showed HepG2 cell proliferative and protective potential by about 61.0, 67.2 and 95%, respectively through inhibition of caspase-3/7 against DCFH-toxicity. In CCl4-injured rats, SSEE (200 mg/kg) significantly (P < 0.001) normalized serum transaminases, alkaline phosphatase, bilirubin, cholesterol, triglycerides, and total protein, including tissue malondialdehyde and nonprotein sulfhydryls levels, supported by the liver histopathology. SSEE further showed strong in vitro anti-oxidative and anti-lipid peroxidative activities, evidenced by the presence of alkaloids, flavonoids, tannins, sterols and saponins. Identification of ß-sitosterol (3.46 µg/mg) strongly supported the anti-oxidative and hepatoprotective salutation of SSEE. CONCLUSION: Our findings suggest the therapeutic potential of S. surattense against chemical-induced oxidative stress and liver damage. However, isolation of the active principles and elucidation of mechanism of action remain to be addressed.


Assuntos
Antioxidantes/análise , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Solanum/química , Animais , Apoptose/efeitos dos fármacos , Intoxicação por Tetracloreto de Carbono/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Células Hep G2 , Humanos , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Ratos Wistar , Sitosteroides/análise
2.
J Food Drug Anal ; 27(3): 758-765, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31324291

RESUMO

In traditional Arabian medicine, the Rhus tripartita plant (family Anacardiaceae) has been used to treat inflammatory conditions. Although Rhus extracts have been reported for their cardioprotective effects, information regarding their active principle compounds remains insufficient. The present investigation was aimed at determining the antioxidant chemical constituents of the methanolic extract of R. tripartita stem bark and evaluating their ability to ameliorate methylglyoxal-induced endothelial cell apoptosis. Ten flavonoid compounds (1-10) were isolated and identified using DPPH radical scavenging bioassay-guided chromatographic separation. A new proanthocyanidin (rhuspartin) (1) was isolated and identified as 3,5,13,14-flavantetrol-(4ß→8)-catechin, using extensive spectroscopic data and high resolution-mass spectrometry. Among the compounds (1, 5, 7-10) tested for toxicity toward cultured endothelial cells (HUVECs), the non-cytotoxic compounds 1 and 7 evinced cytoprotective potential that reversed the methylglyoxal-induced apoptosis (by 62% and 64%, respectively) through downregulation of caspase 3/7.

3.
Acta Trop ; 191: 243-247, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30659804

RESUMO

The present study aimed at isolation the phytocompounds from the aerial parts of Gastrocotyle hispida and to evaluate its antioxidant and anticancer potential using in vitro assay. Gastrocotyle hispida is belonging to the family Boraginaceae used as a refreshing drink like tea. The decoction of the leaves is diuretic and is used in the treatment of rheumatism. Phytochemical study of a methanol extract yielded five known compounds viz: ß-sitosterol (GH-1), ß-sitosterol 3-glucoside (GH-2), 1-O-ß-glucopyranosyl-1,4-dihydroxy-2-prenylbenzene (GH-3), 6-Hydroxy-2,2-dimethyl-3-chrom (GH-4) and rosmarinic acid (GH-5). Total phenolic and flavonoid contents were calculated for the extract and fractions, the methanolic extract contained the highest content of total flavonoids (178 mg/g, expressed as quercetin equivalents) and total polyphenol (98.4 mg/g, expressed as gallic acid equivalent). Compounds were isolated by using column chromatography. In vitro, antioxidant activity of the extract and isolated compounds was investigated by DPPH and ABTS radical scavenging assays. The four different cell lines HepG2 (Liver), HEK-293 (Kidney) MCF-7 (Breast) and MDA-MB 231 (Breast) were used against the compounds. The isolated compounds showed dose-dependent free radical scavenging property in all tested models with the IC50 values of 10.2 µg/mL rosmarinic acid (GH-5), 52.1 µg/mL ß-sitosterol (GH-1) and 85 µg/mL for ß-sitosterol 3-glucoside (GH-2). The ß-sitosterol (GH-1) showed significant activity against HepG2 and HEK 293 cell lines. Rosmarinic acid (GH-5) possesses potent anticancer activity against breast cancer cells (MCF7) with the IC50 value of 4.2 µg/mL. It can be concluded that Gastrocotyle hispida has potential antioxidant, anticancer activities and further used as an anticancer agent.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Boraginaceae/química , Células HEK293/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Flavonoides , Humanos , Fenóis , Compostos Fitoquímicos , Quercetina , Arábia Saudita , Sitosteroides
4.
Drug Des Devel Ther ; 12: 3855-3866, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30510401

RESUMO

Background: The obnoxious bitter taste of orally taken antibiotics is one of the biggest problems in the treatment of children. The pediatric population cannot tolerate the bitter taste of drugs and vomit out which ultimately leads to suboptimal therapeutic value, grimace and mental stress so it is the challenging task for the formulation scientists to formulate a palatable formulation particularly to overcome address the issue. Purpose of study: The study aimed to mask and evaluate the unpleasant bitter taste of azithro-mycin (AZ) in the dry suspension dosage form by physisorption technique. Materials and methods: AZ was selected as an adsorbent and titanium dioxide nanoparticles as adsorbate. The AZ nanohybrids (AZN) were prepared by treating fixed amount of adsorbent with a varied amount of adsorbate, prepared separately by dispersing it in an aqueous medium. The mixture was sonicated, stirred followed by filtration and drying. The AZN produced were characterized by various techniques including scanning electron microscopy (SEM), energy dispersive X-rays (EDX), powder X-ray diffraction (PXRD), HPLC and Fourier-transformed infrared (FTIR). The optimized nanohybrid was blended with other excipients to get stable and taste masked dry suspension dosage form. Results: The results confirmed the adsorption of titanium dioxide nanoparticles on the surface of AZ. The fabricated optimized formulation was subjected for taste masking by panel testing and accelerated stability studies. The results showed a remarkable improvement in bitter taste masking, inhibiting throat bite without affecting the dissolution rate. The product showed an excellent stability both in dry and reconstituted suspension. The optimized formulation of AZN and was found stable when subjected to physical and chemical stability studies, this is because of short and single step process which interns limits the exposure of the product to various environmental factors that could potentially affect the stability of the product. The dissolution rate of the optimized formulation of AZN was compared with its marketed counterpart, showing the same dissolution rate compared to its marketed formulation. Conclusion: The current study concludes that, by fabricating AZ-titanium nanohybrids using physisorption can effectively mask the bitter taste of the drug. The palatability and stability of azithromycin formulation was potentially enhanced without affecting its dissolution rate.


Assuntos
Antibacterianos/farmacologia , Azitromicina/farmacologia , Nanopartículas/química , Paladar/efeitos dos fármacos , Titânio/farmacologia , Adsorção , Antibacterianos/química , Azitromicina/química , Voluntários Saudáveis , Humanos , Conformação Molecular , Tamanho da Partícula , Propriedades de Superfície , Titânio/química
5.
Biomed Res Int ; 2018: 5042430, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30276210

RESUMO

Cystic echinococcosis is a serious zoonotic disease caused by Echinococcus granulosus species complex. The current study is the first attempt to determine the level of infection in domestic livestock and to explore the CE-related knowledge and awareness among livestock farmers in different districts of Khyber Pakhtunkhwa, province of Pakistan. A total of 1297 animals were examined for hydatid cysts including 538 cows, 428 buffaloes, 208 sheep, and 123 goats, at different slaughter houses in different districts of Khyber Pakhtunkhwa in 2 years from September 2015 to September 2017. For epidemiological investigations, prevalence in association with various factors (climate, age, and gender), organ specificity, types of cysts (fertile, sterile, or calcified), and viability of cysts parameters was recorded. Basing on the results obtained, areas with high prevalence were selected for further follow-ups and administration of questionnaires to the farmers and dog owners, to provide baseline data about this parasitic disease and to identify potential areas of emergence with correspondence animal and of public health significance. The finding of this study revealed the presence of CE in livestock of KP, Pakistan. The prevalence of hydatid cysts was the highest in buffaloes (15.88%) followed by cows (15.79%), sheep (15.38%), and goats (3.25%). Our investigation revealed close relationship between prevalence and animal age and gender in different months of the year. These findings also showed the highest prevalence of hydatid cysts in liver (63.49%), followed by lungs (23.80%) and mesentery (2.64%). Fertile and viable cysts were observed in all animal species except goats. The highest percentage of fertile and viable cysts was reported from the liver and lungs of sheep. For evaluation of risk factors, a total of 384 respondents were investigated. The results of current study revealed that 97.9% of farmers are not familiar with CE and transmission of this infection from dogs to human and livestock. The present study shows that CE will continue to be of medical and veterinary importance in Pakistan.


Assuntos
Doenças dos Animais/epidemiologia , Doenças Transmissíveis Emergentes/epidemiologia , Equinococose/epidemiologia , Animais , Búfalos , Bovinos , Equinococose/veterinária , Echinococcus granulosus , Feminino , Doenças das Cabras , Cabras , Humanos , Incidência , Masculino , Paquistão/epidemiologia , Prevalência , Fatores de Risco , Ovinos , Doenças dos Ovinos
6.
Bioorg Chem ; 80: 611-620, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30041137

RESUMO

Dual targeting of EGFR and HER2 is a proven anticancer strategy for the treatment of solid tumors. An array of new N-substituted-2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio) acetamides 5-18 were designed and synthesized from the starting compound 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4. The targeted compounds were screened for their cytotoxic activity against MDA-MB-231 breast cancer cell line. The IC50 of all the compounds were in the range of 0.36-40.90 µM. The percentage inhibition towards EGFR was measured and found to be in the range of 63.00-16.90 %. The most potent compounds 5, 9, 15, 17 and 18 were further screened for their activity against both EGFR and HER2 receptors. The compounds showed IC50 in the range of 0.64-1.81 µM for EGFR and 1.13-2.21 µM for HER2, in comparison to erlotinib, the reference drug. Compound 17, the most potent towards EGFR in this series, undergoes cell cycle analysis and was found to arrest the cycle at the G2/M phase. Measurement of the cytotoxicity of compound 17 against normal breast cell line showed mild cytotoxic activity. The most potent compounds were subjected to a single dose of 8 Gy of γ-radiation and the cytotoxicity of the tested compounds was found to increase after irradiation, thus proving the synergistic effect of γ-irradiation. Molecular docking was adopted for all the synthesized compounds to confirm their mechanism of action.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Quinazolinas/farmacologia , Radiossensibilizantes/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Humanos , Modelos Moleculares , Quinazolinas/química , Radiossensibilizantes/química , Receptor ErbB-2/metabolismo , Sulfonamidas/química
7.
FEMS Microbiol Lett ; 365(12)2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29529176

RESUMO

The present study investigates the optimization of tannase production from Aspergillus nidulans for various physicochemical parameters and harvests tannase for its chemical characterization. The maximum tannase activity was observed on the third day of incubation at 35°C and the stability was observed at pH 5.5-6.0 by holding its 100% activity. The tannase was partially purified from A. nidulans [FT10] by ammonium sulfate precipitation at different concentrations, and it was found that at 80% of ammonium sulfate concentration, the precipitate exhibited the maximum activity for tannase of 96 U/ml. LCMS showed its M/Z value as 162.3 which was reconfirmed by SDS-PAGE. The UV spectrum and FTIR confirmed the presence of two oxy- and three hydroxyl groups in the benzene ring structure. The antibacterial activity of tannase was enhanced with antibiotics such as streptomycin and ceftazidime whereas the biofilm formation was significantly inhibited by the purified tannase. The scavenging activity was greatly increased with purified component and when the concentration of the purified tannase, FT10 was increased. To the best of our knowledge, this is one of the few reports where microbial species was used as the source for producing tannase enzyme and its role in various bioactivities such as antibacterial, anti-biofilm and antioxidant activity was evaluated.


Assuntos
Antibacterianos/farmacologia , Aspergillus nidulans/enzimologia , Hidrolases de Éster Carboxílico/isolamento & purificação , Hidrolases de Éster Carboxílico/metabolismo , Antibacterianos/isolamento & purificação , Bactérias/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Fermentação , Proteínas Fúngicas/metabolismo , Concentração de Íons de Hidrogênio
8.
Exp Ther Med ; 15(4): 3883-3891, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29581744

RESUMO

Atriplex suberecta I. Verd is a known phytomedicinal species of Atriplex; however, studies into its bioactivity remain inconclusive. The in vitro and in vivo antioxidative and hepatoprotective potential of A. suberecta ethanol-extract (ASEE) was assessed in the present study. 1,1-diphenyl-2-picrylhydrazyl radical scavenging and ß-carotene bleaching assays revealed that ASEE possesses free radical scavenging and anti-lipid peroxidative activities. These results were supported by the in vitro protection of HepG2 hepatoblastoma cells via abating 2,7-dichlorofluorescein-activated oxidative and apoptotic molecules (caspase-3/-7). In carbon tetrachloride-treated rats, the oral administration of ASEE significantly normalized serum biomarkers of liver function (serum glutamate oxaloacetate, serum pyruvate transaminase, alkaline phosphatase, γ-glutamyl transferase and bilirubin) and the lipid profile (total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides and malondialdehyde), including tissue non-protein sulfhydryl and total protein levels. These results were also supported by liver histopathology, which demonstrated that the therapeutic effect of ASEE was comparable to silymarin. Furthermore, phytochemical analysis of ASEE revealed the presence of flavonoids, alkaloids, tannins and saponins. Rutin, an antioxidant flavonoid, was identified using the validated high-performance thin-layer chromatography method. In conclusion, this is the first report on the therapeutic potential of A. suberecta against chemical-induced oxidative stress and liver damage.

9.
Drug Des Devel Ther ; 12: 255-269, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29440875

RESUMO

Background and aim: The challenges with current antimicrobial drug therapy and resistance remain a significant global health threat. Nanodrug delivery systems are playing a crucial role in overcoming these challenges and open new avenues for effective antimicrobial therapy. While fluticasone (FLU), a poorly water-soluble corticosteroid, has been reported to have potential antimicrobial activity, approaches to optimize its dissolution profile and antimicrobial activity are lacking in the literature. This study aimed to combine an experimental study with molecular modeling to design stable FLU nanopolymeric particles with enhanced dissolution rates and antimicrobial activity. Methods: Six different polymers were used to prepare FLU nanopolymeric particles: hydroxyl propyl methylcellulose (HPMC), poly (vinylpyrrolidone) (PVP), poly (vinyl alcohol) (PVA), ethyl cellulose (EC), Eudragit (EUD), and Pluronics®. A low-energy method, nanoprecipitation, was used to prepare the polymeric nanoparticles. Results and conclusion: The combination of HPMC-PVP and EUD-PVP was found most effective to produce stable FLU nanoparticles, with particle sizes of 250 nm ±2.0 and 280 nm ±4.2 and polydispersity indices of 0.15 nm ±0.01 and 0.25 nm ±0.03, respectively. The molecular modeling studies endorsed the same results, showing highest polymer drug binding free energies for HPMC-PVP-FLU (-35.22 kcal/mol ±0.79) and EUD-PVP-FLU (-25.17 kcal/mol ±1.12). In addition, it was observed that Ethocel® favored a wrapping mechanism around the drug molecules rather than a linear conformation that was witnessed for other individual polymers. The stability studies conducted for 90 days demonstrated that HPMC-PVP-FLU nanoparticles stored at 2°C-8°C and 25°C were more stable. Crystallinity of the processed FLU nanoparticles was confirmed using differential scanning calorimetry, powder X-ray diffraction analysis and TEM. The Fourier transform infrared spectroscopy (FTIR) studies showed that there was no chemical interaction between the drug and chosen polymer system. The HPMC-PVP-FLU nanoparticles also showed enhanced dissolution rate (P<0.05) compared to the unprocessed counterpart. The in vitro antibacterial studies showed that HPMC-PVP-FLU nanoparticles displayed superior effect against gram-positive bacteria compared to the unprocessed FLU and positive control.


Assuntos
Antibacterianos/farmacologia , Portadores de Fármacos , Fluticasona/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nanopartículas , Polímeros/química , Antibacterianos/química , Cristalização , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Fluticasona/química , Derivados da Hipromelose/química , Estrutura Molecular , Nanomedicina , Ácidos Polimetacrílicos/química , Povidona/química , Solubilidade , Tecnologia Farmacêutica/métodos
10.
J Enzyme Inhib Med Chem ; 33(1): 67-73, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29098904

RESUMO

Targeting EGFR has proven to be beneficial in the treatment of several types of solid tumours. So, a series of novel 2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio)-N-substituted acetamide 5-19 were synthesised from the starting material 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4, to be evaluated as dual EGFR/HER2 inhibitors. The target compounds 5-19, were screened for their cytotoxic activity against A549 lung cancer cell line. The percentage inhibition of EGFR enzyme was measured and compared with erlotinib as the reference drug. Compounds 6, 8, 10, and 16 showed excellent EGFR inhibitory activity and were further selected for screening as dual EGFR/HER2 inhibitors. The four selected compounds showed IC50 ranging from 0.009 to 0.026 µM for EGFR and 0.021 to 0.069 µM for the HER2 enzyme. Compound 8 was found to be the most potent in this study with IC50 0.009 and 0.021 µM for EGFR and HER2, respectively.


Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
11.
Artigo em Inglês | MEDLINE | ID: mdl-30643530

RESUMO

Eriobotrya japonica is traditionally used as an antipyretic, digestive, and diuretic agent. Its flowers possess free radical-scavenging, antioxidative, and hepatoprotective effects. We investigated the hepatoprotective potential of E. japonica leaf extract and its various fractions against hepatotoxicity in rats. Liver injury was stimulated by the oral administration of carbon tetrachloride (CCl4; 2.5 mL/kg b.wt.). Male albino rats (n = 55) were distributed arbitrarily into 11 groups: Group I, normal control group; Group II, CCl4 (positive control group); Group III, CCl4 + silymarin; Groups IV and V, CCl4 + two doses of 250 and 500 mg/kg of the 80% methanolic extract of E. japonica leaves, respectively; Groups VI and VII, CCl4 + 250 mg/kg and 500 mg/kg of the ethyl acetate fraction, respectively; Groups VIII and IX, CCl4 + 250 and 500 mg/kg of the butanol fraction, respectively; and Groups X and XI, CCl4 + 250 and 500 mg/kg of the aqueous fraction of E. Japonica leaves, respectively. CCl4-treated rats that were given 250 or 500 mg/kg of the methanol extract of E. Japonica leaves, or its ethyl acetate, butanol, or aqueous fractions, had significantly lower levels of biochemical parameters such as alanine aminotransferase, aspartate transaminase, alkaline phosphate, total protein, gamma-glutamyl transferase, and bilirubin levels than those of the CCl4 positive group. However, the extract and fractions did not significantly affect lipid profiles. Thus, we conclude that Eriobotrya leaf extract and its fractions have a hepatoprotective effect against CCl4-induced hepatotoxicity in rats.

12.
Chem Cent J ; 11(1): 32, 2017 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-29086809

RESUMO

BACKGROUND: Various thiourea derivatives have been used as starting materials for compounds with better biological activities. Molecular modeling tools are used to explore their mechanism of action. RESULTS: A new series of thioureas were synthesized. Fluorinated pyridine derivative 4a showed the highest antimicrobial activity (with MIC values ranged from 1.95 to 15.63 µg/mL). Interestingly, thiadiazole derivative 4c and coumarin derivative 4d exhibited selective antibacterial activities against Gram positive bacteria. Fluorinated pyridine derivative 4a was the most active against HepG2 with IC50 value of 4.8 µg/mL. Molecular docking was performed on the active site of MK-2 with good results. CONCLUSION: Novel compounds were obtained with good anticancer and antibacterial activity especially fluorinated pyridine derivative 4a and molecular docking study suggest good activity as mitogen activated protein kinase-2 inhibitor. Graphical abstract Compound 4a in the active site of MK-2.

13.
Chem Cent J ; 11(1): 42, 2017 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-29086825

RESUMO

BACKGROUND: A series of novel N-(2, 6-dimethoxypyrimidin-4-yl)-4-(3-(aryl)thioureido) benzenesulfonamides 3a-t was synthesized by the addition of N-(2,6-dimethoxypyrimidin-4-yl)-4-isothiocyanatobenzenesulfonamide 2 to the appropriate aromatic amine. The structures of the synthesized compounds were inspired from the second line antituberculosis pro-drugs. RESULTS: Most of the new compounds were screened for their activity against Mycobacterium tuberculosis. The results of the antimycobacterial assay showed that compound 3i exerted the highest activity (MIC = 3.13 µg/mL), followed by compound 3s (MIC = 6.25 µg/mL). CONCLUSION: The structure-activity relationship (SAR) analysis revealed that the introduction of the benzo[1,3]dioxol moiety in 3i and the 4-morpholinyl-4-phenyl moiety in 3s has proven to give the most potent compounds in this study. Docking of the promising compounds inside the active site of M. tuberculosis enoyl reductase InhA was performed in order to emphasize the results. The compounds showed a similar orientation to that of GSK 625 inside the active site of 5JFO and bind to Met 98 in a way similar to that of the co-crystallized ligand.

14.
Eur J Med Chem ; 141: 84-91, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29028534

RESUMO

An array of some new N-(substituted)-2-((4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)acetamide 5-19 were synthesized from the starting compound 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl)benzenesulfonamide 4, to be assessed for their cytotoxic activity against A549 lung cancer cell line and to determine their inhibitory effect on EGFR tyrosine kinase enzyme. Compounds 5-19 showed high activity towards A549 cell line with IC50 values of 0.12-8.70 µM. Compounds 6, 12 and 18 were the most potent in this series. These compounds were further screened as dual inhibitors for EGFR/HER2 enzymes in comparison with erlotinib and were found to possess very potent activity. Compound 12 showed the highest activity with IC50 values of 0.06 µM and 0.30 µM towards EGFR and HER2, respectively. Accordingly, the apoptotic effect of the most potent compounds 6, 12 and 18 was investigated and showed a marked increase in the level of caspases-3 by 6, 9 and 8 folds, respectively, compared to the control cells. Moreover, Molecular modeling was performed inside the active site of EGFR, keeping in mind their binding possibilities, bond lengths, angles and energy scores. It was found that the most active compounds demonstrated the best binding scores in the active site of EGFR, which may clarify their high inhibition profile.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
15.
Afr J Tradit Complement Altern Med ; 14(2): 161-165, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28573232

RESUMO

BACKGROUND: Several edible plants are used in Kingdom of Saudi Arabia since early time to control microbial infections. In the present study, twenty-four Saudi Arabian medicinal plants d according to traditionally used were select and investigated for the antimicrobial activities. MATERIALS AND METHODS: This study was designed at evaluating the antimicrobial activities of the methanol extracts of twenty-four species of sixteen plant families used in the traditional medicine by Saudi Arabian people for the treatment of numerous ailments of the microbial and non-microbial origin against four Gram-positive, four Gram-negative bacteria and four fungi and yeast using the agar well diffusion method. RESULTS: Of most of the plants tested were found to be active against two to eight organisms. Five plants were active against eight organisms. The data appeared that extracts of Echium arabicum (SY-176), Rhantarium epapposum (SY-Rumex vesicarus (SY-181), Ziziphus nummularia (SY-188), Caylusea hexagyna (SY-197) and Artemisia monosperma (SY-198) have anti-microbial activity against the most of tested bacteria, fungi and yeast. Whereas (SY-, the extracts of Teucrium oliverianum (SY-175), Zilla spinosa (SY-187), and Rhazya stricta (SY-195) have poor action against the tested bacteria, fungi and yeast. CONCLUSION: The antimicrobial activity of plant extracts against bacteria was more effective than against fungi.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Magnoliopsida , Extratos Vegetais/farmacologia , Plantas Medicinais , Artemisia , Bactérias/crescimento & desenvolvimento , Echium , Fungos/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Resedaceae , Rumex , Arábia Saudita , Ziziphus
17.
Eur J Med Chem ; 134: 304-315, 2017 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-28427017

RESUMO

Hybrid molecules are used as anticancer agents to improve effectiveness and diminish drug resistance. So, the current study aimed to introduce twenty novel phenothiazine sulfonamide hybrids 5-22, 24 and 25 of promising anticancer activity. Compounds 11 and 13 revealed more potent anticancer properties (IC50 8.1 and 8.8 µM) than that of the reference drug (doxorubicin, IC50 = 9.8 µM) against human breast cancer cell line (T47D). To determine the mechanism of their anticancer activity, compounds 5, 6, 7, 11, 13, 14, 16, 17, 19 and 22 that showed promising activity on T47D, were evaluated for their aromatase inhibitory effect. The study results disclose that the most potent aromatase inhibitors 11 and 13 showed the lowest IC50 (5.67 µM and 6.7 µM), respectively on the target enzyme. Accordingly, the apoptotic effect of the most potent compound 11 was extensively investigated and showed a marked increase in Bax level up to 55,000 folds, and down-regulation in Bcl2 to 5.24*10-4 folds, in comparison to the control. Furthermore, the effect of compound 11 on caspases 3, 8 and 9 was evaluated and was found to increase their levels by 20, 34, and 8.9 folds, respectively, which indicates the activation of both intrinsic and extrinsic pathways. Also, the effect of compound 11 on the cell cycle and its cytotoxic effect were examined. Moreover, a molecular docking and computer aided ADMET studies were adopted to confirm their mechanism of action.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacologia , Fenotiazinas/química , Fenotiazinas/farmacologia , Apoptose/efeitos dos fármacos , Aromatase/metabolismo , Mama/efeitos dos fármacos , Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
18.
J Asian Nat Prod Res ; 19(11): 1093-1101, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28361549

RESUMO

Two new sesquiterpene lactones 3R, 8R-dihydroxygermacr-4(15),9(10)-dien-6S,7S,11RH,12,6-olide (1) and 1R, 8S-dihydroxy-11R,13-dihydrobalchanin(2), together with two known compounds 11-epiartapshin (3) and 3'-hydroxygenkwanin (4), were isolated from Artemisia sieberi. Their structures were elucidated by 1D, 2D NMR, MS, and X-ray diffraction. Compound 4 inhibited Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus with Minimal inhibitory concentration values of 50 and 25 µg/disk, respectively. All the isolated compounds exhibited moderate antifungal activities.


Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Artemisia/química , Asteraceae/química , Lactonas/isolamento & purificação , Lactonas/farmacologia , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Antibacterianos/química , Bacillus subtilis/efeitos dos fármacos , Lactonas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Extratos Vegetais/química , Sesquiterpenos/química , Staphylococcus aureus/efeitos dos fármacos , Estereoisomerismo
19.
Anticancer Agents Med Chem ; 17(10): 1411-1425, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28356021

RESUMO

BACKGROUND: Thiourea derivatives bearing sulfonamide moiety are well known for their anticancer activity. OBJECTIVE: The anticancer activity of the target compounds was studied, via inhibition of COX-2 enzyme. METHOD: A series of novel thioureas 5a-n, 8, quinazoline 6, benzo[g]quinazoline 7 and benzo[1,3] dioxole 10, bearing a sulfonamide moiety was synthesized from the starting compound N-(2,6-dimethoxypyrimidin-4-yl)-4- isothiocyanatobenzenesulfonamide 2. The target compounds were screened against HepG2, MCF-7, Caco-2, HCT-116, PC-3 cancer cell lines and VERO-B normal cell line. RESULTS: Out of all the tested compounds, compound 5c showed a broad selective cytotoxicity against HepG2, MCF-7, Caco-2 and PC-3 cancer cells. Moreover, a sensitization assay was performed on Caco-2 cells, and compound 5c proved to act as a chemosensitizer for cisplatin on colon cancer (Caco-2) cells. The target compounds were further screened in vitro for their anti COX1/COX2 activity and investigated in vivo as antiinflammatory agents against carrageenan-induced rat paw oedema model. CONCLUSION: Compound 5g showed the most selective inhibitory activity against COX-2. While, compounds 5a, 6, 5m, 5n, 5g and 5i revealed significant anti-inflammatory effect as presented in carrageenan-induced oedema assay. Molecular docking of the tested compounds disclosed important binding modes which may be responsible for their anticancer activity via inhibition of the COX-2 enzyme.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Sulfonamidas/farmacologia , Tioureia/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Tioureia/síntese química , Tioureia/química
20.
J Mol Recognit ; 30(1)2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27594436

RESUMO

The increasing prevalence of antibiotic-resistant bacteria is creating a real challenge for health care systems worldwide, making the development of novel antibiotics a necessity. In addition to the development of new antibiotics, there is an urgent need for in-depth characterization of the mechanisms of bacterial resistance toward new drugs. Here, we used essential oils extracted in our laboratory from Piper cubeba against methicillin-resistant Staphylococcus aureus ATCC 43300, one of the most prominent antibiotic-resistant bacteria. Effects of the essential oils extracted from P cubeba on bacteria were mainly evaluated using 2 powerful microscopy techniques: atomic force microscopy and transmission electron microscopy. High-resolution atomic force microscopy images of the cells were obtained close to their native environment by immobilizing the cells on porous Polyether sulfone membranes, which were prepared in our laboratory with a wide range and distribution of pore sizes and depth. Inhibition zones (mm) and minimum inhibitory concentrations were determined. Two different concentrations of the oil were used to treat the cells: 50 µg/mL minimum inhibitory concentration and 25 µg/mL. The 50 µg/mL oil solution caused severe damage to the bacterial cells at microscopic levels while the 25 µg/mL solution showed no effects compared to the control. However, at nanoscopic levels, the 25 µg/mL oil solution caused significant changes in the cell wall, which could potentially impair bacterial activities. These results were also confirmed by transmission electron microscopy micrographs. Our results indicate that the extract has a good biological activity against methicillin- and oxacillin-resistant S aureus and that it acts on the cell wall and plasma (cytoplasmic) membrane.


Assuntos
Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Óleos Voláteis/farmacologia , Piper/química , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Testes de Sensibilidade Microbiana , Microscopia de Força Atômica , Microscopia Eletrônica de Transmissão , Óleos Vegetais/farmacologia
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