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Rates of obesity increase worldwide year after year. This review explored if customized multivitamins (CMV) resulted in less micronutrient deficiency and higher serum levels of vitamins and minerals when compared to standard multivitamins (SMV) post-bariatric surgery in adults. Vitamins investigated were vitamins B1, B6, B12, D, parathyroid hormone (PTH), calcium, iron, hemoglobin, ferritin, folic acid, zinc, and magnesium. In Roux-en-Y gastric bypass (RYGB) patients weight loss surgeries (WLS) Forte or chewable CMV were studied, while in sleeve gastrectomy (SG) patients, WLS Optimum 1.0 (Opt. 1.0) or WLS Optimum 2.0 (Opt. 2.0) multivitamins were studied. An electronic search was performed on three databases (PubMed (n=28), Embase (n=120), and Cochrane (n=106)) to identify clinical trials and cohort studies. The inclusion criteria focused on studies since 2011 for adults ≥18 years old post-GB and SG. The keywords included bypass, sleeve, WLS, and multivitamins. Four clinical trials and three cohort studies were included. Jadad Scale was used to assess the quality and the bias risk in the clinical trials and the Newcastle-Ottawa scale (NOS) was used for the cohort studies. The PICO model and PRISMA rules were followed, where the outcomes targeted certain vitamin serum levels and the levels of deficiencies. The results of WLS Forte were better than SMV. The chewable CMV and Opt. 1.0 results were comparable to SMV. Opt. 2.0 was slightly better than Opt. 1.0. Further modifications would enhance the CMV presented in this systemic review. SMV would still be recommended until CMV are modified and tested. Multi-center trials that monitor the effect of the modified CMV on the serum levels of vitamins and minerals in the longer term in different wider populations are needed.
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Most of the current chemotherapeutic medications are extremely toxic, exhibit little selectivity, and contribute to the emergence of treatment resistance. Consequently, the discovery of targeted chemotherapy drugs with high selectivity and low side effects is necessary for cancer treatment. The quinazoline system has a broad range and a long history of biological activities. Numerous quinazoline derivatives have been used to treat different types of cancer by working on various molecular targets. This review presents various chemical information, including molecular structure, design, and biological activity of some reported quinazolines that function by inhibiting four types of important molecular targets: dihydrofolate reductase, breast cancer resistant protein, poly-(ADP-ribose)-polymerase, and tubulin polymerization.
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Sixteen new thalidomide analogs were synthesized. The new candidates showed potent in vitro antiproliferative activities against three human cancer cell lines, namely hepatocellular carcinoma (HepG-2), prostate cancer (PC3), and breast cancer (MCF-7). It was found that compounds XII, XIIIa, XIIIb, XIIIc, XIIId, XIVa, XIVb, and XIVc showed IC50 values ranging from 2.03 to 13.39 µg/mL, exhibiting higher activities than thalidomide against all tested cancer cell lines. Compound XIIIa was the most potent candidate, with an IC50 of 2.03 ± 0.11, 2.51 ± 0.2, and 0.82 ± 0.02 µg/mL compared to 11.26 ± 0.54, 14.58 ± 0.57, and 16.87 ± 0.7 µg/mL for thalidomide against HepG-2, PC3, and MCF-7 cells, respectively. Furthermore, compound XIVc reduced the expression of NFκB P65 levels in HepG-2 cells from 278.1 pg/mL to 63.1 pg/mL compared to 110.5 pg/mL for thalidomide. Moreover, compound XIVc induced an eightfold increase in caspase-8 levels with a simultaneous decrease in TNF-α and VEGF levels in HepG-2 cells. Additionally, compound XIVc induced apoptosis and cell cycle arrest. Our results reveal that the new candidates are potential anticancer candidates, particularly XIIIa and XIVc. Consequently, they should be considered for further evaluation for the development of new anticancer drugs.
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Antineoplásicos , Talidomida , Masculino , Humanos , Talidomida/farmacología , Antineoplásicos/farmacología , Relación Estructura-Actividad , Quinazolinas/farmacología , Factor A de Crecimiento Endotelial Vascular/farmacología , Adyuvantes Inmunológicos/farmacología , Células MCF-7 , Factores Inmunológicos/farmacología , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Apoptosis , Línea Celular Tumoral , Relación Dosis-Respuesta a DrogaRESUMEN
An essential target for COVID-19 is the main protease of SARS-CoV-2 (Mpro). With the objective of targeting this receptor, a novel set of pyrido[1,2-a]pyrrolo[2,3-d]pyrimidines with terminal carboxamide fragments was designed, synthesized, and considered as an initial motif for the creation of effective pan-coronavirus inhibitors. Accordingly, nine derivatives (21-29) have been introduced for in vitro assay to evaluate their antiviral activity and cytotoxicity effect against COVID-19 virus using Vero cells. The obtained data revealed that the majority of these derivatives showed potent cellular anti-COVID-19 activity and prevent viral growth by more than 90% at two different concentrations with weak or even no detectable cytotoxic effect on Vero cells. Extensive molecular docking simulations highlighted proper non-covalent interaction of new compounds within the binding pocket of Mpro as a potential target for their antiviral activity. In vitro assay for all the synthesized derivatives against the viral Mpro target indicated that compounds 25 and 29 have promising inhibitory activity with IC50 values at low micromolar concentrations. The molecular dynamic simulation results predicted the stability of compound 29 in the binding cavity of SARS-CoV-2 Mpro and hence supported the high inhibitory activity shown by the In vitro assay. These results suggested that compounds 25 and 29 merit further investigations as promising drug candidates for the management of SARS-CoV-2.
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New quinazoline-sulfonylurea hybrids were prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as a reference drug. Compounds VI-6-a, V, IV-4, VI-4-c, IV-6, VI-2-a, IV-1, and IV-2 were more potent than the reference glibenclamide. They induced significant reduction in the blood glucose levels of diabetic rats: 78.2, 73.9, 71.4, 67.3, 62, 60.7, 58.4, and 55.9%, respectively, while the reference glibenclamide had 55.4%. Compounds IV-1, VI-2-a, IV-2, V, and IV-6 showed more prolonged antidiabetic activity than glibenclamide. Moreover, molecular docking and pharmacokinetic studies were performed to examine binding modes of the prepared compounds against peroxisome proliferator-activated receptor gamma (PPARγ). The highest active compounds exhibited good binding affinity with high free energy of binding against PPARγ. In silico absorption, distribution, metabolism, elimination and toxicity (ADMET) studies were performed to investigate pharmacokinetics and safety of the synthesized compounds. They showed considerable human intestinal absorption with low toxicity profile.
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Diabetes Mellitus Experimental , PPAR gamma , Animales , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Gliburida/farmacología , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Simulación del Acoplamiento Molecular , PPAR gamma/metabolismo , Quinazolinas/efectos adversos , Ratas , Compuestos de Sulfonilurea/efectos adversos , Receptores de Sulfonilureas/agonistasRESUMEN
The lack of effective therapies for epileptic patients and the potentially harmful consequences of untreated seizure incidents have made epileptic disorders in humans a major health concern. Therefore, new and more potent anticonvulsant drugs are continually sought after, to combat epilepsy. On the basis of the pharmacophoric structural specifications of effective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists with an efficient anticonvulsant activity, the present work reports the design and synthesis of two novel sets of quinoxaline derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo according to the pentylenetetrazol-induced seizure protocol, and the results were compared with those of perampanel as a reference drug. Among the synthesized compounds, 24, 28, 32, and 33 showed promising activities with ED50 values of 37.50, 23.02, 29.16, and 23.86 mg/kg, respectively. Docking studies of these compounds suggested that AMPA binding could be the mechanism of action of these derivatives. Overall, the pharmacophore-based structural optimization, in vivo and in silico docking, and druglikeness studies indicated that the designed compounds could serve as promising candidates for the development of effective anticonvulsant agents with good pharmacokinetic profiles.
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Anticonvulsivantes/farmacología , Quinoxalinas/farmacología , Convulsiones/tratamiento farmacológico , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/antagonistas & inhibidores , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/química , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Masculino , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Pentilenotetrazol , Quinoxalinas/síntesis química , Quinoxalinas/química , Convulsiones/inducido químicamente , Relación Estructura-Actividad , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/administración & dosificaciónRESUMEN
A new peroxy fatty acid, tagetnoic acid (5) [4-((3S,6S)-6-((3E,8E)-octadeca-3,8-dien-1-yl)-3,6-dihydro-1,2-dioxin-3-yl)butanoic acid] and four known metabolites: ecliptal (5-formyl-α-terthiophene) (1), 5-(4-hydroxybut-1-ynyl)-2,2'-bithiophene (2), 22,23-dihydrospinasterone (3), and stigmasterol (4) were separated from the n-hexane fraction of the aerial parts of Tagetes minuta L. (Asteraceae). Their chemical structures were verified using IR, UV, 2D and 1D NMR, and HRMS. Compounds 3-5 displayed potent lipoxygenase inhibitory potential with IC50s 2.26, 1.83, and 1.17 µM, respectively compared to indomethacin (IC50 0.89 µM). Moreover, molecular docking study revealed that the potent activity of 5 is due to H-bonding and hydrophobic interaction. The results of this study suggested that Tagetes minuta dietary consumption would be useful for the individuals at risk of acute and chronic inflammatory disorders.
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Ácidos Grasos/aislamiento & purificación , Inhibidores de la Lipooxigenasa/aislamiento & purificación , Extractos Vegetales/química , Tagetes/química , Ácidos Grasos/farmacología , Humanos , Inflamación/tratamiento farmacológico , Inhibidores de la Lipooxigenasa/metabolismo , Inhibidores de la Lipooxigenasa/farmacología , Simulación del Acoplamiento Molecular , Extractos Vegetales/farmacología , Unión Proteica , Arabia Saudita , Estigmasterol/aislamiento & purificación , Tiofenos/aislamiento & purificaciónRESUMEN
A new series of 2-substituted-2,3-dihydrophthalazine-1,4-diones (2- 9) were designed and synthesized to evaluate their anticonvulsant activity. The neurotoxicity was assessed using the rotarod test. Molecular docking was performed for the synthesized compounds to assess their binding affinities as γ-aminobutyric acid A (GABA-A) receptor agonists as a possible mechanism of their anticonvulsant action, to rationalize their anticonvulsant activity in a qualitative way. The data obtained from the molecular modeling was strongly matched with that obtained from the biological screening, which revealed that compounds 5a , 9b , and 9h showed the highest binding affinities toward the GABA-A receptor and also showed the highest anticonvulsant activities with relative potencies of 1.66, 1.63, and 1.61, respectively, compared with diazepam. The most active compounds 5a , 9b , and 9h were further tested against maximal electroshock seizures. Compounds 5a and 9b showed 100% protection at a dose level of 125 µg/kg, while compound 9h exhibited 83.33% protection at the same dose level. A GABA enzymatic assay was performed for these highly active compounds to confirm the obtained results and to explain the possible mechanism for their anticonvulsant action. These agents exerted low neurotoxicity and a high safety margin compared with valproate as a reference drug. Most of our designed compounds exhibited a good ADMET profile.
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Anticonvulsivantes/farmacología , Diseño de Fármacos , Agonistas de Receptores de GABA-A/farmacología , Ftalazinas/farmacología , Receptores de GABA-A/metabolismo , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/química , Simulación por Computador , Relación Dosis-Respuesta a Droga , Agonistas de Receptores de GABA-A/síntesis química , Agonistas de Receptores de GABA-A/química , Modelos Moleculares , Estructura Molecular , Ftalazinas/síntesis química , Ftalazinas/química , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
BACKGROUND: Quinazolines and quinazolinones derivatives are well known for their important range of therapeutic activities. OBJECTIVE: The study aims to carry out the synthesis of some derivatives of substituted fluoroquinazolinones based on structure-based design and evaluation of their antibacterial, antifungal, and anti-biofilm activities. METHODS: Compounds were chemically synthesized by conventional methods. Structures were established on the basis of spectral and elemental analyses. The antimicrobial potential was tested against various microorganisms using the agar disc-diffusion method. MIC and MBC as well as anti-biofilm activity for the highly active compounds were assessed. Moreover, the computational studies were performed using Auto dock free software package (version 4.0) to explain the predicted mode of binding. RESULTS: All derivatives (5-8), (10a-g), and (A-H) were biologically tested and showed significant antimicrobial activity comparable to the reference compounds. Compounds 10b, 10c, and 10d had a good MIC and MBC against Gram-positive bacteria, whereas 10b and 10d showed significant MIC and MBC against Gram-negative bacteria. However, compounds E and F exhibited good MIC and MBC against fungi. Compound 10c and 8 exhibited significant anti-biofilm activity towards S. aureus and M. luteus. Molecular docking study revealed a strong binding of these derivatives with their receptor-site and detected their predicted mode of binding. CONCLUSION: The synthesized derivatives showed promising antibacterial, antifungal, and antibiofilm activities. Modeling study explained their binding mode and showed strong binding affinity with their receptor-site. The highly active compounds 5 and 10c could be subjected to future optimization and investigation to be effective antimicrobial agents.
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Antibacterianos/farmacología , Antifúngicos/farmacología , Quinazolinonas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/metabolismo , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/metabolismo , Aspergillus niger/efectos de los fármacos , Aspergillus oryzae/efectos de los fármacos , Bacterias/efectos de los fármacos , Bacterias/enzimología , Biopelículas/efectos de los fármacos , Candida albicans/efectos de los fármacos , Candida albicans/enzimología , Ligasas de Carbono-Nitrógeno/química , Ligasas de Carbono-Nitrógeno/metabolismo , Diseño de Fármacos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Quinazolinonas/síntesis química , Quinazolinonas/química , Quinazolinonas/metabolismo , Relación Estructura-Actividad , Tetrahidrofolato Deshidrogenasa/química , Tetrahidrofolato Deshidrogenasa/metabolismoRESUMEN
Some fluoroquinazolinones (Aâ»H) were designed, synthesized and biologically evaluated for their antitumor activity against the two cell lines, MCF-7 and MDA-MBA-231. New derivative G (IC50 = 0.44 ± 0.01 µM) showed antitumor activity, better than that of the reference drug erlotinib (IC50 = 1.14 ± 0.04 µM) against MCF-7. New derivative E (IC50 = 0.43 ± 0.02 µM) showed higher activity than the reference drug erlotinib (IC50 = 2.55 ± 0.19 µM) against MDA-MBA-231. Furthermore, the EGFR (epidermal growth factor receptor) and tubulin inhibition assays were carried out for the highest active derivatives to reveal the expected mechanism of action. They exhibited significant results compared to the reference drugs. Molecular docking simulations were performed on EGFR and tubulin binding sites to rationalize the experimental results and describe their binding modes. The results of the molecular modeling study were correlated with that of the antitumor screening.
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Receptores ErbB , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas , Quinazolinas , Moduladores de Tubulina , Tubulina (Proteína) , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Células MCF-7 , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/síntesis química , Quinazolinas/química , Quinazolinas/farmacología , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologíaRESUMEN
A series of new fluoroquinazolinone 6â»8 and 10aâ»g derivatives was designed, prepared and screened for their in vitro cytotoxic activity against human cancer cell lines MCF-7 and MDA-MBA-231. Compounds 6 (IC50 = 0.35 ± 0.01 µM), 10f (IC50 = 0.71 ± 0.01 µM), 10d (IC50 = 0.89 ± 0.02 µM) and 10a (IC50 = 0.95 ± 0.01 µM) displayed broad spectrum anticancer activity better than the reference drug gefitinib (IC50 = 0.97 ± 0.02 µM) against MCF-7. Compounds 10e (IC50 = 0.28 ± 0.02 µM), 10d (IC50 = 0.38 ± 0.01 µM), 7 (IC50 = 0.94 ± 0.07 µM) and 10c (IC50 = 1.09 ± 0.01 µM) showed better activity than the reference gefitinib (IC50 = 1.30 ± 0.04 µM) against MDA-MBA-231. Moreover, EGFR and tubulin inhibition assays were performed for the highest active derivatives and showed remarkable results comparing to the reference drugs. In order to assess and explain their binding affinities, molecular docking simulation was studied against EGFR and tubulin binding sites. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Simulación del Acoplamiento Molecular , Polimerizacion , Quinazolinonas/síntesis química , Quinazolinonas/farmacología , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Sitios de Unión , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Colchicina/farmacología , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib/farmacología , Humanos , Concentración 50 Inhibidora , Quinazolinonas/químicaRESUMEN
ABSTRACT Cyperus rotundus L. (Suada, Sueda, family: Cyperaceae) is vastly spread in several world's subtropical and tropical regions. It had variable traditional uses and bioactivities. A new flavonol derivative: cyperaflavoside (myricetin 3,3',5'-trimethyl ether 7-O-β-D-glucopyranoside) and five flavonoids: vitexin, orientin, cinaroside, quercetin 3-O-β-D-glucopyranoside, and myrcetin 3-O-β-D-glucopyranoside were separated from the methanolic extract of C. rotundus aerial parts. Their structures were verified based on UV, IR, NMR (1D and 2D), HRESIMS, and comparison with literature. All metabolites were assessed for their 5-lipoxygenase inhibitory potential. All compounds possessed 5-lipoxygenase inhibitory potentials with IC50s 5.1, 4.5, 5.9, 4.0, 3.7, and 2.3 µM, respectively, in comparison to indomethacin (IC50 0.98 µM). These results supported the traditional uses of C. rotundus in treating inflammation and its related symptoms.
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Fungi produce a wide range of structurally unique metabolites. Depsidones represent one of the most interesting classes of metabolites, consisting of two 2,4-dihydroxybenzoic acid rings linked together by both ether and ester bonds. Naturally occurring depsidones are produced by lichen, fungi, and plants. They possessed a wide array of bioactivities, including antioxidant, antiproliferative, antimalarial, cytotoxic, antibacterial, radical scavenging, antihypertensive, anti-inflammatory, antifungal, and aromatase and protein kinase inhibitory. In order to point out the potential of this class of compounds, the present review focuses only on the depsidones that have been isolated from fungal source and published from 1978 to 2018. This review outlined the research on the biosynthesis, source, isolation, spectral and physical data, and bioactivities of the naturally occurring fungal depsidones. On the basis of 88 references, >â¯80 compounds have been described.
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Depsidos/química , Depsidos/farmacología , Hongos/química , Lactonas/química , Lactonas/farmacología , Animales , Humanos , Estructura MolecularRESUMEN
Malaria is one of the major infectious diseases and foremost cause of mortality and morbidity in many subtropical and tropical regions. In the last years, the situation has become worst in many ways, due to increase in the parasites resistance to various available antimalarial agents. Furthermore, malaria`s control is beginning to be more sophisticated by the parallel spread of mosquito vector`s resistance to the available insecticides. Recently, there is a wide consensus to seek for target specific, safe, affordable, and effective new antimalarial agents, which can compete with synthetic ones. Endophytic fungi are of a growing interest as prominent sources of structurally unique bioactive natural products. The bio-metabolites isolated from endophytic fungi, possessing antimalarial potential may compose the base for the synthesis of novel drugs that might be utilized to withstand malaria and its resistance. For getting information on the various studies, PubMed, Google Scholar, ScienceDirect, SpringerLink, Scopus, and Wiley search was done using keywords (malaria, endophytic fungi, and antimalarial activity). The present review covers the literature published from 1996 to 2017 and highlights the metabolites for which antimalarial activities have been reported. Overall, 135 fungal metabolites and 72 references are cited. In addition, their structure, chemical class, fungal source, host, and activity have been presented. This review shows the significance of endophytic fungi as a wealthy pool of antimalarial agents.
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Antimaláricos/química , Productos Biológicos/química , Endófitos/química , Alcaloides/química , Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Cromonas/química , Cromonas/aislamiento & purificación , Cromonas/farmacología , Depsipéptidos/química , Depsipéptidos/aislamiento & purificación , Depsipéptidos/farmacología , Endófitos/metabolismo , Humanos , Malaria/tratamiento farmacológico , Malaria/transmisión , Plasmodium/efectos de los fármacos , Pirrolidinonas/química , Pirrolidinonas/aislamiento & purificación , Pirrolidinonas/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/aislamiento & purificación , Compuestos de Espiro/farmacologíaRESUMEN
Some novel anthranilate diamides derivatives 4a-e, 6a-c and 9a-d were designed and synthesized to be evaluated for their in vitro anticancer activity. Structures of all newly synthesized compounds were confirmed by infra-red (IR), high-resolution mass (HR-MS) spectra, ¹H nuclear magnetic resonance (NMR) and 13C nuclear magnetic resonance (NMR) analyses. Cytotoxic screening was performed according to (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium (MTT) assay method using erlotinib as a reference drug against two different types of breast cancer cells. The molecular docking study was performed for representative compounds against two targets, epidermal growth factor receptor (EGFR) and tubulin in colchicine binding site to assess their binding affinities in order to rationalize their anticancer activity in a qualitative way. The data obtained from the molecular modeling was correlated with that obtained from the biological screening. These data showed considerable anticancer activity for these newly synthesized compounds. Biological data for most of the anthranilate diamide showed excellent activity with nanomolar or sub nanomolar half maximal inhibitory concentration (IC50) values against tumor cells. EGFR tyrosine kinase (TK) inhibition assay, tubulin inhibition assay and apoptosis analysis were performed for selected compounds to get more details about their mechanism of action. Extensive structure activity relationship (SAR) analyses were also carried out.
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Antineoplásicos , Neoplasias de la Mama , Sistemas de Liberación de Medicamentos/métodos , Receptores ErbB , Simulación del Acoplamiento Molecular , Proteínas de Neoplasias , Multimerización de Proteína/efectos de los fármacos , Moduladores de Tubulina , Tubulina (Proteína) , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/química , Receptores ErbB/metabolismo , Femenino , Humanos , Células MCF-7 , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologíaRESUMEN
Fusarithioamide B (6), a new aminobenzamide derivative with unprecedented carbon skeleton and five known metabolites: stigmast-4-ene-3-one (1), stigmasta-4,6,8(14),22-tetraen-3-one (2), p-hydroxyacetophenone (3), tyrosol (4), and fusarithioamide A (5) were separated from Fusarium chlamydosporium EtOAc extract isolated from Anvillea garcinii (Burm.f.) DC. leaves (Asteraceae). The structure elucidation and completeassignment of the isolated metabolites were performed mainly by the aid of various NMR and MS data. Fusarithioamide B (6) has been assessed for antibacterial and antifungal activities towards various microbial strains by disc diffusion assay. It exhibited selective antifungal activity towards C. albicans (MIC 1.9⯵g/ml and IZD 14.5â¯mm), comparing to clotrimazole (MIC 2.8⯵g/ml and IZD 17.9â¯mm). Also, it possessed high antibacterial potential towards E. coli, B. cereus, and S. aureus compared to ciprofloxacin. Furthermore, 6 was tested for the in vitro cytotoxic effect against KB, HCT-116, BT-549, MCF-7, SKOV-3, and SK-MEL cell lines. It had selective and potent effect towards BT-549, MCF-7, SKOV-3, and HCT-116 cell lines with IC50s 0.09, 0.21, 1.23, and 0.59⯵M, respectively compared to doxorubicin (IC50s 0.046, 0.05, 0.321, and 0.24⯵M, respectively). Fusarithioamide B may provide a lead molecule for future developing of antitumor and antimicrobial agents.
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Antineoplásicos/química , Antineoplásicos/farmacología , Benzamidas/química , Fusarium/química , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Antibacterianos/toxicidad , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Antifúngicos/farmacología , Antifúngicos/toxicidad , Antineoplásicos/aislamiento & purificación , Antineoplásicos/toxicidad , Asteraceae/química , Asteraceae/metabolismo , Benzamidas/aislamiento & purificación , Benzamidas/farmacología , Benzamidas/toxicidad , Candida albicans/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Fusarium/metabolismo , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Hojas de la Planta/química , Hojas de la Planta/metabolismo , Staphylococcus aureus/efectos de los fármacosRESUMEN
From the culture of the endophytic fungus Fusarium sp. isolated from the roots of Mentha longifolia L. (Labiatae) growing in Saudi Arabia, a new cyclodepsipeptide, namely fusaripeptide A (1), along with three known compounds adenosine (2), 2[(2-hydroxypropionyl)amino]benzamide (3), and cyclopentanol (4), have been isolated. Their structures were determined, using extensive 1D and 2D NMR and HRESI and GC mass spectral data. That is the first report for the isolation of compound 4 from natural source. In addition, compounds 2 and 3 are reported here for the first time from Fusarium sp. The absolute configuration of the amino acid residues of 1 was assigned by chiral GCMS and Marfey's analysis after acid hydrolysis. Fusaripeptide A differs from the reported ones from Fusarium sp. in the length of fatty acidic alkyl chain. Compound 1 was evaluated for its antifungal, anti-malarial, and cytotoxic activities. It exhibited potent antifungal activity toward C. albicans, C. glabrata, C. krusei, and A. fumigates with IC50 values of 0.11, 0.24, 0.19, and 0.14 µM, respectively. Furthermore, it had significant anti-malarial activity toward P. falciparum (D6 clone) with IC50 value of 0.34 µM. However, it showed cytotoxic activity toward the tested cell lines.
Asunto(s)
Antifúngicos/aislamiento & purificación , Antifúngicos/farmacología , Antimaláricos/aislamiento & purificación , Antimaláricos/farmacología , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Depsipéptidos/aislamiento & purificación , Depsipéptidos/farmacología , Fusarium/química , Antifúngicos/química , Antimaláricos/química , Antineoplásicos/química , Depsipéptidos/química , Cromatografía de Gases y Espectrometría de Masas , Humanos , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Raíces de Plantas/química , Arabia SauditaRESUMEN
Garcinia mangostana L. (the queen of fruits, mangosteen, family Guttiferae) is a wealthy source of xanthones. The CHCl3 soluble fraction of the air-dried pericarps of G. mangostana provided a new xanthone: mangostanaxanthone VII (5), along with four known xanthones: mangostanaxanthones I (1) and II (2), gartanin (3) and γ-mangostin (4). The structural verification of these metabolites was achieved by different spectral techniques, including UV, IR, 1D and 2D NMR and HRESIMS. The new metabolite was assessed for cytotoxic potential, using sulforhodamine B (SRB) assay towards the A549 and MCF-7 cancer cell lines. Moreover, its antimicrobial effects were evaluated against various bacterial and fungal strains, using agar disc diffusion assay. Mangostanaxanthone VII showed moderate cytotoxic activity against the A549 and MCF7 cell lines with IC50s 26.1 and 34.8 µM, respectively, compared with doxorubicin (0.74 and 0.41 µM, respectively).
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Garcinia mangostana/química , Xantonas/farmacología , Células A549 , Antineoplásicos Fitogénicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Xantonas/química , Xantonas/aislamiento & purificaciónRESUMEN
Drugs of cancer based upon ionizing radiation or chemotherapeutic treatment may affect breaking of DNA double strand in cell. DNA-PK enzyme has emerged as an attractive target for drug discovery efforts toward DNA repair pathways. Hence, the search for potent and selective DNA-PK inhibitors has particularly considered state-of-the art and several series of inhibitors have been designed. In this article, a novel benchmark DNA-PK database of 43 compounds was built and described. Ligand-based approaches including pharmacophore and QSAR modeling were applied and novel models were introduced and analyzed for predicting activity test for DNA-PK drug candidates. Based upon the modeling results, we gave a report of synthesis of fifteen novel 2-((8-methyl-2-morpholino-4-oxo-4H-benzo[e][1,3]oxazin-7-yl)oxy)acetamide derivatives and in vitro evaluation for DNA-PK inhibitory and antiproliferative activities. These fifteen compounds overall are satisfied with Lipinski's rule of five. The biological testing of target compounds showed five promising active compounds 7c, 7d, 7f, 9e and 9f with micromolar DNA-PK activity range from 0.25 to 5µM. In addition, SAR of the compounds activity was investigated and confirmed that the terminal aryl moiety was found to be quite crucial for DNA-PK activity. Moreover flexible docking simulation was done for the potent compounds into the putative binding site of the 3D homology model of DNA-PK enzyme and the probable interaction model between DNA-PK and the ligands was investigated and interpreted.
Asunto(s)
Acetamidas/farmacología , Antineoplásicos/farmacología , Proteína Quinasa Activada por ADN/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Acetamidas/síntesis química , Acetamidas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Proteína Quinasa Activada por ADN/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
Iris species are well recognized as wealthy sources of isoflavonoids. In the present study, phytochemical investigation of the rhizomes of Iris germanica (Iridaceae) procure the isolation of two new isoflavonoids namely, 8-hydroxyirilone 5-methyl ether (2) and 8-hydroxyirilone (3), along with eight known isoflavonoids: irilone 4'-methyl ether (1), irilone (4), irisolidone (5), irigenin S (6), irigenin (7), irilone 4'-O-ß-d-glucopyranoside (8), iridin S (9), and iridin (10). The isolated flavonoids were structurally characterized with the assist of comprehensive spectroscopic analyses (UV, IR, 1D and 2D NMR, and HRMS) and comparing with the published data. They were estimated for their antioxidant and antidaibetic capacities using DPPH and α-amylase inhibition assays, respectively. Compounds 2, 3, and 4 exhibited prominent antioxidant activities with IC50 values of 12.92, 9.23, and 10.46µM, respectively compared to propyl gallate (IC50 7.11µM). Moreover, 2-5 possessed highest α-amylase inhibitory activity with % inhibition 66.1, 78.3, 67.3, and 70.1, respectively in comparison to acarbose (reference α-amylase inhibitor). Additionally, their structure-activity relationship has been discussed.