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1.
Bioorg Med Chem Lett ; 86: 129241, 2023 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-36933671

RESUMEN

Metformin is the most widely known anti-hyperglycemic, officially acquired by the USA government in 1995 and in 2001 it became the most prescribed treatment for type II diabetes. But how did it become the must-use drug for this disease in such a short period of time? it all started with traditional medicine, by using a plant known as "goat's rue" for the reduction of blood glucose levels. Its use arose in 1918 and evolved to the metformin synthesis in laboratories a couple of years later, using very rudimentary methods which involved melting and strong heating. Thus, a first synthetic route that allowed the preparation of the initial metformin derivates was established. Some of these resulted toxics, and others outperformed the metformin, reducing the blood glucose levels in such efficient way. Nevertheless, the risk and documented cases of lactic acidosis increased with metformin derivatives like buformin and phenformin. Recently, metformin has been widely studied, and it has been associated and tested in the treatment of type II diabetes, cancer, polycystic ovarian syndrome, cell differentiation to oligodendrocytes, reduction of oxidative stress in cells, weight reduction, as anti-inflammatory and even in the recent COVID-19 disease. Herein we briefly review and analyze the history, synthesis, and biological applications of metformin and its derivates.


Asunto(s)
COVID-19 , Diabetes Mellitus Tipo 2 , Metformina , Humanos , Metformina/farmacología , Metformina/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Glucemia
2.
Bioorg Med Chem Lett ; 63: 128649, 2022 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-35245665

RESUMEN

Zygomycetes are ubiquitous saprophytes in natural environments which transform organic matter. Some zygomycetes of gender Mucor have attracted interest in health sector. Due to its ability as opportunistic microorganisms infecting immuno-compromised people and to the few available pharmacological treatments, the mucormycosis is receiving worldwide attention. Concerning to the pharmacological treatments, some triazole-based compounds such as fluconazole are extensively used. Nevertheless, we focused in the quinolines since they are broadly used models for the design and development of new synthetic antifungal agents. In this study, the fungistatic activity on M. circinelloides of various 2-aryl-4-aryloxyquinoline-based compounds was discovered, and in some cases, it resulted better than reference compound fluconazole. These quinoline derivatives were synthesized via the Csp2-O bond formation using diaryliodonium(III) salts chemistry. A QSAR study was carried out to quantitatively correlate the chemical structure of the tested compounds with their biological activity. Also, a docking study to identify a plausible action target of our more active quinolines was carried out. The results highlighted an increased activity with the fluorine- and nitro-containing derivatives. In light of the few mucormycosis pharmacological treatments, herein we present some non-described molecules with excellent in vitro activities and potential use in the mucormycosis treatment.


Asunto(s)
Mucormicosis , Quinolinas , Fluconazol , Humanos , Mucor , Mucormicosis/tratamiento farmacológico , Mucormicosis/microbiología , Relación Estructura-Actividad Cuantitativa , Quinolinas/farmacología , Quinolinas/uso terapéutico
3.
Org Biomol Chem ; 20(25): 5009-5034, 2022 06 29.
Artículo en Inglés | MEDLINE | ID: mdl-35703407

RESUMEN

Iodine(III) reagents have attracted chemical relvance in organic synthesis by their use as safe, non-toxic, green and easy to handle reagents in different transformations. These characteristics make them important alternatives to procedures involving hazardous and harsh reaction conditions. Their versatility as oxidants has been exploited in the functionalization of different aromatic cores, which allow the introduction of several groups. Metal-free arylation using iodine(III) reagents is by far one of the most described topics in the literature; however, other highly relevant non-aromatic groups have been also introduced. Herein, we summarize the most representative developed procedures for the functionalization of aryls and heteroaryls by introducing halogens, using different iodine(III) reagents.


Asunto(s)
Yodo , Halogenación , Indicadores y Reactivos , Yoduros , Oxidación-Reducción , Estrés Oxidativo
4.
Molecules ; 27(9)2022 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-35565963

RESUMEN

Tagetes parryi is a plant empirically used to treat gastrointestinal and inflammatory diseases, its essential oil (EOTP) was obtained from the aerial parts, and the composition was elucidated by GC-MS. The in vivo and in vitro anti-inflammatory activities and the antinociceptive activity of EOTP and (1S)-(-)-verbenone (VERB) were assessed. The major compounds identified for EOTP were verbenone (33.39%), dihydrotagetone (26.88%), and tagetone (20.8%). EOTP and VERB diminished the ear oedema induced with TPA by 93.77 % and 81.13 %, respectively. EOTP and VERB decreased inflammation in a 12-O-tetradecanoylphorbol-13-acetate (TPA) chronic model with ED50 = 54.95 mg/kg and 45.24 mg/kg, respectively. EOTP (15 µg/mL) inhibited the in vitro production of the pro-inflammatory mediators NO (67.02%), TNF-α (69.21%), and IL-6 (58.44%) in LPS-stimulated macrophages. In the acetic induced writhing test, EOTP and VERB showed antinociceptive effects with ED50 = 84.93 mg/kg and ED50 = 45.24 mg/kg, respectively. In phase 1 of the formalin test, EOTP and VERB showed no antinociceptive effects, whereas in phase 2, EOTP (ED50 = 35.45 mg/kg) and VERB (ED50 = 24.84 mg/kg) showed antinociceptive effects. The antinociceptive actions of ETOP and VERB were blocked with the co-administration of L-NAME. This study suggests that EOTP and VERB might be used in the treatment of pain and inflammatory problems.


Asunto(s)
Asteraceae , Aceites Volátiles , Tagetes , Analgésicos/farmacología , Analgésicos/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Monoterpenos Bicíclicos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Aceites Volátiles/farmacología , Aceites Volátiles/uso terapéutico , Extractos Vegetales/farmacología
5.
Drug Dev Res ; 81(5): 600-608, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32181517

RESUMEN

This work describes the neuropharmacological (sedative, anxiolytic, antidepressant, and anticonvulsant) actions of Gardenin A (GA) (0.1-25 mg/kg p.o.), a flavonoid found in medicinal plants. The sedative effects of GA were assessed with the pentobarbital-induced sleep test. The anxiolytic actions of GA were evaluated with the elevated plus-maze, the light-dark box test, the exploratory cylinder assay, and the open field test. Motor coordination was evaluated with the rotarod test and the open field test. The antidepressant-like actions of GA were evaluated with the tail suspension test and forced swimming test. The mechanisms of the anxiolytic-like and antidepressant-like effects of GA were assessed using inhibitors of neurotransmission pathways. The anticonvulsant activity of GA was evaluated with the strychnine-induced seizure test. The sedative effects of GA were evident only at a dose of 25 mg/kg, which increased the duration of sleep but did not alter sleep onset. GA showed anxiolytic-like actions with activity comparable to that of clonazepam in all experimental tests. The GABAA receptor antagonist bicuculline reversed the anxiolytic-like effects of GA. Furthermore, GA showed significant antidepressant-like actions in both models with activity comparable to that of fluoxetine. Yohimbine, an α2-adrenoceptor blocker, inhibited the antidepressant-like actions of GA. In addition, GA (1-10 mg/kg) did not affect locomotor coordination in mice and delayed the onset of convulsions. These findings suggest that GA induces anxiolytic-like effects and has anticonvulsant actions by the possible involvement of the GABAergic system. The antidepressant-like actions of GA may be mediated by noradrenergic neurotransmission.


Asunto(s)
Ansiolíticos/uso terapéutico , Anticonvulsivantes/uso terapéutico , Antidepresivos/uso terapéutico , Flavonas/uso terapéutico , Hipnóticos y Sedantes/uso terapéutico , Convulsiones/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Masculino , Ratones Endogámicos BALB C , Prueba de Desempeño de Rotación con Aceleración Constante , Convulsiones/inducido químicamente , Estricnina , Natación
6.
Drug Dev Res ; 80(7): 981-991, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31343767

RESUMEN

Salvia tiliifolia is used in folk medicine as a relaxant agent and for the treatment of diarrhea and neurodegenerative diseases. Tilifodiolide (TFD) is a diterpene obtained from this plant. The purpose of this work was to evaluate the antidiarrheal, vasorelaxant, and neuropharmacological actions of TFD. These effects were selected based on the folk medicinal use of S. tiliifolia. The antidiarrheal activity of 1-50 mg/kg p.o. TFD was assessed with the castor oil related tests. The vasorelaxant effect of TFD (0.9-298 µM) was performed with smooth muscle tissues from rats, and its mechanism of action was evaluated using different inhibitors. The sedative, anxiolytic, and antidepressant effects of 1-100 mg/kg TFD were assessed. The possible mechanisms of action of the anxiolytic and antidepressant effects of TFD were evaluated using inhibitors. TFD exhibited antidiarrheal (ED50 = 10.62 mg/kg) and vasorelaxant (EC50 = 48 ± 3.51 µM) effects. The coadministration of TFD with N(ω)-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), reverted the vasorelaxant action showed by TFD alone. TFD exerted anxiolytic actions (ED50 = 20 mg/kg) in the cylinder exploratory test, whereas TFD (50 mg/kg) showed antidepressant actions in the tail suspension test by 44%. The pretreatment with 2 mg/kg flumazenil partially reverted the anxiolytic actions of TFD, whereas the pretreatment with 1 mg/kg yohimbine abolished the antidepressant effects of TFD. In summary, TFD exerted antidiarrheal activity by decreasing the intestinal fluid accumulation and vasorelaxant effects mediated by nitric oxide and cyclic guanosine monophosphate. TFD showed anxiolytic and antidepressant effects by the partial involvement of gamma-Aminobutyric acid (GABA) receptors and the possible participation of α2-adrenoreceptors, respectively.


Asunto(s)
Antidiarreicos/farmacología , Conducta Animal/efectos de los fármacos , Diterpenos/farmacología , Músculo Liso/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Ansiolíticos/farmacología , Antidepresivos/farmacología , Diterpenos/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Flumazenil/farmacología , Hipnóticos y Sedantes/farmacología , Masculino , Ratones , NG-Nitroarginina Metil Éster/farmacología , Oxadiazoles/farmacología , Quinoxalinas/farmacología , Vasodilatadores/antagonistas & inhibidores , Yohimbina/farmacología
7.
Drug Dev Res ; 79(1): 38-44, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29314177

RESUMEN

Preclinical Research & Development The objective of the present study was to evaluate the tapentadol-diclofenac combination in three dose-ratios in the mouse acetic acid-induced visceral pain and their ulcerogenic activity on the stomachal mucous. Dose-response curves were generated for tapentadol, diclofenac, and their combination in the acetic acid-induced writhing test in mice. Moreover, the stomachs of animals were surgically removal and gastrointestinal ulcerogenic action of the combination was assessed. The isobolographic analysis, interaction index, and ANOVA were used to analyze the data. The isobolographic analysis and interaction index showed a similar antinociceptive activity for the three combinations of the analgesic mixture. Moreover, tapentadol and the proportions 1:1 or 3:1 of the analgesic combination caused a mild gastrointestinal damage. These data indicate that the systemic co-administration of tapentadol and diclofenac produced a synergistic interaction in the acetic acid-induced visceral pain test with an acceptable gastric damage profile in mice.


Asunto(s)
Analgésicos/uso terapéutico , Diclofenaco/uso terapéutico , Fenoles/uso terapéutico , Dolor Visceral/tratamiento farmacológico , Ácido Acético , Animales , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Masculino , Ratones , Estómago/efectos de los fármacos , Estómago/patología , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/patología , Tapentadol , Dolor Visceral/inducido químicamente
8.
Drug Dev Res ; 79(8): 400-405, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30362140

RESUMEN

Preclinical Research & Development The purpose of this study was to assess the interaction and mechanisms of action of the paracetamol-tapentadol combination in the formalin-induced pain model in mice. Paracetamol (56.23-562.3 mg/kg, i.p.) or tapentadol (1-10 mg/kg, i.p.) were administered 15 min prior the intraplantar injection of formalin. The ED50 value of each drug was determined through the dose-response curves. The ED50 values were used to calculate the combinations in three fixed proportions (1:1, 1:3, and 3:1). Naloxone (1 and 5 mg/kg, i.p.), L-NAME (3 mg/kg, i.p.), or glibenclamide (10 mg/kg, i.p.) were administered before the combination of drugs to evaluate the antinociceptive mechanisms of action. The results showed that the combination 1:1 and paracetamol3-tapenadol1 ratios produced additive effects, whereas the paracetamol1-tapentadol3 proportion showed an antinociceptive synergistic interaction. Moreover, naloxone and glibenclamide reversed the antinociceptive activity of the paracetamol-tapentadol mixture. Our results indicate that the paracetamol-tapentadol combination produces an antinociceptive synergistic interaction with the possible participation of ATP-sensitive K+ channels and µ-opioid receptors in the second phase of the formalin-induced pain model in mice.


Asunto(s)
Canales KATP/agonistas , Dimensión del Dolor/métodos , Dolor/tratamiento farmacológico , Receptores Opioides mu/agonistas , Tapentadol/administración & dosificación , Acetaminofén/administración & dosificación , Analgésicos no Narcóticos/administración & dosificación , Analgésicos Opioides/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Canales KATP/metabolismo , Masculino , Ratones , Dolor/inducido químicamente , Dolor/metabolismo , Receptores Opioides mu/metabolismo
9.
Drug Dev Res ; 77(4): 187-91, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27169518

RESUMEN

Preclinical Research The aim of this experimental assay was to assess the antinociceptive interaction between tapentadol and ketorolac in the acetic acid-induced writhing model in mice. Tapentadol (5.62-31.6 mg/kg ip) or ketorolac (5.62-31.6 mg/kg ip) were administered 15 min before the acetic acid administration. The ED50 values of the individual drugs were determined and different proportions (tapentadol-ketorolac in 1:1, 3:1, and 1:3) were assayed in combination in the writhing test. Isobolographic analysis and the interaction index demonstrated an antinociceptive synergistic interaction between tapentadol and ketorolac in all combination. Thus, the experimental ED50 values were lower when compared with their theoretical ED50 values. These data suggest that the tapentadol-ketorolac combination produces an antinociceptive synergistic interaction in the mouse acetic acid-induced writhing model. Drug Dev Res 77 : 187-191, 2016. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Ketorolaco/farmacología , Fenoles/farmacología , Dolor Visceral/tratamiento farmacológico , Ácido Acético/toxicidad , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Ketorolaco/administración & dosificación , Masculino , Ratones , Fenoles/administración & dosificación , Tapentadol , Dolor Visceral/patología
10.
RSC Adv ; 8(54): 30761-30776, 2018 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-35548717

RESUMEN

A practical, concise and straightforward total synthesis of kealiiquinone 1, a naphtho[2,3-d]imidazole alkaloid obtained from the Micronesian marine sponge Leucetta sp. was accomplished. The squaric acid chemistry to construct the 1,4-quinoid ring and the regioselective N-methylation through a benzo[c][1,2,5]selenadiazolium heterocycle are the key features in this report. The full details of the representative approaches involving the different attempted synthetic strategies are also presented. Finally a successful total synthesis of this complex secondary metabolite is described.

11.
J Maxillofac Oral Surg ; 17(2): 142-149, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29618877

RESUMEN

PURPOSE: The aim of this systematic review and meta-analysis was to evaluate the risk of surgical infection, alveolar osteitis, and adverse effects using systemic metronidazole in comparison with placebo in healthy patients undergoing third molar surgery. MATERIALS AND METHODS: The eligible reports were identified from diverse science sources. Clinical trials meeting the inclusion and exclusion criteria and an acceptable Oxford Quality Score were included in this study. The evaluation of risk was done using the Risk Reduction Calculator and Review Manager 5.3., from the Cochrane Library. A significant risk reduction was assumed when the upper limit of the 95% confidence intervals was <1 and the lower limit did not cross zero (negative number) alongside a p value of <0.05 for the overall test. Data of 667 patients from five clinical trials were used for the assessment of risk. RESULTS: Our analysis showed no reduction of the risk of infection or dry socket in patients receiving metronidazole compared to whom took placebo. Meanwhile, the adverse effects did not exhibit a difference between the studied groups. CONCLUSION: The routine use of systemic metronidazole to prevent surgical site infection and/or dry socket in healthy patients undergoing third molar surgery is not recommended.

12.
RSC Adv ; 8(32): 17806-17812, 2018 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-35542081

RESUMEN

A practical electrophilic bromination procedure for phenols and phenol-ethers was developed under efficient and very mild reaction conditions. A broad scope of arenes was investigated, including the benzimidazole and carbazole core as well as analgesics such as naproxen and paracetamol. The new I(iii)-based brominating reagent PhIOAcBr is operationally easy to prepare by mixing PIDA and AlBr3. Our DFT calculations suggest that this is likely the brominating active species, which is prepared in situ or isolated after centrifugation. Its stability at 4 °C after preparation was confirmed over a period of one month and no significant loss of its reactivity was observed. Additionally, the gram-scale bromination of 2-naphthol proceeds with excellent yields. Even for sterically hindered substrates, a moderately good reactivity is observed.

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