RESUMEN
In the search of new inhibitors for human coronavirus (HCoV), we screened extracts of endemic Annonaceae plants on an assay using a cellular model of Huh-7 cells infected with the human alphacoronavirus HCoV-229E. The EtOAc bark extract of the rare Southeast Asian plant Neo-uvaria foetida exhibited inhibition of HCoV-229E and SARS-CoV-2 viruses with IC50 values of 3.8 and 7.8 µg/mL, respectively. Using LC-MS/MS and molecular networking analysis guided isolation, we discovered two new labdane-type diterpenoids, 8-epi-acuminolide (1) and foetidalabdane A (4), and three known labdane diterpenoids, acuminolide (2), 17-O-acetylacuminolide (3), and spiroacuminolide (5). A new norlabdane diterpene, 16-foetinorlabdoic acid (6), was also isolated and identified. Excluding compounds 5 and 6, all other metabolites were active against the virus HCoV-229E. Terpenoids 1 and 4 presented antiviral activity against SARS-CoV-2 with IC50 values of 63.3 and 93.5 µM, respectively, indicating lower potency. Additionally, virological assays demonstrated that compounds 1, 2, and 3 exert antiviral effects against Zika virus by specifically interfering with the late stage of its infectious cycle with IC50 values of 76.0, 31.9, and 14.9 µM, respectively.
Asunto(s)
Annonaceae , Antivirales , Diterpenos , Corteza de la Planta , SARS-CoV-2 , Espectrometría de Masas en Tándem , Diterpenos/farmacología , Diterpenos/química , Diterpenos/aislamiento & purificación , Antivirales/farmacología , Antivirales/química , Antivirales/aislamiento & purificación , Corteza de la Planta/química , Humanos , Espectrometría de Masas en Tándem/métodos , SARS-CoV-2/efectos de los fármacos , Annonaceae/química , Estructura Molecular , Cromatografía Liquida/métodos , Cromatografía Líquida con Espectrometría de MasasRESUMEN
The Zingiber zerumbet rhizomes are traditionally used to treat fever, and the in vitro inhibitory effect of ethyl acetate extract from Zingiber zerumbet rhizomes (EAEZZR) against DENV2 NS2B/NS3 (two non-structural proteins, NS2 and NS3 of dengue virus type 2) has been reported earlier. This study was carried out to establish an acute toxicity profile and evaluate the anti-fever (anti-pyretic) activities of EAEZZR in yeast-induced fever in rats. The major compound of EAEZZR, zerumbone, was isolated using chromatographic methods including column chromatography (CC) and preparative thin-layer chromatography (PTLC). Additionally, the structure of zerumbone was elucidated using nuclear magnetic resonance (NMR), liquid chromatography mass spectrometer-ion trap-time of flight (LCMS-IT-TOF), infrared (IR), and ultraviolet (UV) spectroscopy. The toxicity of EAEZZR was evaluated using Organization for Economic Cooperation and Development Test Guideline 425 (OECD tg-425) with minor modifications at concentrations EAEZZR of 2000 mg/kg, 3000 mg/kg, and 5000 mg/kg. Anti-fever effect was determined by yeast-induced fever (pyrexia) in rats. The acute toxicity study showed that EAEZZR is safe at the highest 5000 mg/kg body weight dose in Sprague Dawley rats. Rats treated with EAEZZR at doses of 125, 250, and 500 mg/kg exhibited a significant reduction in rectal temperature (TR) in the first 1 h. EAEZZR at the lower dose of 125 mg/kg showed substantial potency against yeast-induced fever for up to 2 h compared to 0 h in controls. A significant reduction of TR was observed in rats treated with standard drug aspirin in the third through fourth hours. Based on the present findings, ethyl acetate extract of Zingiber zerumbet rhizomes could be considered safe up to the dose of 5000 mg/kg, and the identification of active ingredients of Zingiber zerumbet rhizomes may allow their use in the treatment of fever with dengue virus infection.
Asunto(s)
Acetatos , Extractos Vegetales , Rizoma , Sesquiterpenos , Ratas , Animales , Ratas Sprague-Dawley , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Extractos Vegetales/química , Saccharomyces cerevisiae , Fiebre/tratamiento farmacológicoRESUMEN
Acanthamoeba castellanii is an opportunistic free-living amoeba (FLA) pathogen which can cause fatal central nervous system (CNS) infection, granulomatous amoebic encephalitis (GAE) and potentially blinding ocular infection, Acanthamoeba keratitis (AK). Acanthamoeba species remain a challenging protist to treat due to the unavailability of safe and effective therapeutic drugs and their ability to protect themselves in the cyst stage. Natural products and their secondary metabolites play a pivotal role in drug discovery against various pathogenic microorganisms. In the present study, the ethyl acetate extract of Myristica cinnamomea King fruit was evaluated against A. castellanii (ATCC 50492), showing an IC50 of 45.102 ± 4.62 µg/mL. Previously, the bio-guided fractionation of the extract resulted in the identification of three active compounds, namely Malabaricones (A-C). The isolated and thoroughly characterized acylphenols were evaluated for their anti-amoebic activity against A. castellanii for the first time. Among tested compounds, Malabaricone B (IC50 of 101.31 ± 17.41 µM) and Malabaricone C (IC50 of 49.95 ± 6.33 µM) showed potent anti-amoebic activity against A. castellanii trophozoites and reduced their viability up-to 75 and 80 %, respectively. Moreover, both extract and Malabaricones also significantly (p < 0.05) inhibit the encystation and excystation of A. castellanii, while showed minimal toxicity against human keratinocyte cells (HaCaT cells) at lower tested concentrations. Following that, the explanation of the possible mechanism of action of purified compounds were assessed by detection of the state of chromatin. Hoechst/PI 33342 double staining showed that necrotic cell death occurred in A. castellanii trophozoites after 8 h treatment of Malabaricones (A-C). These findings demonstrate that Malabaricones B and C could serve as promising therapeutic options against A. castellanii infections.
Asunto(s)
Queratitis por Acanthamoeba , Acanthamoeba castellanii , Amebiasis , Amebicidas , Myristica , Animales , Humanos , Amebicidas/farmacología , Frutas , Amebiasis/tratamiento farmacológico , TrofozoítosRESUMEN
The genus Myristica is a medicinally important genus belonging to the Myristicaceae. Traditional medicinal systems in Asia have employed plants from the genus Myristica to treat a variety of ailments. Acylphenols and dimeric acylphenols are a rare group of secondary metabolites, which, to date, have only been identified in the Myristicaceae, in particular, in the genus Myristica. The aim of the review would be to provide scientific evidence that the medicinal properties of the genus Myristica could be attributed to the acylphenols and dimeric acylphenols present in the various parts of its plants and highlight the potential in the development of the acylphenols and dimeric acylphenols as pharmaceutical products. SciFinder-n, Web of Science, Scopus, ScienceDirect, and PubMed were used to conduct the literature search between 2013-2022 on the phytochemistry and the pharmacology of acylphenols and dimeric acylphenols from the genus Myristica. The review discusses the distribution of the 25 acylphenols and dimeric acylphenols within the genus Myristica, their extraction, isolation, and characterization from the respective Myristica species, the structural similarities and differences within each group and between the different groups of the acylphenols and dimeric acylphenols, and their in vitro pharmacological activities.
RESUMEN
The use of antidiabetic agents which control glycemic levels in the blood and simultaneously inhibit oxidative stress is an important strategy in the prevention of Diabetes Mellitus and its complications. In our previous study, malabaricone C (3) and its dimer, giganteone A (5) exhibited significant DPPH free radical scavenging activities which were lower than the activity of the positive control, ascorbic acid. These compounds were evaluated for their α-glucosidase inhibitory activities at different concentrations (0.02-2.5 mM) in the present study. Compounds 3 (IC50 59.61 µM) and 5 (IC50 39.52 µM) were identified as active alpha-glucosidase inhibitors, each respectively being 24 and 37 folds more potent than the standard inhibitor, acarbose. Based on the molecular docking studies, compounds 3 and 5 docked into the active site of the α-glucosidase enzyme, forming mainly hydrogen bonds in the active site.
Asunto(s)
Diabetes Mellitus , Inhibidores de Glicósido Hidrolasas , Compuestos de Bifenilo , Diabetes Mellitus/tratamiento farmacológico , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/farmacología , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Simulación del Acoplamiento Molecular , Resorcinoles , Relación Estructura-Actividad , alfa-Glucosidasas/metabolismoRESUMEN
The interaction between natural occurring inhibitors and targeted membrane proteins could be an alternative medicinal strategy for the treatment of metabolic syndrome, notably, obesity. In this study, we identified malabaricones A-C and E (1-4) isolated from the fruits of Myristica cinnamomea King as natural inhibitors for sphingomyelin synthase (SMS), a membrane protein responsible for sphingolipid biosynthesis. Having the most promising inhibition, oral administration of compound 3 exhibited multiple efficacies in reducing weight gain, improving glucose tolerance, and reducing hepatic steatosis in high fat diet-induced obesity mice models. Liver lipid analysis revealed a crucial link between the SMS activities of compound 3 and its lipid metabolism in vitro and in vivo. The nontoxic nature of compound 3 makes it a suitable candidate in search of drugs which can be employed in the treatment and prevention of obesity.
RESUMEN
Giganteone E (1), a new dimeric acylphenol was isolated as a minor constituent from the bark of Myristica maxima Warb. The structure of 1 was established on the basis of 1D and 2D NMR techniques and LCMS-IT-TOF analysis. Malabaricones A-C (2-4), giganteones A and C (5 and 6), maingayones A and B (7 and 8), maingayic acid B (9) and ß-sitosteryl oleate (10) were also characterized in this plant for the first time. Compound 10 was identified for the first time in the Myristicaceae. Compounds 2 and 5 were active against human prostate cancer cell-lines, thus making this the first report on the prostate cancer inhibiting potential of acylphenols and dimeric acylphenols. Compounds 1, 4, 5, 7 and 8 exhibited potent DPPH free radical scavenging activity. This is the first report on their free radical scavenging capacity.
Asunto(s)
Myristicaceae/química , Fenoles/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral/efectos de los fármacos , Depuradores de Radicales Libres/aislamiento & purificación , Depuradores de Radicales Libres/farmacología , Humanos , Masculino , Estructura Molecular , Fenoles/aislamiento & purificación , Neoplasias de la Próstata/patología , Resorcinoles/aislamiento & purificación , Resorcinoles/farmacologíaRESUMEN
Malabaricones A-C (1-3) and giganteone A (4) were isolated from the bark of Myristica cinnamomea King. Their structures were elucidated and characterized by means of NMR and MS spectral analyses. These isolates were evaluated for their anti-quorum sensing activity using quorum sensing biosensors, namely Escherichia coli [pSB401] and Escherichia coli [pSB1075], whereby the potential of giganteone A (4) as a suitable anti-quorum sensing agent was demonstrated.