Search

The Aedes aegypti L. mosquito is considered the most important vector of arboviruses in the world. Insecticide-resistant phenomenon is a difficult barrier to overcome for government health entities around the planet. This problem forces to increase the concentrations of insecticides in the environment causing environmental pollution and health threat to human beings. Plants have been used to combat pests for centuries and are an eco-friendly source for the search for molecules with larvicidal activity. In this work, 65 ethanol-soluble extracts from 56 plants of the Colombian Caribbean region were evaluated as potential larvicides against Aedes aegypti mosquito, as well as, for their toxic effects on non-target organism. A high larvicidal activity was found for 16 ethanol extracts, however, the most potent activity against the larvae was obtained for the five plant extracts corresponding to the seeds of Annona squamosa L., Annona cherimolia L., Annona muricata L., Tabernaemontana cymosa Jacq. and Mammea americana L., with LC50 value of 58.44, 65.10, 84.92, 25.02 and 38.58 ppm, respectively. T. cymosa seeds extract was selected for bio-guided fractionation due to the high larvicidal activity showed. Through chromatographic techniques and Nuclear Magnetic Resonance (NMR), five indole alkaloids were isolated and characterized from T. cymosa active fraction; among them, voacangine showed activity with a LC50 of 5.13 ppm indicating a high larvicidal potency besides low toxicity against model organism Caenorhabditis elegans. We also report a new indole alkaloid from T. cymosa. Our study demonstrated the potential of the Colombian Caribbean flora as a host of bioactive plants against important vectors such as the A. aegypti mosquito with potential use in controlled environments.

Abstract Background In recent years, an increase in the occurrence of illnesses caused by two clinically- important arboviruses has been reported: Zika virus (ZIKV) and Chikungunya virus (CHIKV). There is no licensed antiviral treatment for either of the two abovementioned viruses. Bearing in mind that the antiviral effect of indole alkaloids has been reported for other arboviral models, the present study proposed to evaluate the antiviral in vitro and in silico effects of four indole alkaloids on infections by these two viruses in different cell lines. Methods The antiviral effects of voacangine (VOAC), voacangine-7-hydroxyindolenine (VOAC-OH), rupicoline and 3-oxo voacangine (OXO-VOAC) were evaluated in Vero, U937 and A549 cells using different experimental strategies (Pre, Trans, Post and combined treatment). Viral infection was quantified by different methodologies, including infectious viral particles by plating, viral genome by RT-qPCR, and viral protein by cell ELISA. Moreover, molecular docking was used to evaluate the possible interactions between structural and nonstructural viral proteins and the compounds. The results obtained from the antiviral strategies for each experimental condition were compared in all cases with the untreated controls. Statistically significant differences were identified using a parametric Student’s t-test. In all cases, p values below 0.05 (p

Staphylococcus aureus remains a pathogen of high concern in public health programs worldwide due to antibiotic resistance and emergence of highly virulent strains. Many phytochemicals have demonstrated activity against S. aureus and other Gram-positive bacteria, but the minimum inhibitory concentration (MIC) values comparable to commonly used antibiotics are needed. In the present study, bio-guided fractionation of the ethanol extract of seeds of Mammea americana L. (Calophyllaceae) throughout the antibacterial activity, against S. aureus strains that are sensitive and resistant to methicillin, led to the isolation of four coumarins identified as mammea B/BA, mammea B/BC, mammea A/AA cyclo D and mammea A/AA cyclo F, and a mixture of mammea B/BA cyclo F plus mammea B/BD cyclo F. The extract inhibited the growth of S. aureus with MIC values of 2–4 μg/ml and Mammea B/BA (MaBBA) presented MIC values in a range between 0.5 and 1.0 μg/ml in six methicillin-sensitive strains and eight methicillin-resistant strains evaluated. We consider MaBBA the most potent of all mammea coumarins reported to date, according to the literature review carried out at the time of writing of this article. Toxicity assessment in vivo against the nematode Caenorhabditis elegans and in vitro against human fibroblasts of the extract and the compound MaBBA indicated that both had low toxicity.

The species of the genus Tabernaemontana have a long tradition of use in different pathologies of infectious origins; the antibacterial, antifungal, and antiviral effects related to the control of the pathologies where the species of this genus are used, have been attributed to the indole monoterpene alkaloids, mainly those of the iboga type. There are more than 1000 alkaloids isolated from different species of Tabernaemontana and other genera of the Apocynaceae family, several of which lack studies related to antibacterial activity. In the present study, four monoterpene indole alkaloids were isolated from the seeds of the species Tabernaemontana cymosa Jacq, namely voacangine (1), voacangine-7-hydroxyindolenine (2), 3-oxovoacangine (3), and rupicoline (4), which were tested in an in vitro antibacterial activity study against the bacteria S. aureus, sensitive and resistant to methicillin, and classified by the World Health Organization as critical for the investigation of new antibiotics. Of the four alkaloids tested, only voacangine was active against S. aureus, with an MIC of 50 µg/mL. In addition, an in silico study was carried out between the four isolated alkaloids and some proteins of this bacterium, finding that voacangine also showed binding to proteins involved in cell wall synthesis, mainly PBP2 and PBP2a.

Alkaloids are a group of secondary metabolites that have been widely studied for the discovery of new drugs due to their properties on the central nervous system and their anti-inflammatory, antioxidant and anti-cancer activities. Molecular docking was performed for 10 indole alkaloids identified in the ethanol extract of Tabernaemontana cymosa Jacq. with 951 human targets involved in different diseases. The results were analyzed through the KEGG and STRING databases, finding the most relevant physiological associations for alkaloids. The molecule 5-oxocoronaridine proved to be the most active molecule against human proteins (binding energy affinity average = −9.2 kcal/mol) and the analysis of the interactions between the affected proteins pointed to the PI3K/ Akt/mTOR signaling pathway as the main target. The above indicates that indole alkaloids from T. cymosa constitute a promising source for the search and development of new treatments against different types of cancer.

Currently, no specific licensed antiviral exists for treating the illness caused by dengue virus (DENV). Therefore, the search for compounds of natural origin with antiviral activity is an important area of research. In the present study, three compounds were isolated and identified from seeds of Tabernaemontana cymosa plants. The in vitro antiviral effect of those compounds and voacangine against different DENV strains was assessed using different experimental approaches: compounds added before the infection (Pre), at the same time with the virus (Trans), after the infection (Post) or compounds present in all moments of the experiment (Pre-Trans-Post, Combined treatment). In silico studies (docking and molecular dynamics) were also performed to explain the possible antiviral mechanisms. The identified compounds were three structural analogs of voacangine (voacangine-7-hydroxyindolenine, rupicoline and 3-oxo-voacangine). In the Pre-treatment, only voacangine-7-hydroxyindolenine and rupicoline inhibited the infection caused by the DENV-2/NG strain (16.4% and 29.6% infection, respectively). In the Trans-treatment approach, voacangine, voacangine-7-hydroxyindolenine and rupicoline inhibited the infection in both DENV-2/NG (11.2%, 80.4% and 75.7% infection, respectively) and DENV-2/16681 infection models (73.7%, 74.0% and 75.3% infection, respectively). The latter strain was also inhibited by 3-oxo-voacangine (82.8% infection). Moreover, voacangine (most effective virucidal agent) was also effective against one strain of DENV-1 (DENV-1/WestPac/74) and against the third strain of DENV-2 (DENV-2/S16803) (48.5% and 32.4% infection, respectively). Conversely, no inhibition was observed in the post-treatment approach. The last approach (combined) showed that voacangine, voacangine-7-hydroxyindolenine and rupicoline inhibited over 90% of infections (3.5%, 6.9% and 3.5% infection, respectively) of both strains (DENV-2/NG and DENV-2/16681). The free energy of binding obtained with an in silico approach was favorable for the E protein and compounds, which ranged between −5.1 and −6.3 kcal/mol. Finally, the complex formed between DENV-2 E protein and the best virucidal compound was stable for 50 ns. Our results show that the antiviral effect of indole alkaloids derived from T. cymose depends on the serotype and the virus strain.