The genus Sargassum is well represented by benthic and pelagic species, some of which form massive aggregates that can travel long distances due to the force of the ocean currents. Although they ...constitute an essential habitat for fish and invertebrate species, large accumulations of Sargassum in coastal areas generate several economic, environmental, and health impacts. It is important to recognize the species forming these aggregates, and identify the metabolites they produce, allowing for its exploitation, and therefore, better management practices. NMR metabolic profiling is a technique that can discriminate samples while detecting their unique or differential chemical features, and has been successfully used in the study and classification of several algal species. The present investigation studied the metabolic profiling of Sargassum species found on strandings at Puerto Morelos (Quintana Roo) east coast of the Mexican Caribbean. PCA of the 1H‐NMR profiles corresponding to S. natans, S. natans (morphotype VIII), S. fluitans, and a benthic Sargassum buxifolium allowed the discrimination of samples amongst them. Furthermore, discrimination between the two forms of S. natans was also possible. The PCA loading plot revealed that glutamine and glutamate have the highest influence in the clustering of the benthic Sargassum, while a high abundance of lactate, Myo‐inositol, and trimethylamine is a unique feature from the S. natans morphotype VIII. Additional PLS‐DA models showed that a heat‐drying process improved the extraction of metabolites. Maceration and microwave‐assisted extraction with water‐ethanol led to similar profiles and thus any of them could be used in future investigations.
We have synthesized a small series of five 3-4-arylmethoxy)phenylpropanoic acids employing an easy and short synthetic pathway. The compounds were tested in vitro against a set of four protein ...targets identified as key elements in diabetes: G protein-coupled receptor 40 (GPR40), aldose reductase (AKR1B1), peroxisome proliferator-activated receptor gama (PPARγ) and solute carrier family 2 (facilitated glucose transporter), member 4 (GLUT-4). Compound
displayed an EC
value of 0.075 μM against GPR40 and was an AKR1B1 inhibitor, showing IC
= 7.4 μM. Compounds
and
act as slightly AKR1B1 inhibitors, potent GPR40 agonists and showed an increase of 2 to 4-times in the mRNA expression of PPARγ, as well as the GLUT-4 levels. Docking studies were conducted in order to explain the polypharmacological mode of action and the interaction binding mode of the most active molecules on these targets, showing several coincidences with co-crystal ligands. Compounds
-
were tested in vivo at an explorative 100 mg/kg dose, being
and
orally actives, reducing glucose levels in a non-insulin-dependent diabetes mice model. Compounds
and
displayed robust in vitro potency and in vivo efficacy, and could be considered as promising multitarget antidiabetic candidates. This is the first report of a single molecule with these four polypharmacological target action.
To elucidate interactions between the antifungal cyclic lipopeptides iturin A, fengycin, and surfactin produced by
bacteria and the microtubular protein β-tubulin in plant pathogenic fungi (
,
,
, ...and
) in molecular docking and molecular dynamics simulations, we retrieved the structure of tubulin co-crystallized with taxol from the Protein Data Bank (PDB) (ID: 1JFF) and the structure of the cyclic lipopeptides from PubChem (Compound CID: 102287549, 100977820, 10129764). Similarity and homology analyses of the retrieved β-tubulin structure with those of the fungi showed that the conserved domains shared 84% similarity, and the root mean square deviation (RMSD) was less than 2 Å. In the molecular docking studies, within the binding pocket, residues Pro274, Thr276, and Glu27 of β-tubulin were responsible for the interaction with the cyclic lipopeptides. In the molecular dynamics analysis, two groups of ligands were formed based on the number of poses analyzed with respect to the RMSD. Group 1 was made up of 10, 100, and 500 poses with distances 0.080 to 0.092 nm and RMSDs of 0.10 to 0.15 nm. For group 2, consisting of 1000 poses, the initial and final distance was 0.1 nm and the RMSDs were in the range of 0.10 to 0.30 nm. These results suggest that iturin A and fengycin bind with higher affinity than surfactin to β-tubulin. These two lipopeptides may be used as lead compounds to develop new antifungal agents or employed directly as biorational products to control plant pathogenic fungi.
is a pathogenic and multidrug-resistant fungus that can infect both immunocompetent and immunocompromised patients, with mortality rates up to 87%. The World Health Organization (WHO) included this ...fungal species in its first list of 19 priority fungal pathogens, which focused on fungal pathogens that can cause invasive acute and subacute systemic fungal infections. Therefore, there is a growing interest in finding new therapeutic alternatives. In this work, the synthesis of twelve α-aminophosphonates by the microwave-assisted Kabachnik-Fields reaction and twelve α-aminophosphonic acids by a monohydrolysis reaction is reported. All compounds were evaluated by the agar diffusion method as a preliminary screening in comparison with voriconazole, showing inhibition halos for compounds
,
,
,
and
. The five active compounds in the preliminary tests were evaluated against five strains of
following protocol M38-A2 from CLSI. The results showed that these compounds exhibit antifungal activity in the concentration range of 900->900 μg/mL. Cytotoxicity against healthy COS-7 cells was also evaluated by the MTT assay, and it was shown that compound
was the least cytotoxic, with a viability of 67.91%, comparable to the viability exhibited by voriconazole (68.55%). Docking studies showed that the possible mechanism of action of the active compounds could be through the inhibition of the enzyme lanosterol-14-alpha-demethylase in an allosteric hydrophobic cavity.
The Scedosporium genus is an emerging pathogen with worldwide prevalence and high mortality rates that gives multidrug resistance to antifungals; therefore, pharmacological alternatives must be ...sought for the treatment of diseases caused by this fungus. In the present project, six new α-aminophosphates were synthesized by the Kabachnik–Fields multicomponent reaction by vortex agitation, and six new monohydrolyzed α-aminophosphonic acids were synthesized by an alkaline hydrolysis reaction. Antifungal activity was evaluated using the agar diffusion method as an initial screening to determine the most active compound compared to voriconazole; then it was evaluated against 23 strains of the genus Scedosporium following the M38-A2 protocol from CLSI (activity range: 648.76–700 µg/mL). Results showed that compound 5f exhibited the highest antifungal activity according to the agar diffusion method (≤1 mg/mL). Cytotoxicity against healthy COS-7 cells was also evaluated by the MTT assay and it was shown that compound 5f exhibits a lower toxicity in comparison to voriconazole at the same concentration (1000 µM). A docking study was conducted afterwards, showing that the possible mechanism of action of the compound is through the inhibition of allosteric 14-α-demethylase. Taking these results as a basis, 5f is presented as a compound with attractive properties for further studies.
Marine macroalgae (seaweed) are an excellent source of novel bioactive metabolites. The biorefinery concept applied to seaweed facilitates the extraction of many chemical constituents from the same ...biomass ensuring that the resource is used fully, generating few residues through a succession of extraction steps. In the present study, the biomass of the carragenophyte
(Rhodophyta, Gigartinales) cultured in an integrated multi-trophic aquaculture (IMTA) system was evaluated to obtain valuable products by a biorefinery approach. Enzymatic-assisted extraction (EAE) and microwave-assisted extraction (MAE) were the eco-friendly technologies used to ensure an environmentally friendly valorization of the biomass. Three valuable products were successfully recovered: a water-soluble extract rich in proteins and sulfated polysaccharides suitable as a food supplement; a lipid fraction rich in polyunsaturated fatty acids (PUFAs) with potential to be used in the nutraceutical industry; and a pure ι-carrageenan with a powerful antiviral activity against
virus (EC
= 6.3 µg mL
) comparable to the commercial antiviral acyclovir (EC
= 3.2⁻5.4 µg mL
).
Flavonoids are naturally occurring compounds widely distributed in the
genus. These natural compounds have many health benefits, mainly for metabolic and cardiovascular diseases. In fact, some these ...compounds are components of drug products with approved indications for peripheral vascular insufficiency and hemorrhoids. However, information on pharmacological effects of these compounds remains disperse and there is scarce comprehensive analysis of whole data and evidence. These kinds of evidence analyses could be necessary in drug design and the development of novel and innovate drug products in diabetes and hypertension. We aimed to systematically search for evidence on the efficacy of citroflavonoids in diabetes and hypertension in in vivo models. We searched four literature databases based on a PICO strategy. After database curation, twenty-nine articles were retrieved to analyze experimental data. There was high heterogeneity in both outcomes and methodology. Naringenin and hesperetin derivates were the most studied citroflavonoids in both experimental models. More investigation is still needed to determine its potential for drug design and development.
Substituted phenylacetic (
), phenylpropanoic (
), and benzylidenethiazolidine-2,4-dione (
) derivatives were designed according to a multitarget unified pharmacophore pattern that has shown robust ...antidiabetic activity. This bioactivity is due to the simultaneous polypharmacological stimulation of receptors PPARα, PPARγ, and GPR40 and the enzyme inhibition of aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP-1B). The nine compounds share the same four pharmacophore elements: an acid moiety, an aromatic ring, a bulky hydrophobic group, and a flexible linker between the latter two elements. Addition and substitution reactions were performed to obtain molecules at moderated yields. In silico pharmacological consensus analysis (PHACA) was conducted to determine their possible modes of action, protein affinities, toxicological activities, and drug-like properties. The results were combined with in vivo assays to evaluate the ability of these compounds to decrease glucose levels in diabetic mice at a 100 mg/kg single dose. Compounds
(a phenylpropanoic acid derivative) and
(a benzylidenethiazolidine-2,4-dione derivative) ameliorated the hyperglycemic peak in a statically significant manner in a mouse model of type 2 diabetes. Finally, molecular dynamics simulations were executed on the top performing compounds to shed light on their mechanism of action. The simulations showed the flexible nature of the binding pocket of AR, and showed that both compounds remained bound during the simulation time, although not sharing the same binding mode. In conclusion, we designed nine acid bioisosteres with robust in vivo antihyperglycemic activity that were predicted to have favorable pharmacokinetic and toxicological profiles. Together, these findings provide evidence that supports the molecular design we employed, where the unified pharmacophores possess a strong antidiabetic action due to their multitarget activation.
Sanitary landfill leachates usually have characteristics that depend on the region where they are generated and according to the age of the landfill, which is why a unique treatment for their ...sanitation has not been found. However, the adsorption preceded by the Fenton process has been proven to be highly efficient at removing contaminants. In this study, the adsorptive capacity of two types of activated carbon, granular and powdered, was analyzed to determine which was more efficient in the adsorption stage in the Fenton-adsorption process. Likewise, its behavior was analyzed using three isotherm models (Langmuir, Freundlich and Temkin), testing the raw leachate and the Fenton-treated one with both carbons. The adsorption that is carried out on the carbons is better adjusted to the Freundlich and Temkin models. It concludes that multilayers, through the physical adsorption, carry out the adsorption of pollutants on the surface of the carbons. The results show that, statistically, granular activated carbon is more efficient at removing chemical oxygen demand (COD), and powdered activated carbon removes color better. Finally, an adsorption column was designed for the Fenton-adsorption process that was able to remove 21.68 kgCOD/kg carbon. Removal efficiencies for color and COD were >99%.
Parasitic diseases, including giardiasis caused by Giardia lamblia (G. lamblia), present a considerable global health burden. The limited effectiveness and adverse effects of current treatment ...options underscore the necessity for novel therapeutic compounds. In this study, we employed a rational design strategy to synthesize retroalbendazole (RetroABZ), aiming to address the limitations associated with albendazole, a commonly used drug for giardiasis treatment. RetroABZ exhibited enhanced in vitro activity against G. lamblia trophozoites, demonstrating nanomolar potency (IC50 = 83 nM), outperforming albendazole (189 nM). Moreover, our in vivo murine model of giardiasis displayed a strong correlation, supporting the efficacy of RetroABZ, which exhibited an eleven-fold increase in potency compared to albendazole, with median effective dose (ED50) values of 5 µg/kg and 55 µg/kg, respectively. A notable finding was RetroABZ’s significantly improved water solubility (245.74 µg/mL), representing a 23-fold increase compared to albendazole, thereby offering potential opportunities for developing derivatives that effectively target invasive parasites. The molecular docking study revealed that RetroABZ displays an interaction profile with tubulin similar to albendazole, forming hydrogen bonds with Glu198 and Cys236 of the β-tubulin. Additionally, molecular dynamics studies demonstrated that RetroABZ has a greater number of hydrophobic interactions with the binding site in the β-tubulin, due to the orientation of the propylthio substituent. Consequently, RetroABZ exhibited a higher affinity compared to albendazole. Overall, our findings underscore RetroABZ’s potential as a promising therapeutic candidate not only for giardiasis but also for other parasitic diseases.
PDF
