On the way to potential antifungal compounds: synthesis and in vitro activity of 2-benzofuranylacetic acid amides.

Crop losses caused by microbial infections are a significant global issue, especially in tropical regions. The development of novel antimicrobial agents, particularly antifungal agents, has been explored from various perspectives, including chemical synthesis. However, conventional approaches typically involve synthesizing new and potent compounds on a small scale (a few milligrams), making the scale-up of the reaction a major challenge. In this manuscript, we present a method for the synthesis of new and active (against Fusarium oxysporum) benzofuranyl acetic acid amides. Our strategy allows us to synthesize the key precursor on the gram scale, enabling the production of sufficient quantities of other active compounds within short timeframes for conducting biological studies. All the reactions used in this manuscript are recognized by their industrial application.

Anti-Inflammatory Effect of Izalpinin Derived from Chromolaena leivensis: λ-Carrageenan-Induced Paw Edema and In Silico Model.

The flavonoid izalpinin was isolated from the aerial parts of Chromolaena leivensis. Its structural determination was carried out using MS and NMR spectroscopic techniques (1H, 13C). This compound was evaluated for its anti-inflammatory effect in a rat model on λ-carrageenan-induced plantar edema. Paw inflammation was measured at one-hour intervals for seven hours following the administration of λ-carrageenan. Serum creatine kinase (CK) levels were evaluated, obtaining statistically significant results with the treatments at doses of 10 mg/kg (* p < 0.01) and 20 mg/kg (** p < 0.005). The anti-inflammatory effect of the compound was evaluated by using plethysmography, and the results showed significant differences at the three concentrations (10 mg/kg, 20 mg/kg, 40 mg/kg) in the first and third hours after treatment. * p < 0.05; ** p < 0.001; **** p < 0.0001 vs. the negative control group treated with vehicle (DMSO). Lastly, molecular docking analyses reveal that izalpinin has a strong binding affinity with five target proteins involved in the inflammatory process. The analysis using molecular dynamics allowed demonstrating that the ligand-protein complexes present acceptable stability, with RMSD values within the allowed range.

Second-Generation Enamine-Type Schiff Bases as 2-Amino Acid-Derived Antifungals against Fusarium oxysporum: Microwave-Assisted Synthesis, In Vitro Activity, 3D-QSAR, and In Vivo Effect.

In this manuscript, the synthesis of enamine-type Schiff bases 1−48 derived from the amino acids L-Ala, L-Tyr, and L-Phe was carried out. Their in vitro activity and in vivo protective effect against Fusarium oxysporum were also evaluated through mycelial growth inhibition and disease severity reduction under greenhouse conditions. The in vitro activity of test compounds 1−48 showed half-maximal inhibitory concentrations (IC50) at different levels below the 40 mM range. Deep analysis of the IC50 variations indicated that the size of the substituent on the acetylacetone derivatives and the electronic character on the cyclohexane-3-one fragment influenced the antifungal effect. 3D-QSAR models based on atoms (atom-based approach) were built to establish the structure−activity relationship of the test Schiff bases, showing a good correlation and predictive consistency (R2 > 0.70 and Q2 > 0.60). The respective contour analysis also provided information about the structural requirements for potentiating their antifungal activity. In particular, the amino acid-related fragment and the alkyl ester residue can favor hydrophobic interactions. In contrast, the nitrogen atoms and enamine substituent are favorable regions as H-donating and electron-withdrawing moieties. The most active compounds (40 and 41) protected cape gooseberry plants against F. oxysporum infection (disease severity index < 2), involving adequate physiological parameters (stomatal conductance > 150 mmol/m2s) after 45 days of inoculation. These promising results will allow the design of novel Schiff base-inspired antifungals using 2-amino acids as precursors.

Síntesis y actividad antifúngica in vitro frente a Fusarium oxysporum de amidas N-alquilsustituidas derivadas de 2-aminoácidos

Una serie de amidas N-alquilsustituidas 1-16 fueron sintetizadas a partir de malonato de dietilo y ésteres de alquilo derivados de los aminoácidos L-triptófano, L-alanina, L-fenilalanina y L-tirosina. Los métodos de síntesis empleados involucraron calentamiento por irradiación de microondas empleando tanto un ácido de Lewis (AlCl3) o 4-dimetilaminopiridina (DMAP) como catalizador y auxiliar nucleofílico, respectivamente. Los resultados sugieren que el uso de irradiación de microondas y de DMAP conlleva mejores rendimientos en un tiempo de reacción más corto. Para ilustrar las diferencias observadas, se presentan las propuestas mecanísticas de cada método de reacción para la formación de amidas N-alquilsustituidas. Finalmente, las amidas sintetizadas se evaluaron en condiciones in vitro frente a Fusarium oxysporum; mostraron actividad antifúngica a diferentes niveles (0,40 mM < IC50 < 29,1 mM), lo cual indicó que las variaciones de la actividad observada de este grupo de compuestos pueden deberse al efecto de la amida acíclica como bioisóstero no clásico de algunas fitoalexinas heterocíclicas.

N-alkyl substituted amides 1-16 were synthesized from diethyl malonate and alkyl esters derived from the amino acids L -tryptophan, L -alanine, L -phenylalanine, and L -tyrosine. In addition, a microwave-assisted protocol was employed using a Lewis acid (AlCl3) or dimethylaminopyridine (DMAP) as a catalyst and nucleophilic auxiliary, respectively, affording the desired compounds. The results suggest that DMAP-catalyzed reactions under microwave irradiation yield higher during short reaction times. Each reaction method's mechanistic proposals for forming N-alkyl-substituted amides are presented to illustrate the observed differences. The synthesized amides were evaluated under in vitro conditions against Fusarium oxysporum. The compounds exhibited antifungal activity at different levels (0.40 mM < IC50 < 29.1 mM). These results indicated that the observed activity variations of this compound group might be due to the effect of acyclic amide as a non-classical bioisostere of some heterocyclic phytoalexins.

Uma série de amidas N-alquil substituídas foram sintetizadas a partir de malonato de dietila e ésteres alquílicos derivados dos aminoácidos ʟ-triptofano, L -alanina, L-fenilalanina e L-tirosina. Os métodos de síntese empregados foram realizados usando aquecimento por irradiação de micro-ondas empregando um ácido de Lewis (AlCl3) ou dimetilaminopiridina (DMAP) como catalisador. Os resultados sugerem que a irradiação de micro-ondas usando DMAP leva a melhores rendimentos em um tempo de reação mais curto. Para ilustrar as diferenças observadas, são apresentadas as propostas mecanísticas de cada método de reação para a formação de amidas N-alquilsubstituídas. Finalmente, as amidas sintetizadas foram avaliadas in vitro contra Fusarium oxysporum, mostrando atividade antifúngica em diferentes níveis (0.40 mM < IC50 < 29.1 mM), o que indica que as variações observadas na atividade desse grupo de compostos podem ser devidas ao efeito de amida acíclica como um bioisóstero não clássico de algumas fitoalexinas heterocíclicas.

New Drug Design Avenues Targeting Alzheimer's Disease by Pharmacoinformatics-Aided Tools.

Neurodegenerative diseases (NDD) have been of great interest to scientists for a long time due to their multifactorial character. Among these pathologies, Alzheimer's disease (AD) is of special relevance, and despite the existence of approved drugs for its treatment, there is still no efficient pharmacological therapy to stop, slow, or repair neurodegeneration. Existing drugs have certain disadvantages, such as lack of efficacy and side effects. Therefore, there is a real need to discover new drugs that can deal with this problem. However, as AD is multifactorial in nature with so many physiological pathways involved, the most effective approach to modulate more than one of them in a relevant manner and without undesirable consequences is through polypharmacology. In this field, there has been significant progress in recent years in terms of pharmacoinformatics tools that allow the discovery of bioactive molecules with polypharmacological profiles without the need to spend a long time and excessive resources on complex experimental designs, making the drug design and development pipeline more efficient. In this review, we present from different perspectives how pharmacoinformatics tools can be useful when drug design programs are designed to tackle complex diseases such as AD, highlighting essential concepts, showing the relevance of artificial intelligence and new trends, as well as different databases and software with their main results, emphasizing the importance of coupling wet and dry approaches in drug design and development processes.

Synthesis (Z) vs (E) Selectivity, Antifungal Activity against Fusarium oxysporum, and Structure-Based Virtual Screening of Novel Schiff Bases Derived from l-Tryptophan.

Schiff bases are widely used molecules due to their potential biological activity. In this manuscript, we presented the synthesis and NMR study of new enamine Schiff bases derived from l-tryptophan, showing that the Z-form of the enamine is the main tautomeric form for aliphatic precursors. The DFT-B3LYP methodology at the 6-311+G**(d,p) level suggested that the tautomeric imine forms are less stable than the corresponding enamine forms. Their isomerism depends on the formation of intramolecular hydrogen bonds and steric factors associated with the starting carbonyl precursors. The in vitro biological activity tests against Fusarium oxysporum revealed that acetylacetone derivatives are the most active agents (IC50 < 0.9 mM); however, the antifungal activity could be disfavored by bulky groups on ester and enamine moieties. Finally, the structure-based virtual screening through molecular docking and MM-GBSA rescoring revealed that Schiff bases 3e, 3g, and 3j behave putatively as binders for target proteins involved in the life processes of F. oxysporum. In this sense, molecular dynamics analysis showed that the ligand-protein complexes have good stability with root-mean-square deviation (RMSD) values within the allowed range. Therefore, the present study paves the way for designing new antifungal compounds based on l-tryptophan-derived Schiff bases.

High polarity extracts obtained from Ilex guayusa Loes. leaves, exhibit antioxidant capacity / Extractos de alta polaridad obtenidos a partir de las hojas de Ilex guayusa Loes. exhiben capacidad antioxidante

Background: Ilex guayusa Loes. belongs to the family Aquifoliaceae. It is an evergreen tree native to the Amazon region. According to traditional uses, it is used as a diaphoretic, narcotic, purgative, among other uses. Objective: To evaluate the antioxidant capacity, quantify phenols and total flavonoids of extracts obtained from Ilex guayusa leaves. Methods: Total ethanolic extract was obtained using Soxhlet-type equipment, with subsequent liquid/liquid fractionation with solvents of different polarities (petroleum ether, dichloromethane, and ethyl acetate); were reacted with 2,2-diphenyl-1-picrylhydrazyl (DPPH•) and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS•+), determining the inhibitory concentration 50 (IC50) and relative antioxidant activity (%AAR), with subsequent statistical analysis (ANOVA and Tukey's post-hoc). Total phenols and flavonoids were quantified using the Folin-Ciocalteu method and complex formation with AlCl3, respectively. Results: The ethanolic extract of leaves showed the highest antioxidant activity in both the DPPH• and ABTS•+ methods with IC50 values of 4.58 and 3.82 ppm, respectively. Conclusions: According to the results obtained in this study, it was possible to corroborate that the ethanolic extract (EE) obtained from the leaves of I. guayusa showed the highest antioxidant capacity, by the DPPH• and ABTS•+ methods. Additionally, it was possible to relate this capacity to the high flavonoids content present in this extract. Based on the above and accompanied by future studies, the Ilex guayusa species could be proposed as an important source of antioxidant compounds with possible application in medicine and the food industry

Antecedentes:Ilex guayusa Loes. pertenece a la familia Aquifoliaceae. Es un árbol perenne, nativo de la región amazónica. De acuerdo con los usos tradicionales es empleada como diaforético, narcótico, purgativo, entre otros usos. Objetivo: Evaluar la capacidad antioxidante, cuantificar fenoles y flavonoides totales de extractos obtenidos a partir de las hojas de Ilex guayusa. Métodos: El extracto etanólico total se obtuvo mediante un equipo tipo "Soxhlet", con posterior fraccionamiento líquido/líquido con solventes de diferentes polaridades (éter de petróleo, diclorometano y acetato de etilo); se hicieron reaccionar con 2,2-difenil-1-picrilhidracilo (DPPH•) y ácido 2,2'-azino-bis-3-etilbenzotiazolin-6-sulfónico (ABTS•+), determinando la concentración inhibitoria 50 (IC50) y la actividad antioxidante relativa (%AAR), con posterior análisis estadístico (ANOVA y post-hoc de Tukey). Los fenoles y flavonoides totales se cuantificaron con el método de Folin-Ciocalteu y el de formación de complejos con AlCl3, respectivamente. Resultados: El extracto etanólico de las hojas fue el que presentó mayor actividad antioxidante tanto en el método DPPH• como en el ABTS•+ con valores de IC50 de 4,58 y 3,82 ppm, respectivamente. Conclusiones: De acuerdo con los resultados obtenidos en este estudio, se pudo corroborar que el extracto etanólico obtenido de las hojas de I. guayusamostró la mayor capacidad antioxidante, por los métodos DPPH• y ABTS•+. Adicionalmente, se pudo relacionar esta capacidad con el alto contenido de flavonoides presentes en este extracto. Con base en lo anterior y acompañado de futuros estudios, la especie I. guayusa podría proponerse como una importante fuente de compuestos antioxidantes con posible aplicación en los campos de la medicina y la industria alimentaria

A Compendium of the Most Promising Synthesized Organic Compounds against Several Fusarium oxysporum Species: Synthesis, Antifungal Activity, and Perspectives.

Vascular wilt caused by F. oxysporum (FOX) is one of the main limitations of producing several agricultural products worldwide, causing economic losses between 40% and 100%. Various methods have been developed to control this phytopathogen, such as the cultural, biological, and chemical controls, the latter being the most widely used in the agricultural sector. The treatment of this fungus through systemic fungicides, although practical, brings problems because the agrochemical agents used have shown mutagenic effects on the fungus, increasing the pathogen's resistance. The design and the synthesis of novel synthetic antifungal agents used against FOX have been broadly studied in recent years. This review article presents a compendium of the synthetic methodologies during the last ten years as promissory, which can be used to afford novel and potential agrochemical agents. The revision is addressed from the structural core of the most active synthetic compounds against FOX. The synthetic methodologies implemented strategies based on cyclo condensation reactions, radical cyclization, electrocyclic closures, and carbon-carbon couplings by metal-organic catalysis. This revision contributes significantly to the organic chemistry, supplying novel alternatives for the use of more effective agrochemical agents against F. oxysporum.

PSC-db: A Structured and Searchable 3D-Database for Plant Secondary Compounds.

Plants synthesize a large number of natural products, many of which are bioactive and have practical values as well as commercial potential. To explore this vast structural diversity, we present PSC-db, a unique plant metabolite database aimed to categorize the diverse phytochemical space by providing 3D-structural information along with physicochemical and pharmaceutical properties of the most relevant natural products. PSC-db may be utilized, for example, in qualitative estimation of biological activities (Quantitative Structure-Activity Relationship, QSAR) or massive docking campaigns to identify new bioactive compounds, as well as potential binding sites in target proteins. PSC-db has been implemented using the open-source PostgreSQL database platform where all compounds with their complementary and calculated information (classification, redundant names, unique IDs, physicochemical properties, etc.) were hierarchically organized. The source organism for each compound, as well as its biological activities against protein targets, cell lines and different organism were also included. PSC-db is freely available for public use and is hosted at the Universidad de Talca.