Márcia Machado Marinho

Sophalines isolated from Sophora alopecuroides have been recognized for their antiviral properties; however, their potential neurotoxic and ecotoxicological effects remain poorly understood. In this study, the toxicity and putative GABAergic-like activity of these compounds were investigated using computational approaches. Model-based ecotoxicological estimations suggested that sophalines may present moderate to high toxicity toward Daphnia magna and may be associated with inhibition of biomass growth in green algae. These findings are consistent with a narcotic-like mode of action, which may be related to reduced locomotor activity and central nervous system (CNS)-associated effects, as inferred from physicochemical descriptors and CNS multiparameter optimization (CNS MPO) profiles. Comparative analysis with the reference compound diazepam indicated overlapping concentration ranges, suggesting a possible similarity in their predicted toxicological profiles. Molecular docking results suggested that sophaline derivatives may interact with the GABAAR, with some compounds occupying regions overlapping the diazepam binding site, while others were positioned in adjacent regions, indicating potential modulatory interactions. These interactions were characterized by hydrophobic contacts, hydrogen bonding, and π-interactions, which may contribute to complex stability. Molecular dynamics simulations supported the structural stability of the ligand–receptor complexes, with the D2/GABAA receptor system presenting the most favorable interaction profile among the evaluated compounds. Overall, these findings provide computational insights into the potential GABAergic-like sedative effects of sophalines. However, as all results are derived from in silico approaches, they should be interpreted as predictive rather than confirmatory. Experimental validation through in vitro and in vivo studies is required to substantiate these observations and to better assess their ecological and pharmacological relevance.

Leishmaniasis represents one of the major global public health problems. Canine leishmaniasis plays a significant role in perpetuating this condition, due to the limited therapeutic options available, which are costly, require prolonged treatment regimens, and are associated with the growing emergence of drug resistance. In this context, β-lapachone, a bioactive naphthoquinone derived from lapachol, has emerged as a potential therapeutic alternative due to its pharmacological properties, including antiparasitic activity, which characterizes it as a promising alternative for the development of new antileishmanial agents. In this study, a group of β-lapachone derivatives was evaluated using an integrated computational approach to investigate their antileishmanial potential and pharmacokinetic profile. Molecular docking simulations indicated greater selectivity of the compounds for Leishmania spp. targets compared to currently used drugs. Among the derivatives analyzed, compound LPI3 stood out as the lead compound, exhibiting a promising multitarget profile. Molecular dynamics analyses based on normal mode analysis revealed high conformational stability of the protein-ligand complexes involving LPI3, similar to that observed for the reference drugs. The physicochemical properties, as well as predictions of pharmacokinetic descriptors related to absorption, distribution, metabolism, excretion, and toxicity, indicated a favorable profile for the lead compound, consistent with drug-likeness and safety criteria. Therefore, the findings identified LPI3 as a potential candidate for future experimental evaluations in the treatment of leishmaniasis. Graphical abstract The alternative text for this image may have been generated using AI.

Gentamicin (GM)-induced nephrotoxicity is closely linked to oxidative stress, with few therapeutic alternatives available. Chalcones are structurally versatile compounds with reported antioxidant properties, making them attractive candidates for nephroprotection. The 4′-aminochalcones substituted with p -NO ₂ (31.25–15.62 µM) or p -N(CH3) ₂ (7.81 µM) groups demonstrated significant protective effects, partially restoring (∼11 %) HK-2 cell viability after GM-induced injury. Both derivatives increased intracellular glutathione levels, reduced superoxide accumulation, and lowered cytoplasmic ROS concentration. Structural and electronic analyses revealed that the electron-donating group p -N(CH3) ₂ enhanced antioxidant reactivity, whereas the electron-withdrawing group p -NO ₂ decreased cytotoxicity. HK-2 cells were exposed to GM (IC ₅₀ = 5.0 ± 0.7 mmol/L) for 24 h, followed by treatment with 4′-aminochalcones (250–7.81 µM). Cell viability was assessed by MTT assay. ROS were quantified by flow cytometry using DCFH-DA, while redox balance was evaluated through glutathione content and superoxide accumulation. The electronic properties of chalcone derivatives were further investigated by density functional theory calculations. The 4′-aminochalcones mitigate GM-induced oxidative stress in renal cells, and their antioxidant and cytoprotective activities are strongly influenced by electronic substituents. Electron-donating groups enhance reactivity, whereas electron-withdrawing groups improve safety, underscoring the importance of structure-effect relationships in the design of chalcone-based nephroprotective agents.

Background/Objectives: Hydrazones are organic compounds with the general structure R₂C=NNHR₁, distinguished by their versatility and modifiability, and are widely used in various applications due to their physicochemical and biological properties. They exhibit anticancer, anti-inflammatory, antibiofilm, and antibacterial activities. Antibiotic-resistant bacteria pose a serious public health threat, employing mechanisms such as enzymatic inactivation and efflux pumps. This study evaluated the antibacterial activity of the hydrazone HDZH1,4BENZ, a hydralazine-derived compound, as well as its potential adjuvant effect in combination with antibiotics against Staphylococcus aureus strains expressing efflux pumps. Methods: The strains used were 1199B (NorA efflux pump-expressing) and K2068 (MepA efflux pump-expressing). All assays were conducted using the broth microdilution method in Brain Heart Infusion (BHI) medium. Initially, the intrinsic antibacterial activity of the compound was determined. Subsequently, modulation assays were performed to evaluate its potential effect on efflux pump activity, with a standard efflux pump inhibitor included as a positive control. Results: Although HDZH1,4BENZ did not demonstrate significant direct antibacterial activity, the results indicate that this hydrazone exerts a notable inhibitory effect on the NorA (Norfloxacin resistance efflux pump A) and MepA (Multidrug efflux protein A) efflux pumps in S. aureus, thereby enhancing the efficacy of antibacterial agents. Conclusions: The activity of the hydrazone was comparable to that of chlorpromazine, suggesting that it may represent a promising alternative in the fight against antibiotic-resistant bacterial infections.

Thiosemicarbazones (TSCBZ) are promising insecticidal compounds, but their potential neurotoxicity remains unclear. This study aimed to evaluate the toxicity and cholinesterase inhibition of six substituted TSCBZ derivatives using ligand- and structure-based computational approaches. Electronic property analysis revealed that bromine substitution enhances electrophilicity, while sulfur (in TSCBZ1–3) and nitrogen (in TSCBZ4–6) are the most nucleophilic sites. Toxicity prediction indicated that TSCBZ1, 4, and 6 may induce acute and chronic effects in aquatic organisms. Molecular docking showed that TSCBZ1 and TSCBZ4 exhibit higher affinity for acetylcholinesterase than galantamine, suggesting potential selective inhibition. These findings provide novel insights into the structure–toxicity relationship of TSCBZ and their environmental safety profile.

Cenostigma pyramidale, a species native to the Brazilian Caatinga and traditionally used to treat respiratory and gastrointestinal disorders, was investigated for its neuropharmacological potential related to Alzheimer’s disease (AD). The ethanolic leaf extract was evaluated as a natural acetylcholinesterase (AChE) inhibitor through in vitro and in silico approaches. The quantification of total phenolic compounds in the ethanolic extract showed 414.70 ± 21.48 mg GAE g-1 of extract, and the flavonoid content was estimated at 41.42 ± 0.41 mg QE g-1 of extract. The extract exhibited strong AChE inhibitory activity, with an IC₅₀ of 7.04 ± 0.04 µg mL-1. Remarkable antioxidant performance was also recorded, with IC₅₀ values of 12.64 ± 0.11 µg mL-1 in the DPPH● assay, 12.38 ± 0.09 µg mL-1 in ABTS+●, and 7.95 ± 0.08 µg mL-1 in the β-carotene test. Chromatographic analysis indicated seven main constituents: gallic acid, geraniin, rutin, ellagic acid, isoquercitrin, quercetin, and agathisflavone. Molecular docking revealed favorable interactions between these compounds and AChE, particularly for geranin, rutin, and agathisflavone, mainly at allosteric regions of the enzyme. These findings suggest that C. pyramidale may be a promising source of multifunctional compounds with cholinesterase inhibitory and antioxidant properties, supporting its potential for AD therapeutics.

Vitex gardneriana Schauer, known as “Jaramataia”, is widely used in folk medicine for its anti-inflammatory and analgesic properties. This study aimed to determine the chemical composition and evaluate the antifungal, antioxidant, and cytotoxic effects of the essential oil (EO) from its leaves. The EO was obtained via hydrodistillation and analyzed by GC-FID, identifying 16 components, with trans-calamenene (25.31%), 6,9-guaiadiene (18.33%), and caryophyllene oxide (15.14%) as major compounds. Antifungal activity was assessed by broth microdilution, showing a MIC of 5 mg/mL for all strains. A synergistic effect was observed when combined with amphotericin B, reducing the EO’s inhibitory concentration by over 30-fold. Antioxidant activity (DPPH method) showed an IC50 of 85.86 mg/mL, while hemolytic assays on human erythrocytes showed an IC50 of 20 mg/mL. Molecular docking revealed a stronger affinity of EO compounds to Sap5 (-7.3 kcal/mol) than Als3 (-6.2 kcal/mol), with some ligands (e.g., 1-epi-cubenol, caryophyllene oxide) binding to different regions than amphotericin B. These findings suggest that V. gardneriana EO has moderate antifungal activity. However, it shows promising potential when combined with conventional antifungal agents and supports future research toward the development of therapeutic formulations.

Semicarbazones have been used as insecticides and act through different mechanisms of action by inhibiting enzymes essential for insect metabolism, including enzymes that act on the central nervous system of insects associated with other general toxic effects for these organisms. In this context, the purpose of the study was to evaluate the toxicity of semicarbazones and their respective substituent groups using in silico toxicological modeling approach, analyzing the stability between ligand-receptor and their structure/activity relationship (SAR) to establish relationships between behavioral toxicity syndrome (BTS) in fish as a method of environmental biomonitoring. Quantum calculations were obtained using the Density Functional Theory method for electronic structural characterization. Toxicity prediction was carried out using the Ecological Structure Activity Relationship (ECOSAR) predictive model, which estimates the acute and chronic toxicity of organic compounds in aquatic organisms such as fish, aquatic invertebrates, and aquatic plants. Molecular docking simulations were conducted using the Autodock Vina software against the target acetylcholinesterase (AChE). The protein–ligand complexes with the lowest energy and RMSD of less than 2 Å were submitted to molecular dynamics simulations. The quantum data corroborates the surface analysis of lipophilicity, which indicates that the alkenyl substituent chain has a greater partition contribution fragment in which dihalogenated derivatives increase in this proportion. The HOMO–LUMO gap (∆E) and log Pow properties can infer toxicity and latency induction, delineating that organic compounds with log Pow lower than 2 and ∆E higher than 9 eV are more susceptible to low toxicity. The S2-AChE complex showed greater stability, characterized by low conformational variations and high cohesion between the results. This stability was corroborated by the formation of hydrogen bonds with amino acid residues present in the receptor's active site.