Emmanuel Silva Marinho

Chalcones constitute a relevant class of flavonoids with diverse pharmacological potential, including activity in the central nervous system. In this study, the anxiolytic potential of the chalcone (2E)-1-(4′-aminophenyl)-3-furan-2-yl-prop-2-en-1-one (CPAfurf) was investigated through in vivo and in silico assays using adult zebrafish (Danio rerio). Molecular docking studies revealed a significant affinity of CPAfurf for the serotonergic receptors 5-HT2A, 5-HT2C, and 5-HT3A, with interaction patterns similar to reference antagonists. In acute toxicity tests, the molecule showed no toxic effects at the evaluated doses (LD50 > 40 mg/kg). In behavioral assays, CPAfurf demonstrated a consistent anxiolytic effect, evidenced by an increased time spent in the light zone and greater exploration of the upper region of the tank, with minimal interference in locomotion at low concentrations. Furthermore, the anxiolytic effect was reversed by pretreatment with serotonergic antagonists, indicating the direct involvement of the 5-HT pathway, especially the 5-HT3A receptors. Taken together, the findings suggest that the chalcone CPAfurf presents potential as a serotonergic modulator and a promising bioactive compound candidate for the development of new anxiolytic agents with a reduced toxicity profile.

Leishmaniasis is a globally distributed zoonosis and a major challenge to public health, with increasing incidence and limited therapeutic options marked by toxicity and emerging resistance. Aiming to identify safer and more effective alternatives for disease control, this study evaluated the antileishmanial potential of coumarin‐benzimidazole hybrids through structure‐based virtual screening, targeting two essential enzymes of Leishmania spp., Cathepsin B (CatB), and N‐myristoyltransferase (NMT). Molecular docking simulations revealed higher binding affinities for all hybrids compared with the reference drug miltefosine (MTF), with CBZ2 and CBZ3 showing the strongest interactions with CatB and NMT, respectively. Molecular dynamics simulations (200 ns) confirmed the conformational stability of these complexes, supported by Root‐mean‐square deviation (RMSD)/Root‐mean‐square fluctuation (RMSF) analyses and persistent hydrogen bonds. MM/GBSA calculations further indicated favorable binding free energies. Additionally, CBZ2 and CBZ3 presented a favorable balance between permeability and lipophilicity, suggesting adequate passive membrane diffusion and a viable predicted pharmacokinetic profile. These findings highlight coumarin‐benzimidazole hybrids as promising candidates for future antileishmanial drug development research.

Context: Erectile dysfunction (ED) significantly affects male psychosocial health and has an increasing incidence. Although phosphodiesterase 5 (PDEi-5) inhibitors are the first-line therapy, the occurrence of visual side effects resulting from cross-inhibition of the PDE-6 isoform limits their adoption. In this context, the plant Veronica anagallis-aquatica L. emerges as a promising source of bioactive therapeutic compounds. This work investigated the inhibitory potential and selectivity of eight iridoid glycosides from this species against PDE-5 and PDE-6. The results identified catalposide as the most potent ligand, exhibiting an affinity energy of -8.6 kcal/mol against PDE-5, surpassing the reference drug Vardenafil (-8.3 kcal/mol) and showing high selectivity towards PDE-6. Trajectory analyses confirmed the robustness of the catalposide-PDE-5 complex, which exhibited smaller structural fluctuations than the commercial control. Despite initial predictions indicating low oral bioavailability, structural optimization through increased sp3 fraction proved to be a viable strategy for enhancing membrane permeability. In conclusion, the findings position catalposide as a promising prototype for the development of more selective and safe drugs for the treatment of ED. Methods: The two-dimensional structures of the ligands were constructed in Marvin JS and subjected to energy minimization using the semi-empirical PM7 method in MOPAC software. The preparation of macromolecules (addition of polar hydrogens and Gasteiger and Kollman charges) was performed in AutoDockTools. Virtual screening by molecular docking was performed in AutoDock Vina, with exhaustiveness set to 64. The stability of the protein-ligand complexes was evaluated through 500 ns molecular dynamics (MD) simulations using GROMACS 2020.4 software. The systems were solvated with the three-point water model (TIP3P) in a cubic box and described by the CHARMM36 force field. The ligand parameterization was generated via the SwissParam server. The simulations employed the LeapFrog integrator, temperature maintained constant at 310 K via V-rescale thermostat, and pressure coupling maintained at 1 bar using the Parrinello-Rahman method. For predictions of physicochemical properties, pharmacokinetic optimization, and ADMET profile analysis (including hERG toxicity), the predictive servers ADMETlab 3.0, optADMET, ADMET-AI, XenoSite, StopTox, and Pred-hERG were used. Three-dimensional structural complexity was evaluated from the calculation of the MCE-18 function.

Naphthoquinones are redox-active compounds with antitumor potential, often linked to NQO1 overexpression in cancer cells. This study evaluated the cytotoxic activity of two synthetic 1,4-naphthoquinones, compound 1 and its dual redox analog, compound 4, against NQO1-overexpressing DU-145 prostate cancer cells through integrated in vitro, enzymatic, and computational (docking and quantum) analyses. Compound 4 exhibited over 2-fold greater cytotoxicity against DU-145 cells compared to nontumor MRC-5 cells, while maintaining low hemolytic activity. Evidence of membrane damage, ROS generation, lipid peroxidation, and reversal by deferoxamine indicated ferroptosis induction by 4, whereas 1 triggered caspase-3-dependent apoptosis. Both caused ROS-mediated DNA damage attenuated by NAC. Docking and enzymatic assays confirmed partial dependence on NQO1, with 4 showing greater ROS production despite lower enzymatic activity. Overall, compound 4 highlights the potential of dual-redox quinone platforms to induce ferroptosis, providing a viable lead candidate for novel antineoplastic drug discovery in prostate cancer and other malignancies.

Anxiety and seizures are prevalent conditions worldwide, with conventional treatment relying on benzodiazepines. However, the long‐term use of these drugs is associated with adverse effects and the development of dependence, driving the search for safer therapeutic alternatives. (+)‐Dihydrocarvone is a monoterpene ketone with documented biological activities, including antifungal, antiparasitic, and anti‐inflammatory effects. This study utilized adult zebrafish (*Danio rerio*), an animal model widely used in pharmacological and behavioral research due to its neurobiological similarity to mammals. Toxicity tests, assessments of anxiolytic activity and memory effects, and *in silico* studies were conducted. The results demonstrated anxiolytic‐like effects and memory preservation associated with (+)‐dihydrocarvone, with pharmacological data suggesting the possible involvement of GABAergic and serotonergic pathways. Furthermore, molecular interaction analyses revealed affinity for the GABA∼A receptor, indicating a potential pharmacological effect.

Background/Objectives: Synthetic compounds, particularly thiadiazine derivatives with antibacterial properties, have emerged as promising candidates in addressing the growing challenge of bacterial multidrug resistance. Thiadiazine derivatives are six-membered heterocyclic compounds containing two nitrogen atoms and one sulfur atom, exhibiting diverse medical and pharmacological activities. This study aimed to evaluate the potentiating activity of thiadiazine derivatives against multidrug-resistant bacteria. Methods: ADMET (absorption, distribution, metabolism, excretion, and toxicity) assays were performed to assess similarity with more than 370,000 three-dimensional structures of bioactive compounds. The multidrug-resistant bacterial strains Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to investigate both the direct antibacterial activity and the antibiotic-modifying activity of thiadiazine derivatives. Results: The thiadiazine analogs did not exhibit direct antibacterial activity, presenting a minimum inhibitory concentration of 1024 μg/mL. However, they demonstrated a significant antibiotic-modifying effect, potentiating the activity of conventional antibiotics, particularly norfloxacin, against the tested strains. In silico analyses indicated that the analogs predominantly exhibited affinity for G protein-coupled receptors and possessed physicochemical characteristics compatible with potential drug candidates. Conclusions: Although the evaluated thiadiazine derivatives lacked direct antibacterial activity, they significantly enhanced the efficacy of antibiotics against multidrug-resistant bacteria. Combined with their favourable in silico pharmacokinetic and physicochemical profiles, these findings suggest that thiadiazine derivatives may represent promising antibiotic adjuvants for combating multidrug-resistant bacterial infections.