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Bacterial resistance has become a global concern for public health agencies. Various resistance mechanisms found in Staphylococcus aureus strains grant this bacterium resistance to a wide range of antibiotics, contributing to the rise in human mortality worldwide. Resistance mediated by efflux pumps is one of the most prevalent mechanisms in multi-resistant bacteria, which has aroused the interest of several researchers in the search for possible efflux pump inhibitors. In view of the aforementioned considerations, it is important that new strategies, such as the synthesis of chalcones, be made available as a viable strategy in antimicrobial therapy. In this study, the synthesized chalcone (2E)-1-(3'-aminophenyl)-3-(4-dimethylaminophenyl)-prop-2-en-1-one was tested for its antibacterial activity, focusing on antibiotic modification and the inhibition of the MepA efflux pump present in S. aureus strain K2068. The broth microdilution method, using microdilution plates, was employed in microbiological tests to determine the minimum inhibitory concentration of the chalcone, antibiotics, and ethidium bromide. The results show that while the chalcone did not exhibit direct antibacterial activity, it synergistically enhanced the effects of ciprofloxacin and ethidium bromide, as evidenced by the reduction in MICs. In addition, computer simulations of molecular docking demonstrate that the tested chalcone acts on the same binding site as the efflux pump inhibitor chlorpromazine, interacting with essentially the same residues. These data suggest that the chalcone may act as a MepA inhibitor., Competing Interests: Declarations Ethical statement This article is in accordance with the international, national, and institutional rules considering biodiversity rights. Competing interests The authors declare no competing interests., (© 2024. Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i.)

(1) Background: Lippia sidoides Cham is a Brazilian aromatic plant rich in phenolic compounds. In traditional medicine, its leaves are used to treat diseases of the Central Nervous System such as stress and anxiety. This study evaluates the capacity of the aqueous extract of L. sidoides as an anticonvulsant, anticholinesterase and antihemolytic agent. (2) Methods: The extract was obtained from the leaves using water as a solvent, then dried in a spray dryer. The anticonvulsant effect was evaluated in zebrafish models using the pentylenetetrazol (PTZ) method. The anticholinesterase effect was determined using the acetylcholinesterase enzyme and physostigmine as a positive control. The antihemolytic action was evaluated by exposing erythrocytes to different concentrations of NaCl in the presence and absence of the extract. (3) Results: The anticonvulsant effect was observed at a concentration of 400 mg/kg, delaying convulsive crises. In the anticholinesterase assay, a dose-dependent action and variation in the effect over time were observed, demonstrating a reversible effect of the extract. For the osmotic fragility test, the extract showed satisfactory results, providing cellular protection across all variations of NaCl concentration. (4) Conclusions: These results demonstrate the promising potential of L. sidoides extract for the development of drugs that act in the treatment of diseases that affect the Central Nervous System.

This study investigated the anxiolytic and anticonvulsant effects and safety profile of limonene enantiomers and their oxidized derivatives. The toxicity test was performed by monitoring the animals for 96 hours, with no deaths or significant toxicity observed up to the highest dose, which allowed the determination of the LD50. Doses of 4, 20 and 40 mg/kg were tested, with no toxicity observed up to 96 h (LD50>40 mg/kg). Anxiolytic activity was measured in a preference test for light and dark areas, and the effect of the compounds was evaluated in the presence of serotonergic antagonists. The (S)-(-)-LIM and (R)-(+)-LIM enantiomers showed anxiolytic effects, with (S)-(-)-LIM being effective at all doses. In the anticonvulsant test, the oxidized derivatives, such as perilyl acid (PAC), significantly delayed PTZ-induced seizures, an effect blocked by flumazenil (FMZ). The oxidized derivatives, especially perilyl acid (PAC), showed anxiolytic effects at all doses and significantly delayed the three PTZ-induced seizure events. This effect was blocked by FMZ, suggesting a relationship between PAC and the GABAergic pathway. PAC, being the most oxidized derivative, was the most effective for both anxiety and delaying seizure progression, suggesting that oxidation of limonene compounds may increase their therapeutic efficacy., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

This study aims to evaluate the antitrypanosomiasis activity of a synthetic dichloro-substituted aminochalcone via in vitro assays against infected cell cultures, as well as a theoretical characterization of pharmacokinetics and pharmacodynamics against the protein targets of the evolutionary cycle of T. cruzi. The in vitro evaluation of parasite proliferation inhibition was performed via cytotoxicity analysis on mammalian host cells, effect on epimastigote and trypomastigote forms, and cell death analysis, while computer simulations characterized the electronic structure of (2E)-1-(4-aminophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one (DCl), the mechanism of action against the proteins of the evolutionary cycle of T. cruzi: Cruzain, Trypanothione reductase, TcGAPDH, and CYP51 by molecular docking and dynamics and predictive pharmacokinetics by MPO-based ADMET. The in vitro tests showed that the DCl LC 50 in order of 178.9 ± 23.9 was similar to the BZN, evidencing the effectiveness of chalcone against Trypomastigotes. Molecular docking and dynamics simulations suggest that DCl acts on the active site of the CYP51 receptor, with hydrogen interactions that showed a high degree of occupation, establishing a stable complex with the target. MPO analysis and ADMET prediction tests suggest that the compound presents an alignment between permeability and hepatic clearance, although it presents low metabolic stability. Chalcone showed stable pharmacodynamics against the CYP51 target, but can form reactive metabolites from N-conjugation and C = C epoxidation, as an indication of controlled oral dose, although the estimated LD 50 rate > 500 mg/kg is a indicative of low incidence of lethality by ingestion, constituting a promising therapeutic strategy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This work describes the evaluation the potentiating activity of antibiotics by campesterol (1) and its derivatives (2-11) against multiresistant strains of Staphylococcus aureus 10, Escherichia coli 06 and Pseudomonas aeruginosa 24 employing the microdilution test. When subjected to the in vitro potentiating activity bioassay, all compounds showed a potentiating effect associated with norfloxacin against E. coli and P. aeruginosa with a reduction in the MIC of the antibiotic of up to 75 %. These compounds also reduced the MIC of gentamicin by 37 % to 87 % in S. aureus and E. coli. Additionally, molecular docking studies were conducted to gain a deeper understanding of the interactions between the appropriate proteins and the most effective compounds (2, 4, 9, and 10 against E. coli; 1, 2, 3, 5, 8, and 9 against S. aureus), including antibiotics. This paper registers for the first time the in vitro and in silico studies on the action of compounds 1-11 in antibiotic potentiation., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The compilation of ligand and structure-based molecular modeling methods has become an important practice in virtual screening applied to drug discovery. This systematic review addresses and ranks various virtual screening strategies to drive the selection of the optimal method for studies that have as their starting point a multi-ligand investigation and investigation based on the protein structure of a therapeutic target. This study shows examples of applications and an evaluation based on the objective and problematic of a series of virtual screening studies present in the ScienceDirect® database. The results showed that the molecular docking technique is widely used in scientific production, indicating that approaches that use protein structure as a starting point are the most promising strategy for drug discovery that relies on virtual screening-based research., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Antimicrobials fight microorganisms, preventing and treating infectious diseases. However, antimicrobial resistance (AMR) is a growing concern due to the inappropriate and excessive use of these drugs. Several mechanisms can lead to resistance, including efflux pumps such as the NorA pump in Staphylococcus aureus, which reduces the effectiveness of fluoroquinolones. Thiadiazines are heterocyclic compounds whose chemical structure resembles that of cephalosporins. Therefore, these compounds and their derivatives have been studied for their potential in combating increased bacterial resistance. To analyze this hypothesis, direct activity assays, antibiotic action-modifying activity, fluorescence assays to evaluate the retention of ethidium bromide inside bacteria, and molecular docking were carried out. These experiments involved serial dilutions in microplates against Staphylococcus aureus strain 1199B under the influence of six thiadiazine derivatives (IJ10, IJ11, IJ21, IJ22, IJ23, and IJ25). The tests revealed that, despite not showing effective direct activity, some thiadiazine derivatives (IJ11, IJ21, and IJ22) inhibited the function of the bromide pump both in microdilution tests and in fluorescence and docking assays. Particularly, the IJ11 compound stood out for its activity similar to efflux inhibitors, as well as its inhibition of the norfloxacin pump of this bacterium. Among the results of this study, it deserves to be highlighted for anchoring future experiments, as it represents the first investigation of this group of thiadiazine derivatives against the NorA pump., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The study focuses on the anxiolytic potential of chalcone (2E,4E)-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-one (CHALCNM) in adult zebrafish. Successfully synthesized in 58 % yield, CHALCNM demonstrated no toxicity after 96 h of exposure. In behavioral tests, CHALCNM (40 mg/kg) reduced locomotor activity and promoted less anxious behavior in zebrafish, confirmed by increased permanence in the light zone of the aquarium. Flumazenil reversed its anxiolytic effect, indicating interaction with GABAA receptors. Furthermore, CHALCNM (4 and 20 mg/kg) preserved zebrafish memory in inhibitory avoidance tests. Virtual screening and ADMET profile studies suggest high oral bioavailability, access to the CNS, favored by low topological polarity (TPSA≤75 Å 2 ) and low incidence of hepatotoxicity, standing out as a promising pharmacological agent against the GABAergic system. In molecular coupling, CHALCNM demonstrated superior affinity to diazepam for the GABAA receptor. These results reinforce the therapeutic potential of CHALCNM in the treatment of anxiety, highlighting its possible future clinical application., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Severe Acute Respiratory Syndrome caused by a coronavirus is a recent viral infection. There is no scientific evidence or clinical trials to indicate that possible therapies have demonstrated results in suspected or confirmed patients. This work aims to perform a virtual screening of 1430 ligands through molecular docking and to evaluate the possible inhibitory capacity of these drugs about the M pro protease of Covid-19. The selected drugs were registered with the FDA and available in the virtual drug library, widely used by the population. The simulation was performed using the MolAiCalD algorithm, with a Lamarckian genetic model (GA) combined with energy estimation based on rigid and flexible conformation grids. In addition, molecular dynamics studies were also performed to verify the stability of the receptor-ligand complexes formed through analyses of RMSD, RMSF, H-Bond, SASA, and MMGBSA. Compared to the binding energy of the synthetic redocking coupling (-6.8 kcal/mol/RMSD of 1.34 Å), which was considerably higher, it was then decided to analyze the parameters of only three ligands: ergotamine (-9.9 kcal/mol/RMSD of 2.0 Å), dihydroergotamine (-9.8 kcal/mol/RMSD of 1.46 Å) and olysio (-9.5 kcal/mol/RMSD of 1.5 Å). It can be stated that ergotamine showed the best interactions with the M pro protease of Covid-19 in the in silico study, showing itself as a promising candidate for treating Covid-19., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Antimicrobial resistance is a global health issue, in which microorganisms develop resistance to antimicrobial drugs, making infections more difficult to treat. This threatens the effectiveness of standard medical treatments and necessitates the urgent development of new strategies to combat resistant microbes. Studies have increasingly explored natural sources of new antimicrobial agents that harness the rich diversity of compounds found in plant species. This pursuit holds promise for the discovery of novel treatments for combating antimicrobial resistance. In this context, the chemical composition, antibacterial, and antibiofilm activities of the essential oil from Croton urticifolius Lam. leaves (CuEO) were evaluated. CuEO was extracted via hydrodistillation, and its chemical constituents were identified via gas chromatography-mass spectrometry (GC/MS). The antibacterial activity of CuEO was evaluated in a 96-well plate via the microdilution method, and the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were determined. The effect of CuEO on biofilm formation was assessed by quantifying the biomass using crystal violet staining and viable cell counting. In addition, alterations in the cellular morphology of biofilms treated with CuEO were examined using scanning electron microscopy (SEM) and laser confocal microscopy. GC/MS analysis identified 26 compounds, with elemicine (39.72%); eucalyptol (19.03%), E-caryophyllene (5.36%), and methyleugenol (4.12%) as the major compounds. In terms of antibacterial activity, CuEO showed bacteriostatic effects against Staphylococcus aureus ATCC 700698, S. aureus ATCC 25923, Staphylococcus epidermidis ATCC 12228, and Escherichia coli ATCC 11303, and bactericidal activity against S. aureus ATCC 700698. In addition, CuEO significantly inhibited bacterial biofilm formation. Microscopic analysis showed that CuEO damaged the bacterial membrane by leaching out the cytoplasmic content. Therefore, the results of this study show that the essential oil of C. urticifolius may be a promising natural alternative for preventing infections caused by bacterial biofilms. This study is the first to report the antibiofilm activity of C. urticifolius essential oil., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This is the first study to analyze the anti-inflammatory and antinociceptive effect of withanicandrin, isolated from Datura Ferox leaves, and the possible mechanism of action involved in adult zebrafish (ZFa). To this end, the animals were treated intraperitoneally (i. p.) with withanicandrin (4; 20 and 40 mg/kg; 20 μL) and subjected to locomotor activity and acute toxicity. Nociception tests were also carried out with chemical agents, in addition to tests to evaluate inflammatory processes induced by κ-Carrageenan 1.5 % and a Molecular Docking study. As a result, withanicandrin reduced nociceptive behavior by capsaicin at a dose of 40 mg/kg and by acid saline at doses of 4 and 40 mg/kg, through neuromodulation of TRPV1 channels and ASICs, identified through blocking the antinociceptive effect of withanicandrin by the antagonists capsazepine and naloxone. Furthermore, withanicandrin caused an anti-inflammatory effect through the reduction of abdominal edema, absence of leukocyte infiltrate in the liver tissue and reduction of ROS in thel liver tissue and presented better affinity energy compared to control morphine (TRPV1) and ibuprofen (COX-1 and COX-2)., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Parkinson's disease (PD) is a debilitating condition that can cause locomotor problems in affected patients, such as tremors and body rigidity. PD therapy often includes the use of monoamine oxidase B (MAOB) inhibitors, particularly phenylhalogen compounds and coumarin-based semi-synthetic compounds. The objective of this study was to analyze the structural, pharmacokinetic, and pharmacodynamic profile of a series of Triazolo Thiadiazepine-fused Coumarin Derivatives (TDCDs) against MAOB, in comparison with the inhibitor safinamide. To achieve this goal, we utilized structure-based virtual screening techniques, including target prediction and absorption, distribution, metabolism, and excretion (ADME) prediction based on multi-parameter optimization (MPO) topological analysis, as well as ligand-based virtual screening techniques, such as docking and molecular dynamics. The findings indicate that the TDCDs exhibit structural similarity to other bioactive compounds containing coumarin and MAOB-binding azoles, which are present in the ChEMBL database. The topological analyses suggest that TDCD3 has the best ADME profile, particularly due to the alignment between low lipophilicity and high polarity. The coumarin and triazole portions make a strong contribution to this profile, resulting in a permeability with P app estimated at 2.15 × 10 -5  cm/s, indicating high cell viability. The substance is predicted to be metabolically stable. It is important to note that this is an objective evaluation based on the available data. Molecular docking simulations showed that the ligand has an affinity energy of - 8.075 kcal/mol with MAOB and interacts with biological substrate residues such as Pro102 and Phe103. The results suggest that the compound has a safe profile in relation to the MAOB model, making it a promising active ingredient for the treatment of PD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The Enterobacteriaceae family is recognized as a primary group of Gram-negative pathogens responsible for foodborne illnesses and is frequently associated with antibiotic resistance. The present study explores the natural-based compound trans-cinnamaldehyde (TC) against drug-resistant Enterobacteriaceae and its synergism with gentamicin (GEN) to address this issue. The research employs three strains of Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae, previously isolated from shrimp. The antibacterial activity was evaluated by the disk diffusion method, microdilution test, kinetics of growth, and time-kill curve. In addition, the synergistic effect between TC/GEN was investigated by checkerboard assay. All strains showed sensitivity to TC with an inhibition zone diameter > 35 mm. The TC showed inhibitory and bactericidal action in the most tested bacteria around 625 μg/mL. Sub-inhibitory amounts (1/2 and 1/4 MIC) of TC interfered with the growth kinetics by lag phase extension and decreased the log phase. Time-kill curves show a reduction of viable cells after the first hour of TC treatment at bactericidal concentrations. The synergistic effect between TC/GEN was observed for E. coli and E. cloacae strains with FICi ranging from 0.15 to 0.50. These findings, therefore, suggest TC as a promising alternative in the fight against drug-resistant Enterobacteriaceae that can cause foodborne illnesses., (© 2024. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Background: Anxiety disorders represent the complex interaction between biological, psychological, temperamental, and environmental factors; drugs available to treat anxiety such as benzodiazepines (BZDs) are associated with several unwanted side effects. Although there are useful treatments, there is still a need for more effective anxiolytics with better safety profiles than BZDs. Chalcones or 1,3-diphenyl-2-proper-1-ones can be an alternative since this class of compounds has shown therapeutic potential mainly due to interactions with GABA A receptors and serotonergic system., Objectives: This study evaluated the anxiolytic potential of chalcone (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (C2OHPDA) in adult zebrafish (Danio rerio) (ZFa)., Methods: Each animal (n = 6/group) was treated intraperitoneally (i.p.; 20 μL) with the chalcone (4, 20, and 40 mg/kg) and with the vehicle (DMSO 3%; 20 μL), being submitted to the tests of locomotor activity and 96-h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR 1 , 5-HTR 2A/2C , and 5-HTR 3A/3B receptors. It was investigated the prediction of the chalcone's position and preferential orientation concerning its receptor, as well as the pharmacokinetic parameters (ADMET) involved in the process after administration., Results: As a result, C2OHPDA was not toxic and reduced the locomotor activity of ZFa. Furthermore, chalcone demonstrated an anxiolytic effect on the central nervous system (CNS), mediated by the serotonergic system, with action on 5-HT 2A and 5-HTR 3A/3B receptors. The interaction of C2OHPDA with 5-HT 2A R and 5-HT 3A receptors was confirmed by molecular docking study, the affinity energy observed was -8.7 and -9.1 kcal/mol, respectively., Conclusion: Thus, this study adds new evidence and highlights that chalcone can potentially be used to develop compounds with anxiolytic properties., (© 2023 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Chalcones have an open chain flavonoid structure that can be obtained from natural sources or by synthesis and are widely distributed in fruits, vegetables, and tea. They have a simple and easy to handle structure due to the α-β-unsaturated bridge responsible for most biological activities. The facility to synthesize chalcones combined with its efficient in combating serious bacterial infections make these compounds important agents in the fight against microorganisms. In this work, the chalcone ( E )-1-(4-aminophenyl)-3-(4-nitrophenyl)prop-2-en-1-one (HDZPNB) was characterized by spectroscopy and electronic methods. In addition, microbiological tests were performed to investigate the modulator potential and efflux pump inhibition on S. aureus multi-resistant strains. The modulating effect of HDZPNB chalcone in association with the antibiotic norfloxacin, on the resistance of the S. aureus 1199 strain, resulted in increase the MIC. In addition, when HDZPNB was associated with ethidium bromide (EB), it caused an increase in the MIC value, thus not inhibiting the efflux pump. For the strain of S. aureus 1199B, carrying the NorA pump, the HDZPNB associated with norfloxacin showed no modulatory, and when the chalcone was used in association with EB, it had no inhibitory effect on the efflux pump. For the tested strain of S. aureus K2068, which carries the MepA pump, it can be observed that the chalcone together the antibiotic resulted in an increase the MIC. On the other hand, when chalcone was used in association with EB, it caused a decrease in bromide MIC, equal to the reduction caused by standard inhibitors. Thus, these results indicate that the HDZPNB could also act as an inhibitor of the S. aureus gene overexpressing pump MepA. The molecular docking reveals that chalcone has a good binding energies -7.9 for HDZPNB/MepA complexes, molecular dynamics simulations showed that Chalcone/MetA complexes showed good stability of the structure in an aqueous solution, and ADMET study showed that the chalcone has a good oral bioavailability, high passive permeability, low risk of efflux, low clearance rate and low toxic risk by ingestion. The microbiological tests show that the chalcone can be used as a possible inhibitor of the Mep A efflux pump.Communicated by Ramaswamy H. Sarma.

Background: The bacterium Staphylococcus aureus has stood out for presenting a high adaptability, acquiring resistance to multiple drugs. The search for natural or synthetic compounds with antibacterial properties capable of reversing the resistance of S. aureus is the main challenge to be overcome today. Natural products such as chalcones are substances present in the secondary metabolism of plants, presenting important biological activities such as antitumor, antidiabetic, and antimicrobial activity., Objectives: In this context, the aim of this work was to synthesize the chalcone (2E)-1-(3'-aminophenyl)-3-(4-dimethylaminophenyl)-prop-2-en-1-one with nomenclature CMADMA, confirm its structure by nuclear magnetic resonance (NMR), and evaluate its antibacterial properties., Methods: The synthesis methodology used was that of Claisen-Schmidt, and spectroscopic characterization was performed by NMR. For microbiological assays, the broth microdilution methodology was adopted in order to analyze the antibacterial potential of chalcones and to analyze their ability to act as a possible inhibitor of β-lactamase and efflux pump resistance mechanisms, present in S. aureus strain K4100., Results: The results obtained show that CMADMA does not show direct antibacterial activity, expressing a MIC of ≥1024 μg/mL, or on the enzymatic mechanism of β-lactamase; however, when associated with ethidium bromide in efflux pump inhibition assays, CMADMA showed promising activity by reducing the MIC of the bromide from 64 to 32 μg/mL., Conclusion: We conclude that the chalcone synthesized in this study is a promising substance to combat bacterial resistance, possibly acting in the inhibition of the QacC efflux pump present in S. aureus strain K4100, as evidenced by the reduction in the MIC of ethidium bromide., (© 2023 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Bufadienolides are digitalis-like aglycones mainly found in skin secretions of toads. Among their biological properties, the mechanisms of antiproliferative action on tumor cells remain unclear for many compounds, including against leukemia cells. Herein, it was evaluated the mechanisms involved in the antiproliferative and genotoxic actions of hellebrigenin on tumor cell lines and in silico capacity to inhibit the human topoisomerase IIa enzyme. Firstly, its cytotoxic action was investigated by colorimetric assays in human tumor and peripheral blood mononuclear cells (PBMC). Next, biochemical and morphological studies were detailed by light microscopy (trypan blue dye exclusion), immunocytochemistry (BrdU uptake), flow cytometry and DNA/chromosomal damages (Cometa and aberrations). Finally, computational modelling was used to search for topoisomerase inhibition. Hellebrigenin reduced proliferation, BrdU incorporation, viability, and membrane integrity of HL-60 leukemia cells. Additionally, it increased G 2 /M arrest, internucleosomal DNA fragmentation, mitochondrial depolarization, and phosphatidylserine externalization in a concentration-dependent manner. In contrast to doxorubicin, hellebrigenin did not cause DNA strand breaks in HL-60 cell line and lymphocytes, and it interacts with ATPase domain residues of human topoisomerase IIa, generating a complex of hydrophobic and van der Waals interactions and hydrogen bonds. So, hellebrigenin presented potent anti-leukemic activity at concentrations as low as 0.06 μM, a value comparable to the clinical anticancer agent doxorubicin, and caused biochemical changes suggestive of apoptosis without genotoxic/clastogenic-related action, but it probably triggers catalytic inhibition of topoisomerase II. These findings also emphasize toad steroid toxins as promising lead antineoplasic compounds with relatively low cytotoxic action on human normal cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tinnitus is a syndrome that affects the human auditory system and is characterized by a perception of sounds in the absence of acoustic stimuli, or in total silence. Research indicates that muscarinic acetylcholine receptors (mAChRs), especially the M1 type, have a fundamental role in the alterations of auditory perceptions of tinnitus. Here, a series of computer-aided tools were used, from molecular surface analysis software to services available on the web for estimating pharmacokinetics and pharmacodynamics. The results infer that the low lipophilicity ligands, that is, the 1a-d alkyl furans, present the best pharmacokinetic profile, as compounds with an optimal alignment between permeability and clearance. However, only ligands 1a and 1b have properties that are safe for the central nervous system, the site of cholinergic modulation. These ligands showed similarity with compounds deposited in the European Molecular Biology Laboratory chemical (ChEMBL) database acting on the mAChRs M1 type, the target selected for the molecular docking test. The simulations suggest that the 1 g ligand can form the ligand-receptor complex with the best affinity energy order and that, together with the 1b ligand, they are competitive agonists in relation to the antagonist Tiotropium, in addition to acting in synergism with the drug Bromazepam in the treatment of chronic tinnitus., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Anxiety-related mental health problems are estimated at 3.6% globally, benzodiazepines (BZDs) are the class of drugs indicated for the treatment of anxiety, including lorazepam and diazepam. However, concerns have been raised about the short- and long-term risks associated with BZDs. Therefore, despite anxiolytic and antidepressant drugs, there is a need to develop more effective pharmacotherapies with fewer side effects than existing drugs. The present work reported the synthesis, anxiolytic activity, mechanism of action in Adult Zebrafish ( Danio rerio ) and in silico study of a europium metallic complex with Lapachol, [Eu(DBM) 3 . LAP]. Each animal (n = 6/group) was treated intraperitoneally ( i.p .; 20 µL) with the synthesized complex (4, 20 and 40 mg/Kg) and with the vehicle (DMSO 3%; 20 µL), being submitted to the tests of locomotor activity and 96h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR 1 , 5-HTR 2A/2C and 5-HTR 3A/3B receptors. The complex was characterized using spectrometric techniques, and the anxiolytic effect of complex may be involved the neuromodulation of receptors 5-HT3A/3B, since the pre-treatment with pizotifen and cyproheptadine did not block the anxiolytic effect of [Eu(DBM) 3 . LAP], unlike fluoxetine had its anxiolytic effect reversed. In addition, molecular docking showed interaction between the [Eu(DBM) 3 . LAP] and 5HT 3A receptor with binding energy -7.8 kcal/mol and the ADMET study showed that complex has low toxic risk. It is expected that the beginning of this study will allow the application of the new anxiolytic drugs, given the pharmacological potential of the lapachol complex.Communicated by Ramaswamy H. Sarma.

Background: Thiadiazines are heterocyclic compounds that contain two nitrogen atoms and one sulfur atom in their structure. These synthetic molecules have several relevant pharmacological activities, such as antifungal, antibacterial, and antiparasitic., Objectives: The present study aimed to evaluate the possible in vitro and in silico interactions of compounds derived from thiadiazines., Methods: The compounds were initially synthesized, purified, and confirmed through HPLC methodology. Multi-drug resistant bacterial strains of Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to evaluate the direct and modifying antibiotic activity of thiadiazine derivatives. ADMET assays (absorption, distribution, metabolism, excretion, and toxicity) were conducted, which evaluated the influence of the compounds against thousands of macromolecules considered as bioactive targets., Results: There were modifications in the chemical synthesis in carbon 4 or 3 in one of the aromatic rings of the structure where different ions were added, ensuring a variability of products. It was possible to observe results that indicate the possibility of these compounds acting through the cyclooxygenase 2 mechanism, which, in addition to being involved in inflammatory responses, also acts by helping sodium reabsorption. The amine group present in thiadiazine analogs confers hydrophilic characteristics to the substances, but this primary characteristic has been altered due to alterations and insertions of other ligands. The characteristics of the analogs generally allow easy intestinal absorption, reduce possible hepatic toxic effects, and enable possible neurological and anti-inflammatory action. The antibacterial activity tests showed a slight direct action, mainly of the IJ23 analog. Some compounds were able to modify the action of the antibiotics gentamicin and norfloxacin against multi-drug resistant strains, indicating a possible synergistic action., Conclusions: Among all the results obtained in the study, the relevance of thiadiazine analogs as possible coadjuvant drugs in the antibacterial, anti-inflammatory, and neurological action with low toxicity is clear. Need for further studies to verify these effects in living organisms is not ruled out., (© 2023 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

General anxiety disorders are among the most prevalent mental health problems worldwide. The emergence and development of anxiety disorders can be due to genetic (30-50%) or non-genetic (50-70%) factors. Despite medical progress, available pharmacotherapies are sometimes ineffective or can cause undesirable side effects. Thus, it becomes necessary to discover new safe and effective drugs against anxiety. This study evaluated the anxiolytic effect in adult zebrafish ( Danio rerio ) of a natural pyrroloformamide (PFD), N -(4,5-dihydro-5-oxo-1,2-dithiolo-[4,3,b]-pyrrole-6-yl)- N -methylformamide, isolated from a Streptomyces sp. bacterium strain recovered from the ascidian Eudistoma vannamei . The complete structure of PFD was determined by a detailed NMR analysis, including 1 H- 13 C and 1 H- 15 N-HBMC data. In addition, conformational and DFT computational studies also were performed. A group of fishes ( n  = 6) was treated orally with PFD (0.1, 0.5 and 1.0 mg/mL; 20 μL) and subjected to locomotor activity and light/dark tests, as well as, acute toxicity 96 h. The involvement of the GABAergic and serotonergic (5-HT) systems was investigated using flumazenil (a silent modulator of GABA receptor) and 5-HT 1 , 5-HT 2A/2C and 5-HTR 3A/3B receptors antagonists, known as pizotifen, granisetron and cyproheptadine, respectively. PFD was nontoxic, reduced locomotor activity and promoted the anxiolytic effect in zebrafish. Flumazenil did not inhibit the anxiolytic effect of the PFD via the GABAergic system. This effect was reduced by a pretreatment with pizotifen and granisetron, and was not reversed after treatment with cyproheptadine. Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.Communicated by Ramaswamy H. Sarma.

Aim: Our objective was to investigate the trypanocidal effect of the chalcone (2 E ,4 E )-1-(2-hydroxy-3,4,6-trimethoxyphenyl)-5-phenylpenta-2,4-dien-1-one (CPNC). Material & methods: Cytotoxicity toward LLC-MK2 host cells was assessed by MTT assay, and the effect on Trypanosoma cruzi life forms (epimastigotes, trypomastigotes and amastigotes) was evaluated by counting. Flow cytometry analysis was performed to evaluate the possible mechanisms of action. Finally, molecular docking simulations were performed to evaluate interactions between CPNC and T. cruzi enzymes. Results: CPNC showed activity against epimastigote, trypomastigote and amastigote life forms, induced membrane damage, increased cytoplasmic reactive oxygen species and mitochondrial dysfunction on T. cruzi . Regarding molecular docking, CPNC interacted with both trypanothione reductase and TcCr enzymes. Conclusion: CPNC presented a trypanocidal effect, and its effect is related to oxidative stress, mitochondrial impairment and necrosis.

Background: Staphylococcus aureus is a human pathogen responsible for high mortality rates. The development of new antimicrobials is urgent. Materials & methods: The authors evaluated the activity of hydralazine along with its synergism with other drugs and action on biofilms. With regard to action mechanisms, the authors evaluated cell viability, DNA damage and molecular docking. Results: MIC and minimum bactericidal concentration values ranged from 128 to 2048 μg/ml. There was synergism with oxacillin (50%) and vancomycin (25%). Hydralazine reduced the viability of biofilms by 50%. After exposure to hydralazine 2× MIC, 58.78% of the cells were unviable, 62.07% were TUNEL positive and 27.03% presented damage in the comet assay (p < 0.05). Hydralazine showed affinity for DNA gyrase and TyrRS. Conclusion: Hydralazine is a potential antibacterial.

Background: Clove volatile oil (CVO) and its major compound, eugenol (EUG), have anxiolytic effects, but their clinical use has been impaired due to their low bioavailability. Thus, their encapsulation in nanosystems can be an alternative to overcome these limitations., Objectives: This work aims to prepare, characterize and study the anxiolytic potential of CVO loaded-nanoemulsions (CVO-NE) against anxious-like behavior in adult zebrafish (Danio rerio)., Methods: The CVO-NE was prepared using Agaricus blazei Murill polysaccharides as stabilizing agent. The drug-excipient interactions were performed, as well as colloidal characterization of CVO-NE and empty nanoemulsion (B-NE). The acute toxicity and potential anxiolytic activity of CVO, EUG, CVO-NE and B-NE against adult zebrafish models were determined., Results: CVO, EUG, CVO-NE and B-NE presented low acute toxicity, reduced the locomotor activity and anxious-like behavior of the zebrafish at 4 - 20 mg kg -1 . CVO-NE reduced the anxious-like behavior of adult zebrafish without affecting their locomotor activity. In addition, it was demonstrated that anxiolytic activity of CVO, EUG and CVO-NE is linked to the involvement of GABAergic pathway., Conclusion: Therefore, this study demonstrates the anxiolytic effect of CVO, in addition to providing a new nanoformulation for its administration., (© 2023. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

The pandemic caused by Sars-CoV-2 is a viral infection that has generated one of the most significant health problems worldwide. Previous studies report the main protease (Mpro) as a potential target for this virus, as it is considered a crucial enzyme in mediating replication and viral transcription. This work presented the construction of new bioactive compounds for possible inhibition. The De novo molecular design of drugs method in the incremental construction of a ligant model within a receptor model was used, producing new structures with the help of artificial intelligence. The research algorithm and the scoring function responsible for predicting orientation and affinity in the molecular target at the time of coupling showed, as a result of the simulation, the compound with the highest bioaffinity value, Hit 998, with the energy of -17.62 kcal/mol, and synthetic viability close to 50%. While hit 1103 presented better synthetic viability (80%), its affinity energy of -10.28 kcal/mol. Both were compared with the reference linker N3, with a binding affinity of -7.5 kcal/mol. ADMET tests demonstrated that simulated compounds have a low risk of metabolic activation and do not exert effective distribution in the CNS, suggesting a pharmacokinetic mechanism based on local action, even with high topological polarity, which resulted in low oral bioavailability. In conclusion, MMGBSA, H-bonds, RMSD, SASA, and RMSF values were also obtained through molecular dynamics to verify the stability of the receptor-ligant complex within the active protein site to seek new therapeutic propositions in the fight against the pandemic.Communicated by Ramaswamy H. Sarma.

Lantana camara L. (Verbenaceae), commonly called lead cambará, has often been used in folk medicine as antiseptic, antispasmodic, against hemorrhages, flu, colds, and diarrheic. This plant is considered a weed and an ornamental and medicinal plant and is an essential source of natural organic compounds, mainly flavonoids. This work aims to investigate the chemical composition and evaluate the biological properties such as antioxidant and acetylcholinesterase of the constituents from L. camara flowers. In addition, the computational simulation was carried out with the constituents identified. The results showed that methanolic extract of the flowers of L. camara presents toxicity, antioxidant activity with 97.8% inhibition percentage in the concentration of 0.25 mg mL -1 against the DPPH radical, and acetylcholinesterase activity. The phytochemical study of extract from L. camara flowers resulted in LC-MS identification of 18 polyphenolic compounds, such as phenolic acid derivatives, phenylethanoid glycosides, and flavonoids. In the in silico study, flavonoid isoverbascoside showed affinity energy of -9.9 kcal.mol -1 with the AChE enzyme. Their phytochemical content, mainly the presence of flavonoids and phenolic compounds in L. camara extracts, may be related to the antioxidant and anticholinesterase potential observed.

Characterized as a neglected disease, Chagas disease is an infection that, in the current scenario, affects about 8 million people per year, with a higher incidence in underdeveloped countries, Chagas is responsible for physiological disabilities that result in impacts that are slightly reflected in world socioeconomic stability. Although treatments are based on drugs such as Benznidazole, the pathology lacks a continuous treatment method with low toxicological incidence. The present study estimates the anti-chagasic activity of the synthetic chalcone CPN2F based on the alignment between in vitro tests and structural classification in silico studies, molecular docking and ADMET studies. The in vitro tests showed a reduction in the protozoan metabolism in host cells (LLC-MK2). At the same time, the molecular docking models evaluate this growth inhibition through the synergistic effect associated with Benznida- zole against validated therapeutic target key stages (Cruzaine TcGAPDH and Trypanothione reductase) of the Trypanosoma cruzi development cycle. The in silico prediction results reveal an alignment between pharmacokinetic attributes, such as renal absorption and release, which allow the preparation of CPN2F as an antichagasic drug with a low incidence of organic toxicity.Communicated by Ramaswamy H. Sarma.

This work presents the synthesis of 12 phenol and chromone derivatives, prepared by the analogs, and the possibility of conducting an in silico study of its derivatives as a therapeutic alternative to combat the SARS-CoV-2, pathogen responsible for COVID-19 pandemic, using its S-glycoprotein as a macromolecular target. After the initial screening for the ranking of the products, it was chosen which structure presented the best energy bond with the target. As a result, derivative 4 was submitted to a molecular growth study using artificial intelligence, where 8436 initial structures were obtained that passed through the interaction filters and similarity to the active glycoprotein pocket through the MolAICal computational package. Thus, 557 Hits with active configuration were generated, which is very promising compared to the BLA reference link for inhibiting the biological target. Molecular dynamics also simulated these compounds to verify their stability within the active protein site to seek new therapeutic propositions to fight against the pandemic. The Hit 48 and 250 are the most active compounds against SARS-CoV-2. In summary, the results show that the Hit 250 would be more active than the natural compound, which could be further developed for further testing against SARS-CoV-2. The study employs the de novo approach to design new drugs, combining artificial intelligence and molecular dynamics simulations to create efficient molecular structures. This research aims to contribute to the development of effective therapeutic strategies against the pandemic., Competing Interests: Conflict of interestThe authors also declare no conflict of interest., (© King Abdulaziz City for Science and Technology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Introduction. Antibiotic resistance is a major threat to public health, particularly with methicillin-resistant Staphylococcus aureus (MRSA) being a leading cause of antimicrobial resistance. To combat this problem, drug repurposing offers a promising solution for the discovery of new antibacterial agents. Hypothesis. Menadione exhibits antibacterial activity against methicillin-sensitive and methicillin-resistant S. aureus strains, both alone and in combination with oxacillin. Its primary mechanism of action involves inducing oxidative stress. Methodology. Sensitivity assays were performed using broth microdilution. The interaction between menadione, oxacillin, and antioxidants was assessed using checkerboard technique. Mechanism of action was evaluated using flow cytometry, fluorescence microscopy, and in silico analysis. Aim. The aim of this study was to evaluate the in vitro antibacterial potential of menadione against planktonic and biofilm forms of methicillin-sensitive and resistant S. aureus strains. It also examined its role as a modulator of oxacillin activity and investigated the mechanism of action involved in its activity. Results. Menadione showed antibacterial activity against planktonic cells at concentrations ranging from 2 to 32 µg ml -1 , with bacteriostatic action. When combined with oxacillin, it exhibited an additive and synergistic effect against the tested strains. Menadione also demonstrated antibiofilm activity at subinhibitory concentrations and effectively combated biofilms with reduced sensitivity to oxacillin alone. Its mechanism of action involves the production of reactive oxygen species (ROS) and DNA damage. It also showed interactions with important targets, such as DNA gyrase and dehydroesqualene synthase. The presence of ascorbic acid reversed its effects. Conclusion. Menadione exhibited antibacterial and antibiofilm activity against MRSA strains, suggesting its potential as an adjunct in the treatment of S. aureus infections. The main mechanism of action involves the production of ROS, which subsequently leads to DNA damage. Additionally, the activity of menadione can be complemented by its interaction with important virulence targets.

Diabetes is a disease linked to pathologies, such as chronic inflammation, neuropathy, and pain. The synthesis by the Claisen-Schmidt condensation reaction aims to obtain medium to high yield chalconic derivatives. Studies for the synthesis of new chalcone molecules aim at the structural manipulation of aromatic rings, as well as the replacement of rings by heterocycles, and combination through chemical reactions of synthesized structures with other molecules, in order to enhance biological activity. A chalcone was synthesized and evaluated for its antinociceptive, anti-inflammatory and hypoglycemic effect in adult zebrafish. In addition to reducing nociceptive behavior, chalcone (40 mg/kg) reversed post-treatment-induced acute and chronic hyperglycemia and reduced carrageenan-induced abdominal edema in zebrafish. It also showed an inhibitory effect on NO production in J774A.1 cells. When compared with the control groups, the oxidative stress generated after chronic hyperglycemia and after induction of abdominal edema was significantly reduced by chalcone. Molecular docking simulations of chalcone with Cox -1, Cox-2, and TRPA1 channel enzymes were performed and indicated that chalcone has a higher affinity for the COX-1 enzyme and 4 interactions with the TRPA1 channel. Chalcone also showed good pharmacokinetic properties as assessed by ADMET., Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03696-8., Competing Interests: Conflict of interestAll authors have no conflicts of interest to declare with respect to the research, authorship, and/or publication of this work., (© King Abdulaziz City for Science and Technology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Leishmaniasis disease is a serious public health problem. This disease reaches about 10 to 12 million people, and 20-30 thousand people die yearly. The disease treatment is realized through pentavalent antimonial and glucantime. However, some studies indicated that these drugs presented high toxicity and cost. Therefore, it is urgent the search for new drugs that may combat this disease and are less toxic. This work analyzed for the first time the interaction potential of ( E )-1-(4-aminophenyl)-3-phenylprop-2-en-1-one (C1), ( E )-1-(4-aminophenyl)-3-(4-methoxyphenyl)-prop-2-en-1-one (C4), ( E )-1-(4-aminophenyl)-3-(4ethoxyphenyl)-prop-2-en-1-one (C9) chalcones through in silico approach. The molecular docking and the molecular electrostatic potential results indicated that the chalcones analyzed presented a strong interaction with the Leishmania major receptor, with affinity energy similar to the ligand co-crystallized. Besides, the interaction potential energy analysis from molecular dynamics simulations indicated the C9 ligand interacted more strongly than the 4-bromo-2,6-dichloro- N -(1,3,5-trimethyl-1 H -pyrazolyl) benzenesulfonamide ligand with the Leishmania major receptor, especially for the Phe 88, Tyr 217 and His 219 residues. Therefore, the C9 chalcone might potentially treat Leishmaniasis disease.Communicated by Ramaswamy H. Sarma.

Rauvolfia species are well known as producers of bioactive monoterpene indole alkaloids, which exhibit a broad spectrum of biological activities. A new vobasine-sarpagan-type bisindole alkaloid (1: ) along with six known monomeric indoles (2, 3/4, 5: , and 6/7: ) were isolated from the ethanol extract of the roots of Rauvolfia ligustrina . The structure of the new compound was elucidated by interpretation of their spectroscopic data (1D and 2D NMR and HRESIMS) and comparison with published data for analog compounds. The cytotoxicity of the isolated compounds was screened in a zebrafish ( Danio rerio ) model. The possible GABAergic (diazepam as the positive control) and serotoninergic (fluoxetine as the positive control) mechanisms of action in adult zebrafish were also evaluated. No compounds were cytotoxic. Compound 2: and the epimers 3: /4: and 6: /7: showed a mechanism action by GABA A , while compound 1: showed a mechanism action by a serotonin receptor (anxiolytic activity). Molecular docking studies showed that compounds 2: and 5: have a greater affinity by the GABA A receptor when compared with diazepam, whereas 1: showed the best affinity for the 5HT2AR channel when compared to risperidone., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Dengue (DENV), Zica virus (ZIKV), and Chikungunya fever (CHIK) are tropical diseases that have caused a lot of problems in general worldwide. Transmitted by mosquitoes of the species Aedes aegypti and albopictus , they have not been completely eradicated in the country, and their proliferation has only increased in the Northeast region. Within the structure of the virus, it is possible to verify the presence of glycoprotein SN1, which is responsible for its replication. If this macromolecule is inhibited using a specific or complex linker, it can interrupt its replication activity. An alternative to this problem has been using structures derived from natural products that have pharmacological properties. A dynamic and molecular docking combined study used computational simulation in the four isomeric forms of bixin against the SN1 protein. The Z,E-bixin and E,E-bixin isomers, both with affinity energy -6.7 and -6.5 Kcal/mol, presented the best results. Thus, bixin and its isomers, found in annatto seeds, maybe an initial proposal in the search for prototype compounds to study to fight this lethal virus in the future.Communicated by Ramaswamy H. Sarma.

The increased resistance of microorganisms to antimicrobial drugs makes it necessary to search for new active compounds, such as chalcones. Their simple chemical structure makes them molecules easy to synthesize. Therefore, the aim of this study was to evaluate the antimicrobial and potentiating activity of antibiotics and antifungals by synthetic chalcones against strains of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans and Candida tropicalis. The synthesis of chalcones was carried out by Claisen-Schimidt aldol condensation. Nuclear Magnetic Resonance (NMR) and Gas Chromatography Coupled to Mass Spectrometry (GC/MS) were also performed. Microbiological tests were performed by the broth microdilution method, using gentamicin, norfloxacin and penicillin as standard drugs for the antibacterial assay, and fluconazole for the antifungal assay. Three chalcones were obtained (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one (DB-Acetone), (1E,3E,6E,8E)-1,9-diphenylnone-1,3,6,8-tetraen-5-one (DB-CNM), (1E,4E)-1,5-bis (4-methoxyphenyl) penta-1,4-dien-3-one (DB-Anisal). The compound DB-Acetone was able to inhibit P. aeruginosa ATCC 9027 at a concentration of 1.4 × 10 2  μM (32 μg/mL), while DB-CNM and DB-Anisal inhibited the growth of S. aureus ATCC 25923 at 17.88 × 10 2  μM and 2.71 × 10 1  μM (512 μg/mL and 8 μg/mL) respectively. In the combined activity, DB-Anisal was able to potentiate the effect of the three antibacterial drugs tested against E. coli 06, norfloxacin (128 for 4 μg/mL ±1) against P. aeruginosa 24 and penicillin (1,024 for 16 μg/mL ±1) against S. aureus 10. In antifungal assays, chalcones were not able to inhibit the growth of fungal strains tested. However, both showed potentiating activity with fluconazole, ranging from 8.17 x 10 -1  μM (0.4909 μg/mL) to 2.35 μM (13.96 μg/mL). It is concluded that synthetic chalcones have antimicrobial potential, demonstrating good intrinsic activity against fungi and bacteria, in addition to potentiating the antibiotics and antifungal tested. Further studies are needed addressing the mechanisms of action responsible for the results found in this work., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To assess trabecular bone structure as calculated with fractal analysis by 2 binarization processes: White and Rudolph's original method (WR.o) and a revised version (WR.r). Fractal dimension (FD) values calculated with WR.r (FD.r) and a gray-scale-based method (FD.f) were also compared. FD, histogram parameters, and lacunarity were compared by dentate status, jaw location, and sex., Study Design: Regions of interest from digital periapical radiographs were defined below the teeth roots and in the edentulous sites of 37 patients. Histograms were assessed for pixel values. Binarization was performed with WR.o and then with WR.r, in which the outliers were removed. FD was assessed using WR.r (FD.r) and (FD.f). Histograms were assessed to obtain pixel values. Lacunarity was calculated., Results: WR.r revealed fewer trabeculae, branches, and junctions than WR.o (P < .0001). The majority of the mean differences between FD.r and FD.f were within the 95% CI. Dentate areas had greater mean gray levels than partially edentulous areas (P = .0027). FD.f was higher in the mandible (P = .01), but gray-level SD (P < .0001) and lacunarity (P = .02) were greater in the maxilla. FD.f and lacunarity were higher (P = .0005) and lower (P = .0014) in males, respectively., Conclusion: WR.r was effective in revealing skeletonized bone trabeculae by removing non-trabecular noise. FD.r and FD.f revealed good agreement. FD.f, histogram parameters, and lacunarity differed based on dentate status, jaw location, and sex., Competing Interests: Declaration of interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Chagas disease (CD) is a tropical disease caused by the parasite Trypanosoma cruzi, transmitted by the barber insect. Currently, there are approximately 7 million infected people in the world, and it is estimated that 70 million people could contract this disease. The anacardic acid (AA) showed effectiveness in in silico and in vitro tests. The antichagasic potential of five sulfonamide molecules, derived from anacardic acid, was evaluated from a molecular approach based on the density functional theory (DFT), molecular dynamics (MD), and molecular docking (docking) calculations. Methyl 2-methoxy-6- (8- (methylsulfonamide) octyl) benzoate (SA1); 2-methoxy-6- (8- (phenylsulfonamide) octyl) benzoate (SA2); methyl 2-methoxy-6- (8- (2methylphenyl sulfonamide) octyl) benzoate (SA3); methyl 2-methoxy-6- (8-(methylphenylsulfonamide)octyl)benzoate (SA4); methyl2-(8-(2,5-dimethylphenylsulfonamide)octyl)-6-methoxybenzoate (SA5) were the investigated molecules. The DFT calculations were performed using the B3LYP/6-311+G (d, p) level of theory. The global and local reactivity data showed that SA1 shows the highest molecular reactivity, while SA2 is the most stable derivative. In addition, the structures of investigated molecules were confirmed by the linear correlations higher than 0.98 displayed between the experimental and calculated spectroscopic data (IR and NMR). Molecular docking of the molecules showed a greater prominence for the SA1, SA2, and SA4 molecules in the results of distances of ligand-cruzain. In molecular dynamics, SA2 obtained better stability due to greater interactions with important amino acids of cruzain., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diabetes mellitus is a chronic metabolic disorder that has been increasing drastically around the worldwide. It is important to emphasize that although many drugs are commercially available to treat diabetes, many of them have shown a number of adverse effects. Therefore, search for new antidiabetic agents is of great interest, and natural products, especially those obtained from plants sources, may be an alternative to available drugs. This study reports the in vivo and in silico evaluation of the hypoglycemic activity of fisetinidol. The conformational analysis confirmed that the fisetinidol compound possesses two valleys in the potential energy curve, showing a stable conformer on the global minimum of the PES defined by the dihedral angle θ (C6-C7-O-H) at 179.9°, whose energy is equal to zero. In addition, fisetinidol has shown promise in glycemic control and oxidative stress caused by hyperglycemia induced by high sucrose concentration, causing hypoglycemic and hepatoprotective effects in adult zebrafish. ADMET studies showed that fisetinidol has high passive permeability, low clearance and low toxic risk by ingestion, and computational studies demonstrated that fisetinidol complexes in the same region as metformin and α-acarbose, which constitutes a strong indication that fisetinidol has the same inhibitory mechanisms of α-acarbose and metformin.Communicated by Ramaswamy H. Sarma.

Candida spp. infections are a serious health problem, especially in patients with risk factors. The acquisition of resistance, often associated with biofilm production, makes treatment more difficult due to the reduced effectiveness of available antifungals. Drug repurposing is a good alternative for the treatment of infections by Candida spp. biofilms. The present study evaluated the in vitro antibiofilm activity of sertraline in reducing the cell viability of forming and matured biofilms, in addition to elucidating whether effective concentrations are safe. Sertraline reduced biofilm cell viability by more than 80 % for all Candida species tested, acting at low and safe concentrations, both on mature biofilm and in preventing its formation, even the one with highest virulence. Its preventive mechanism seemed to be related to binding with ALS3. These data indicate that sertraline is a promising drug with anticandidal biofilm potential in safe doses. However, further studies are needed to elucidate the antibiofilm mechanism and possible application of pharmaceutical forms.

Chalcones are present in a wide variety of plants, having in their structure two aromatic rings that are linked together by a chain composed of three carbon atoms with α, β-unsaturated to carbonyl system. Bacteria have several drug resistance mechanisms, among them the efflux pump; this mechanism, when active, is able to expel different compounds from inside bacterial cells. Several efflux pumps have already been identified for Staphylococcus aureus bacteria, including MepA and NorA. Many chalcones have been isolated and identified with various activities, such as antimicrobial. In view of this, this article aimed to evaluate the antibiotic modifying effect of chalcone (E)-1-(2-hydroxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one against S. aureus carrier of NorA and MepA efflux pump. Regarding the antibiotic, there was a synergism when associated with ciprofloxacin in SA-K2068 strain, showing this chalcone as an alternative to reverse the resistance to this medicine. The physicochemical properties calculated were fundamental in the description of the predicted pharmacokinetic properties. Despite the mutagenic risk caused by the metabolic activation of nitrochalcone, it is possible to notice a pharmacological principle in a longer half-life for the performance of biological activities. The compound has a good bioavailability, as it is highly absorbed in the intestine and easily transported by plasma proteins, in addition to not presenting neurotoxic, hepatotoxic, and cardiotoxic damage., (© 2022 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

This study investigated the chemical composition and evaluated the antibacterial and antibiofilm activities of essential oils (EOs) extracted from Ruellia asperula (EORA) and Ruellia paniculata (EORP) against oral streptococci. The EO constituents were analyzed by gas chromatography/mass spectrometry. The antimicrobial potential of EOs was evaluated using the minimum inhibitory concentration, minimum bactericidal concentration, and time-kill determination. Furthermore, the quantification of total biomass and the number of viable cells in the biofilms were evaluated. The major constituents of EORA were cariophylla-4(12)-8-(13)-dien-5β-ol (14.1%), (β)-caryophyllene (22.7%), and caryophyllene oxide (29.4%). For EORP, the major constituents were (β)-caryophyllene (11.0%), spathulenol (13.1%), and δ-amorphene (14.9%). The tested EOs exhibited antibacterial activity against planktonic growth and biofilm formation. Thus, the EOs from R. asperula and R. paniculata prove to be promising alternatives for bacterial growth control and biofilm formation prevention of oral streptococci.

Some insects produce venoms to defend against predators and directly interact with opioid receptors. In the present study, it was identified two alkaloids in the wasp venom species Hymenoepimecis bicolor . It was demonstrated that these could act as potential inhibitors of opioid receptors through their robust affinity to the receptors. The interaction profile was given to opioid receptors (μOR), with 60% of targets similar to alkaloid 1, with 0.25 probability, and 46.7% of targets similar to alkaloid 2, with a probability 0.17 of affinity as a target, which is considered signaling macromolecules and can mediate the most potent analgesic and addictive properties of opiate alkaloids. Notably, both alkaloids showed -7.6 kcal/mol affinity to the morphine agonies through six residues, Gly124, Asp147, Trp293, Ile296, Ile322, and Tyr326. These observations suggest further research on opioid receptors using in vitro studies of possible therapeutic applications.Communicated by Ramaswamy H. Sarma.

A new worldwide concern has emerged with the recent emergence of infections caused by Candida auris . This reflects its comparative ease of transmission, substantial mortality, and the increasing level of resistance seen in the three major classes of antifungal drugs. Efforts to create a better design for structure-based drugs that described numerous modifications and the search for secondary metabolic structures derived from plant species are likely to reduce the virulence of several fungal pathogens. In this context, the present work aimed to evaluate in silico two naphthoquinones isolated from the roots of Capraria biflora , biflorin, and its dimmer, bis-biflorin, as potential inhibitors of Candida auris polymerase. Based on the simulation performed with the two naphthoquinones, biflorin and bis-biflorin, it can be stated that bis-biflorin showed the best interactions with Candida auris polymerase. Still, biflorin also demonstrated favorable coupling energy. Predictive pharmacokinetic assays suggest that biflorin has high oral bioavailability and more excellent metabolic stability compared to the bis-biflorin analogue. constituting a promising pharmacological tool.Communicated by Ramaswamy H. Sarma.

The prevalence of anxiety is a significant public health problem, being the 24th leading cause of disability in individuals affected by this disorder. In this context, chalcones, a flavonoid subclass obtained from natural or synthetic sources, interact with central nervous system (CNS) receptors at the same binding site as benzodiazepines, the primary drugs used in the treatment of anxiety. Thus, our study investigates the anxiolytic effect of synthetic chalcones derived from the natural product 2-hydroxy-3,4,6-trimethoxyacetophenone isolated from Croton anisodontus Müll.Arg. in modulating anxiolytic activity via GABAergic and serotoninergic neurotransmission in an adult zebrafish model. Chalcones 1 and 2 were non-toxic to adult zebrafish and showed anxiolytic activity via GABA A receptors. Chalcone 2 also had its anxiolytic action reversed by the antagonist granisetron, indicating the participation of serotonergic receptors 5HTR 3A/3B in the anxiolytic effect. In addition, molecular docking results showed that chalcones have a higher affinity for the GABA A receptor than DZP and binding in the same region of the DZP binding site, indicating a similar effect to the drug. Furthermore, the interaction of chalcones with GABA A and 5-HT 3A receptors demonstrates the anxiolytic effect potential of these molecules.Communicated by Ramaswamy H. Sarma.

The present study focused on investigating the antioxidant, antiglycation activity, digestive enzymes inhibition, bioaccessibility and hypoglycemic effect of C. arabica leaves extracts. The extracts deactivated the O 2 • - , ROO•, H 2 O 2 , HOCl reactive oxygen species. Coffee leaves showed strong inhibition of α-glucosidase (IC 50 = 40.30 μg mL -1 ) greater than the isolated metabolites and acarbose. There was also inhibition of pancreatic lipase (IC 50 = 56.43 μg mL -1 ) in addition to a hypoglycemic effect in zebrafish similar to acarbose and metformin. With the exception of rutin, all biocompounds were detected at all stages of in vitro digestion. Finally, these results suggest that C. arabica leaf extracts possess antidiabetic and anti-obesity properties that can be attributed to the main metabolites and the synergistic action between them.Communicated by Ramaswamy H. Sarma.

Anxiety and epilepsy affect millions of people worldwide, and the treatment of these pathologies involves the use of Benzodiazepines, drugs that have serious adverse effects such as dependence and sedation, so the discovery of new anxiolytic and antiepileptic drugs are necessary. Many routes for synthesizing ibuprofen derivatives have been developed, and these derivatives have shown promising pharmacological effects. Therefore, this study aims to evaluate its anxiolytic and anticonvulsant effect against the adult Zebrafish animal model of Ibuprofen (IBUACT) and its interaction with the GABAergic receptor through in silico studies. The light/dark preference test (Scototaxis test) was used to evaluate the anxiolytic behavior of adult Zebrafish acutely treated with IBUACT and Diazepam, and their anticonvulsant effects were investigated through the pentylenetetrazol (PTZ)-induced seizure model. Animals treated with IBUACT showed anxiolytic behavior similar to Diazepam, and pretreatment with flumazenil reversed this behavior. PTZ-induced seizures were delayed by IBUACT in all three stages and were shown to bind strongly in the Diazepam region of GABA A . In addition, this work presents evidence of new pharmacological applications of ibuprofen derivative in pathologies of the central nervous system (CNS), opening the horizon for new studies.Communicated by Ramaswamy H. Sarma.

Chalcones are natural substances found in the metabolism of several botanical families. Their structure consists of 1,3-diphenyl-2-propen-1-one and they are characterized by having in their chains an α, β-unsaturated carbonyl system, two phenol rings and a three-carbon chain that unites them. In plants, Chalcones are mainly involved in the biosynthesis of flavonoids and isoflavonoids through the phenylalanine derivation. This group of substances has been shown to be a viable alternative for the investigation of its antibacterial potential, considering the numerous biological activities reported and the increase of the microbial resistance that concern global health agencies. Staphylococcus aureus is a bacterium that has stood out for its ability to adapt and develop resistance to a wide variety of drugs. This literature review aimed to highlight recent advances in the use of Chalcones and derivatives as antibacterial agents against S. aureus , focusing on research articles available on the Science Direct, Pub Med and Scopus data platforms in the period 2015-2021. It was constructed informative tables that provided an overview of which types of Chalcones are being studied more (Natural or Synthetic); its chemical name and main Synthesis Methodology. From the analysis of the data, it was observed that the compounds based on Chalcones have great potential in medicinal chemistry as antibacterial agents and that the molecular skeletons of these compounds as well as their derivatives can be easily obtained through substitutions in the A and B rings of Chalcones, in order to obtain the desired bioactivity. It was verified that Chalcones and derivatives are promising agents for combating the multidrug resistance of S. aureus to drugs., Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03398-7., Competing Interests: Conflict of interestThe authors declare that they have no known conflict of interest to disclose., (© King Abdulaziz City for Science and Technology 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

In recent years, bacterial resistance to traditional drugs has increased, and the need to find new effective antibiotics to treat infections caused by multidrug-resistant bacteria has consequently become more important. The current study aimed to evaluate the potentiation of antibiotic activity and efflux pumps inhibition by (2E)-1-(4-aminophenyl)-3-(4-fluorophenyl)prop-2-en-1-one (PA-Fluorine) against the standard and resistant bacterial strains of Staphylococcus aureus and Escherichia coli. The association between PA-Fluorine and ampicillin reduced the minimum inhibitory concentration (MIC), showing a synergistic effect against S. aureus. For E. coli, PA-Fluorine did not show any significant results when associated with ampicillin. Ciprofloxacin and chlorpromazine showed synergy with PA-Fluorine on the two studied strains. An efflux pump mechanism was involved in the mechanism of action of chlorpromazine, norfloxacin, and ethidium bromide. PA-Fluorine synergistically modulated norfloxacin and bromide. It was thus concluded that PA-Fluorine has the potential to enhance antibacterial activity when combined with antibiotics. Molecular docking studies showed the effect of intermolecular interactions of PA-Fluorine on the NorA and MepA efflux pumps. Physicochemical and pharmacokinetic properties were also obtained by ADMET studies for this chalcone, which presents be a strong candidate as an efflux pump inhibitor., (© 2022 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Lippia sidoides Cham. (Verbenaceae) is a species often mentioned in traditional medicine due to the medicinal properties attributed to its leaves, which include antibacterial, antifungal, acaricidal and antioxidant. Several of these actions have been scientifically proven, according to reports in the literature; however, little is known about toxicological aspects of this plant. This work included studies to determine the chemical composition and toxicity tests, using several methods aiming to evaluate the safety for use of the aqueous extract of L. sidoides leaves, in addition, the anxiolytic effect on adult zebrafish was investigated, thus contributing to the pharmacological knowledge and traditional medicine concerning the specie under study. The chemical profile was determined by liquid chromatography coupled to mass spectrometry-HPLC/MS with electrospray ionization. Toxicity was evaluated by zebrafish, Drosophila melanogaster, blood cells, and Artemia salina models. 12 compounds belonging to the flavonoid class were identified. In the toxicity assays, the observed results showed low toxicity of the aqueous extract in all tests performed. In the analysis with zebrafish, the highest doses of the extract were anxiolytic, neuromodulating the GABAa receptor. The obtained results support the safe use of the aqueous extract of L. sidoides leaves for the development of new drugs and for the use by populations in traditional medicine., (© 2022. The Author(s).)

Aims: This study aimed to evaluate the antibacterial effect of two new cationic surfactants based on phenylalanine-arginine (LPAM) and tryptophan-arginine (LTAM). Materials & methods: Antibacterial activity, mechanism of action and interactions with Staphylococcus aureus enzymes were measured through microbiological, flow cytometry and molecular docking assays, respectively. Results & conclusion: These compounds showed antibacterial activity in the range of 4.06-16.24 μg/ml against planktonic cells and no activity against mature biofilms, since they caused a loss of membrane integrity and increased DNA damage, as revealed by flow cytometry analysis. In silico assays revealed the existence of molecular bonds such as hydrogen bonds, mainly with DNA. Therefore, these compounds have promising pharmacological activity against MRSA strains.