Synthesis, molecular docking, ADMET, and evaluation of the anxiolytic effect in adult zebrafish of synthetic chalcone (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one: An in vivo and in silico approach.

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 GABAA 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-HTR1 , 5-HTR2A/2C , and 5-HTR3A/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-HT2A and 5-HTR3A/3B receptors. The interaction of C2OHPDA with 5-HT2A R and 5-HT3A 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.

Naphthoquinones biflorin and bis-biflorin (Capraria biflora) as possible inhibitors of the fungus Candida auris polymerase: molecular docking, molecular dynamics, MM/GBSA calculations and in silico drug-likeness study.

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.

Synthesis of aminochalcones and in silico evaluation of their antiparasitic potential against Leishmania.

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-1H-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.

Potentiation of antibiotic activity, and efflux pumps inhibition by (2E)-1-(4-aminophenyl)-3-(4-fluorophenyl)prop-2-en-1-one.

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.