Toxicological assessment of the Achyrocline satureioides aqueous extract in the Caenorhabditis elegans alternative model.

Achyrocline satureioides, popularly called "marcela" in Brazil, is used in traditional medicine in South America. A. satureioides, inflorescences are used for many conditions, including to minimize the Sars-Cov-2 symptoms. Therefore, the aim of this study was to determine the toxicity profile of A. satureioides aqueous extract (ASAE), using the Caenorhabditis elegans (C. elegans) alternative model. Survival, reproduction, development, and transgenerational assays were performed. The effects of ASAE were investigated under conditions of thermal stress and presence of oxidant hydrogen peroxide (H2O2). In addition, C. elegans strains containing high antioxidant enzyme levels and elevated lineages of daf-16, skn-1 and daf-2 regulatory pathways were examined. The ASAE LC50 value was found to be 77.3 ± 4 mg/ml. The concentration of ASAE 10 mg/ml (frequently used in humans) did not exhibit a significant reduction in worm survival at either the L1 or L4 stage, after 24 or 72 hr treatment. ASAE did not markedly alter the body area. In N2 strain, ASAE (10 or 25 mg/ml) reversed the damage initiated by H2O2. In addition, ASAE protected the damage produced by H2O2 in strains containing significant levels of sod-3, gst-4 and ctl - 1,2,3, suggesting modulation in these antioxidant systems by this plant extract. ASAE exposure activated daf-16 and skn-1 stress response transcriptional pathways independently of daf-2, even under extreme stress. Data suggest that ASAE, at the concentrations tested in C. elegans, exhibits a reliable toxicity profile, which may contribute to consideration for safe use in humans.

8-Amide and 8-carbamate substitution patterns as modulators of 7-hydroxy-4-methylcoumarin's antidepressant profile: Synthesis, biological evaluation and docking studies.

Psychiatric and neurological disorders affect millions of people worldwide. Currently available treatments may help to improve symptoms, but they cannot cure the diseases. Therefore, there is an urgent need for potent and safe therapeutic solutions. 8-Amide and 8-carbamatecoumarins were synthetized and evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Comparison between both scaffolds has been established, and we hypothesized that the introduction of different substituents can modulate hMAO activity and selectivity. N-(7-Hydroxy-4-methylcoumarin-8-yl)-4-methylbenzamide (9) and ethyl N-(7-hydroxy-4-methylcoumarin-8-yl)carbamate (20) proved to be the most active and selective hMAO-A inhibitors (IC50 = 15.0 nM and IC50 = 22.0 nM, respectively), being compound 9 an irreversible hMAO-A inhibitor twenty-four times more active in vitro than moclobemide, a drug used in the treatment of depression and anxiety. Based on PAMPA assay results, both compounds proved to be good candidates to cross the blood-brain barrier. In addition, these compounds showed non-significant cytotoxicity on neuronal viability assays. Also, the best compound proved to have a t1/2 of 6.84 min, an intrinsic clearance of 195.63 µL min-1 mg-1 protein, and to be chemically stable at pH 3.0, 7.4 and 10.0. Docking studies were performed to better understand the binding affinities and selectivity profiles for both hMAO isoforms. Finally, theoretical drug-like properties calculations corroborate the potential of both scaffolds on the search for new therapeutic solutions for psychiatric disorders as depression.

Novel coumarin-pyridazine hybrids as selective MAO-B inhibitors for the Parkinson's disease therapy.

The 3-pyridazinylcoumarin scaffold was previously reported as an efficient core for the discovery of reversible and selective inhibitors of MAO-B, a validated drug target for PD therapy which also plays an important role in the AD progress. Looking for its structural optimization, novel compounds of hybrid structure coumarin-pyridazine, differing in polarizability and lipophilicity properties, were synthesized and tested against the two MAO isoforms, MAO-A and MAO-B (compounds 17a-f and 18a-f). All the designed compounds selectively inhibited the MAO-B isoenzyme, exhibiting many of them IC50 values ranging from sub-micromolar to nanomolar grade and lacking neuronal toxicity. The 7-bromo-3-(6-bromopyridazin-3-yl)coumarin (18c), the most potent compound of these series (IC50 = 60 nM), was subjected to further in vivo studies in a reserpine-induced mouse PD model. The obtained results suggest a promising potential for 18c as antiparkinsonian agent. Molecular modeling studies also provided valuable information about the enzyme-drug interactions and the potential pharmacokinetic profile of the novel compounds.

Gamma-decanolactone attenuates acute and chronic seizures in mice: a possible role of adenosine A1 receptors.

This study aimed to investigate the possible gamma-decanolactone mechanisms of action in the GABAergic and adenosine systems using the aminophylline-induced acute crisis model and the pentylenetetrazole-induced kindling model. In the acute model, male mice received administration of bicuculline (GABAA receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (A1 receptor antagonist) or ZM241385 (A2A receptor antagonist), 15 min before the treatment with gamma-decanolactone (300 mg/kg). After a single dose of aminophylline was administered, the animals were observed for 60 min. In the chronic model of seizure, 30 min after the treatment with gamma-decanolactone, mice received pentylenetetrazole once every third day. On the last day of kindling, the animals received the same GABA and adenosine antagonists used in the acute model, 15 min before gamma-decanolactone administration. The protein expression of GABAA α1 receptor and adenosine A1 receptor was detected using western blotting technique in hippocampal samples. The results showed that gamma-decanolactone increased the latency to first seizure and decreased seizure occurrence in the acute and chronic models. The adenosine A2A receptor antagonist and GABAA receptor antagonist were not able to change gamma-decanolactone behavioral seizure induced by aminophylline or pentylenetetrazole. The administration of adenosine A1 receptor antagonist reversed the protective effect of gamma-decanolactone in both models. In addition, gamma-decanolactone promoted an increase in the expression GABAA α1 receptor, in the hippocampus. The results suggest that the neuroprotective effect of gamma-decanolactone observed during the investigation could have a straight connection to its action on A1 adenosine receptors.

Discovery and optimization of 3-thiophenylcoumarins as novel agents against Parkinson's disease: Synthesis, in vitro and in vivo studies.

Monoamine oxidase B (MAO-B) inhibitors are still receiving great attention as promising therapeutic agents for central nervous system disorders. This study explores, for the first time, the potential of 3-thiophenylcoumarins as in vitro and in vivo agents against Parkinsons disease. Twelve compounds were synthesized via Perkin-Oglialoro reaction, and in vitro evaluation of six hydroxylated molecules was performed. MAO-A and MAO-B inhibition, DPPH scavenging and inhibition of ROS formation, neurotoxicity on motor cortex neurons and neuroprotection against H2O2, were studied. In vivo effect on locomotor activity using the open field test was also evaluated for the best candidate [3-(4'-bromothiophen-2'-yl)-7-hydroxycoumarin, 5], a potent, selective and reversible MAO-B inhibitor (IC50 = 140 nM). This compound proved to have a slightly better in vivo profile than selegiline, one of the currently treatments for Parkinson's disease, in reserpinized mice pretreated with levodopa and benserazide. Results suggested that, comparing positions 7 and 8, substitution at position 7 of the coumarin scaffold is better for the enzymatic inhibition. However, the presence of a catechol at positions 7 and 8 exponentially increases the antioxidant potential and the neuroprotective properties. Finally, all the molecules present good theoretical physicochemical properties that make them excellent candidates for the optimization of a lead compound.

Synthesis, pharmacological study and docking calculations of new benzo[f]coumarin derivatives as dual inhibitors of enzymatic systems involved in neurodegenerative diseases.

BACKGROUND: Due to the complex etiology of neurodegenerative diseases, there is growing interest in multitarget drugs. In this study we synthesized and evaluated a new series of compounds, with benzo[f]coumarin structure, as potential inhibitors of MAO-A, MAO-B, AChE and BuChE. RESULTS: In vitro studies show that most of the studied compounds inhibited the activity of MAO-B in the nano- to micro-molar range. 3-(3´-methoxyphenyl)benzo[f]coumarin is the most active compound with an IC50 value against MAO-B of 2.44 nM. Most of the derivatives exhibited an important selectivity profile against the MAO-B isoform. Some of them also acted as in vitro inhibitors of BuChE, with 3-(2´-hydroxyphenyl)benzo[f]coumarin being the most active with an IC50 value of 1.13 µM. In addition, a theoretical study of the physicochemical properties of the new compounds, as well as a docking study in both MAO isoforms, were carried out. Important structure-activity relationships were obtained. CONCLUSION: Important preliminary structure-activity relationships were concluded from the experimental results. These results encourage us to further explore the potential of this chemical family as potential drug candidates for the treatment of Alzheimer's disease.

Synthesis of glycosyl derivatives as dopamine prodrugs: interaction with glucose carrier GLUT-1.

Glucosyl dopamine (DA) derivatives may represent a new class of DA prodrugs that would interact with glucose transporter GLUT-1, present in the blood-brain barrier, and generate DA in the brain. Therefore, compounds bearing the sugar moiety linked to either the amino group or the catechol ring of DA through amide, ester, carbamate, peptide or glycosidic bonds were synthesized. The behavior of the compounds as prodrugs was monitored in different media and the affinity of the glycoconjugates for the glucose carrier GLUT-1 using human erythrocytes was also studied. Most of the compounds were markedly stable in buffer and plasma, and several compounds released DA when incubated with brain extracts and the rate was related to the bond linking DA with glucose. The new glucosyl conjugates substituted at the C-6 position of the sugar were more potent inhibitors of glucose transport when compared to C-1 and C-3 substituted derivatives. This work provides structure-activity information about the interaction of substituted glucose with the GLUT-1 transporter.