Honokiol and Magnolol: Insights into Their Antidermatophytic Effects.

Dermatophyte infections represent a significant public health concern, with an alarming negative impact caused by unsuccessful therapeutic regimens. Natural products have been highlighted as a promising alternative, due to their long-standing traditional use and increasing scientific recognition. In this study, honokiol and magnolol, the main bioactives from Magnolia spp. bark, were investigated for their antidermatophytic activity. The antifungal screening was performed using dermatophyte standard strains and clinical isolates. The minimal inhibitory concentration (MIC) and the minimal fungicidal concentration (MFC) were determined in accordance with EUCAST-AFST guidelines, with minor modifications. The effects on ergosterol biosynthesis were assessed in Trichophyton rubrum cells by HPLC-DAD. Putative interactions with terbinafine against T. rubrum were evaluated by the checkerboard method. Their impact on cells' viability and pro-inflammatory cytokines (IL-1ß, IL-8 and TNF-α) was shown using an ex vivo human neutrophils model. Honokiol and magnolol were highly active against tested dermatophytes, with MIC and MFC values of 8 and 16 mg/L, respectively. The mechanism of action involved the inhibition of ergosterol biosynthesis, with accumulation of squalene in T. rubrum cells. Synergy was assessed for binary mixtures of magnolol with terbinafine (FICI = 0.50), while honokiol-terbinafine combinations displayed only additive effects (FICI = 0.56). In addition, magnolol displayed inhibitory effects towards IL-1ß, IL-8 and TNF-α released from lipopolysaccharide (LPS)-stimulated human neutrophils, while honokiol only decreased IL-1ß secretion, compared to the untreated control. Overall, honokiol and magnolol acted as fungicidal agents against dermatophytes, with impairment of ergosterol biosynthesis.

Synthesis, biological evaluation and docking studies of a novel class of sulfur-bridged diazabicyclo[3.3.1]nonanes.

A small library of 3-thia-7,9-diazabicyclo[3.3.1]nonanes was synthesized and their opioid receptors affinity and selectivity evaluated. Among these novel sulfur-bridged compounds, the (E) 9-[3'-(3-chlorophenyl)-but-2'-en-1'-yl]-7-propionyl-3-thia-7,9-diazabicyclo[3.3.1]nonane 2i emerged as the derivative with the highest µ receptor affinity (Ki = 85 nM) and selectivity (Ki µ/δ = 58.8, Ki µ/κ > 117.6). The antinociceptive activity of 2i was also evaluated in acute thermal pain. Docking studies disclosed the specific pattern of interactions of these derivatives.

Isolation and Characterization of Acetylcholinesterase Inhibitors from Piper longum and Binding Mode Predictions.

Restoration of cholinergic function is considered a rational approach to enhance cognitive performance. Acetylcholinesterase inhibitors are still the best therapeutic option for Alzheimer's disease. The fruits of Piper longum have been used in traditional medicines for the treatment of memory loss. It was demonstrated that the dichloromethane extract of these fruits is able to inhibit acetylcholinesterase. Thus, the aim of this study was to identify the contained acetylcholinesterase inhibitors. The active zones were presented via TLC-bioautography, and five compounds were isolated in the process of a bioassay-guided phytochemical investigation. Their structures were characterized as piperine, methyl piperate, guineenisine, pipercide, and pellitorine using spectroscopy and spectrometry methods (UV, IR, MS, 1H-, and 13C-NMR). In vitro acetylcholinesterase inhibitory activities of the isolates and their IC50 values were determined via a colorimetric assay. Three of them exhibited enzyme inhibitory activities, with piperine being the most potent compound (IC50 of 0.3 mM). In order to investigate the binding mode of the tested compounds, docking studies were performed using the X-ray crystal structure of acetylcholinesterase from Tetronarce californica with the Protein Data Bank code 1EVE. The content of the active compounds in the extract was determined by a developed HPLC method. Piperine was present in the maximum quantity in the fruits (0.57%), whereas methyl piperate contained the minimum content (0.10%).

Polyacetylenes from Oplopanax horridus and Panax ginseng: Relationship between Structure and PPARγ Activation.

Oplopanax horridus and Panax ginseng are members of the plant family Araliaceae, which is rich in structurally diverse polyacetylenes. In this work, we isolated and determined structures of 23 aliphatic C17 and C18 polyacetylenes, of which five are new compounds. Polyacetylenes have a suitable scaffold for binding to PPARγ, a ligand-activated transcription factor involved in metabolic regulation. Using a reporter gene assay, their potential was investigated to activate PPARγ. The majority of the polyacetylenes showed at least some PPARγ activity, among which oplopantriol B 18-acetate (1) and oplopantriol B (2) were the most potent partial PPARγ activators. By employing in silico molecular docking and comparing the activities of structural analogues, features are described that are involved in PPARγ activation, as well as in cytotoxicity. It was found that the type of C-1 to C-2 bond, the polarity of the terminal alkyl chain, and the backbone flexibility can impact bioactivity of polyacetylenes, while diol structures with a C-1 to C-2 double bond showed enhanced cytotoxicity. Since PPARγ activators have antidiabetic and anti-inflammatory properties, the present results may help explain some of the beneficial effects observed in the traditional use of O. horridus extracts. Additionally, they might guide the polyacetylene-based design of future PPARγ partial agonists.

Interference of Paraben Compounds with Estrogen Metabolism by Inhibition of 17ß-Hydroxysteroid Dehydrogenases.

Parabens are effective preservatives widely used in cosmetic products and processed food, with high human exposure. Recent evidence suggests that parabens exert estrogenic effects. This work investigated the potential interference of parabens with the estrogen-activating enzyme 17ß-hydroxysteroid dehydrogenase (17ß-HSD) 1 and the estrogen-inactivating 17ß-HSD2. A ligand-based 17ß-HSD2 pharmacophore model was applied to screen a cosmetic chemicals database, followed by in vitro testing of selected paraben compounds for inhibition of 17ß-HSD1 and 17ß-HSD2 activities. All tested parabens and paraben-like compounds, except their common metabolite p-hydroxybenzoic acid, inhibited 17ß-HSD2. Ethylparaben and ethyl vanillate inhibited 17ß-HSD2 with IC50 values of 4.6 ± 0.8 and 1.3 ± 0.3 µM, respectively. Additionally, parabens size-dependently inhibited 17ß-HSD1, whereby hexyl- and heptylparaben were most active with IC50 values of 2.6 ± 0.6 and 1.8 ± 0.3 µM. Low micromolar concentrations of hexyl- and heptylparaben decreased 17ß-HSD1 activity, and ethylparaben and ethyl vanillate decreased 17ß-HSD2 activity. However, regarding the very rapid metabolism of these compounds to the inactive p-hydroxybenzoic acid by esterases, it needs to be determined under which conditions low micromolar concentrations of these parabens or their mixtures can occur in target cells to effectively disturb estrogen effects in vivo.

New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells.

In pursuing our research targeting the identification of potent inhibitors of PTP1B and LMW-PTP, we have identified new 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids endowed with interesting in vitro inhibitory profiles. Most compounds proved to be inhibitors of PTP1B and LMW-PTP isoform IF1. The tested inhibitors also showed selectivity towards PTP1B over the closely related TC-PTP. These compounds were found to activate the insulin-mediated signalling on mouse C2C12 skeletal muscle cells by increasing the phosphorylation levels of the insulin receptor and promoting cellular 2-deoxyglucose uptake. Interestingly, 4-{[5-(4-benzyloxybenzylidene)-2-(4-trifluoromethylphenylimino)-4-oxo-3-thiazolidinyl]methyl}benzoic acid (7d), the best in vitro inhibitor of PTP1B and the isoform IF1 of LMW-PTP, provided the highest activation level of the insulin receptor and was found to be endowed with an excellent insulinomimetic effect on the selected cells. This compound therefore represents an interesting lead compound for developing novel PTP1B and LMW-PTP inhibitors which could be achieved by improving both its pharmacological profile and its potentiating effects on insulin signalling.