In silico and in vitro evaluation of a safety profile of a cosmetic ingredient: 4-methoxychalcone (4-MC).

Chalcone is an important scaffold within medicinal and cosmetic chemistry. The structure enables multiple modifications which may result in obtaining compounds with desirable bioactivity. One of the chalcone derivatives, 4-methoxychalcone is a known cosmetic ingredient indexed in Cosing database as an antioxidant, bleaching, and skin conditioning substance. We investigated its in silico and in vitro safety profile. In silico study using Derek Nexus showed its potential of skin sensitisation, equivocal nature of chromosome damage in vitro in mammals, but also no mutagenic properties. In vitro research proved its activity as melanogenesis inhibitor in B16F10 cell line at the doses 12.5-3.125 µM. Evaluations performed in various cell lines showed that the cytotoxic doses were 50-25 µM. Tests in Episkin™ proved its ability to penetrate across epidermis and enabled classification of 2% formulation in PEG as non-irritant. In micronucleus tests it showed no genotoxicity. Studies in Cunninghamella echinulata model proved that 4-methoxychalcone was metabolised to less lipophilic products. 4-methoxychalcone showed phototoxic potential, its EC50(+UV) = 3.57 µg/mL, PIF = 10.19 and MPE = 0.428 were comparable to chlorpromazine. Moreover, 4-methoxychalcone showed ecotoxic potential in Microtox® assay with EC50(5 min) = 0.0047 mg/L and EC50(15 min) = 0.0033 mg/L. Although active doses were lower than toxic ones, some potential safety risks were noticed. Especially, due to the phototoxicity potential of 4-methoxychalcone, its use as depigmenting agent should involve avoidance of sunlight and use of appropriate photoprotection.

Design and synthesis of novel arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines with antimicrobial activity against multidrug-resistant Gram-positive bacteria.

The alarming increase in the resistance of bacteria to the currently available antibiotics necessitates the development of new effective antimicrobial agents that are active against bacterial pathogens causing major public health problems. For this purpose, our in-house libraries were screened against a wide panel of clinically relevant Gram-positive and Gram-negative bacteria, based on which compound I was selected for further optimization. Synthetic efforts in a group of arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines, followed with an in vitro evaluation of the activity against multidrug-resistant strains identified compound 44 (1-(3-chlorophenyl)-3-(1-{3-phenyl-3-[3-(trifluoromethyl)phenoxy] propyl}piperidin-4-yl)urea). Compound 44 showed antibacterial activity against Gram-positive bacteria including fatal drug-resistant strains i.e., Staphylococcus aureus (methicillin-resistant, MRSA; vancomycin-intermediate, VISA) and Enterococcus faecium (vancomycin-resistant, VREfm) at low concentrations (0.78-3.125 µg/mL) comparable to last resort antibiotics (i.e., vancomycin and linezolid). It is also potent against biofilm-forming S. aureus and Staphylococcus epidermidis (including linezolid-resistant, LRSE) strains, but with no activity against Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa). Compound 44 showed strong bactericidal properties against susceptible and drug-resistant Gram-positive bacteria. Depolarization of the bacterial cytoplasmic membrane induced by compound 44 suggests a dissipation of the bacterial membrane potential as its mechanism of antibacterial action. The high antimicrobial activity of compound 44, along with its selectivity over mammalian cells (lung MCR-5 and skin BJ fibroblast cell lines) and no hemolytic properties toward horse erythrocytes, proposes arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines for development of novel antibacterial agents.

Ligand assisted CuAAC labelling and RP-HPLC analysis of zidovudine and Retrovir using propargyl-Fmoc probe.

The extensive application of zidovudine (ZDV) as a stand-alone anti-HIV drug and a component in antiviral combination therapies, has made its analysis important both in the pharmaceutical and environmental context. The azide group in ZDV structure makes it a ready-to-use substrate for copper-catalyzed azide-alkyne cycloaddition (CuAAC), which is an efficient method for "click chemistry" labeling. In this paper, we describe a ligand-assisted CuAAC procedure for the precolumn derivatization of ZDV. We used propargyl-Fmoc fluorescent label and trans-2-(4-((dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)cyclohexan-1-ol (AMTC) as a copper-binding ligand. We tested the applicability of AMTC for precolumn derivatization and developed chromatographic analytical procedures for ZDV and its formulation (50 mg/5 ml oral solution, Retrovir™ syrup). Our research aimed to improve labeling efficiency with a Cu-chelating ligand, using an accessible and affordable fluorescent probe. We also developed a sustainable mechanochemical synthesis procedure for obtaining propargyl-Fmoc in a gram scale and thus boosted the accessibility of this probe. The advantages of the developed derivatization procedure are its simplicity and easy availability of the propargyl-Fmoc probe. Moreover, the high lipophilicity of the propargyl-Fmoc probe enables efficient separation of the analyte from polar matrix components. In addition, the derivatization procedure can be performed directly on a sample solution. We tested its usability for samples in environmental and biological matrices, including tap water, river water, urine, and human serum.

Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties.

The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α2-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α2-adrenoceptors and 5-HT7 receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α2A/5-HT7 receptor antagonist and displayed moderate-to-high selectivity over α1-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.