Antonella Fais

New halogenated phenylcoumarins as tyrosinase inhibitors

With the aim to find out structural features for the tyrosinase inhibitory activity, in the present communication we report the synthesis and pharmacological evaluation of a new series of phenylcoumarin derivatives with different number of hydroxyl or ether groups and bromo substituent in the scaffold. The synthesized compounds 5-12 were evaluated as mushroom tyrosinase inhibitors showing, two of them, lower IC(50) than the umbelliferone. Compound 12 (IC(50)=215 μM) is the best tyrosinase inhibitor of this series.

Tyrosinase inhibitor activity of coumarin-resveratrol hybrids.

In the present work we report on the contribution of the coumarin moiety to tyrosinase inhibition. Coumarin-resveratrol hybrids 1-8 have been resynthesized to investigate the structure-activity relationships and the IC50 values of these compounds were measured. The results showed that these compounds exhibited tyrosinase inhibitory activity. Compound 3-(3’,4’,5’-trihydroxyphenyl)-6,8-dihydroxycoumarin (8) is the most potent compound (0.27 mM), more so than umbelliferone (0.42 mM), used as reference compound. The kinetic studies revealed that compound 8 caused non-competitive tyrosinase inhibition.

PEG-immobilization of cardol and soluble polymer-supported synthesis of some cardol–coumarin derivatives: Preliminary evaluation of their inhibitory activity on mushroom tyrosinase

In this work, the PEG-immobilization and the liquid phase synthesis of some coumarins derived from cardol are presented. Some preliminary results on their tyrosinase inhibitory activity are also included.

2-Phenylbenzofuran derivatives as butyrylcholinesterase inhibitors: Synthesis, biological activity and molecular modeling.

A series of 2-phenylbenzofurans compounds was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. Among these benzofuran derivatives, compound 16 exhibited the highest BChE inhibition with an IC50 value of 30.3 μM. This compound was found to be a mixed-type inhibitor as determined by kinetic analysis. Moreover, molecular dynamics simulations revealed that compound 16 binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE and it displayed the best interaction energy value, in agreement with our experimental data.

Design and discovery of tyrosinase inhibitors based on a coumarin scaffold

In this manuscript we report the synthesis, pharmacological evaluation and docking studies of a selected series of 3-aryl and 3-heteroarylcoumarins with the aim of finding structural features for the tyrosinase inhibitory activity. The synthesized compounds were evaluated as mushroom tyrosinase inhibitors. Compound 12b showed the lowest IC50 (0.19 μM) of the series, being approximately 100 times more active than kojic acid, used as a reference compound. The kinetic studies of tyrosinase inhibition revealed that 12b acts as a competitive inhibitor of mushroom tyrosinase with L-DOPA as the substrate. Furthermore, the absence of cytotoxicity in B16F10 melanoma cells was determined for this compound. The antioxidant profile of all the derivatives was evaluated by measuring radical scavenging capacity (ABTS and DPPH assays). Docking experiments were carried out on mushroom tyrosinase structures to better understand the structure–activity relationships.

Synthesis and biological evaluation of a novel series of bis-salicylaldehydes as mushroom tyrosinase inhibitors.

A series of novel bis-salicylaldehydes were synthesised and evaluated as tyrosinase inhibitors using a tyrosinase-dependent L-DOPA oxidation assay. The bis-salicylaldehydes exhibited greater inhibitory activity than salicylaldehyde. Our data suggests that these novel compounds may serve as a structural template for the design and development of novel tyrosinase inhibitors.

Tyramine oxidation by copper/TPQ amine oxidase and peroxidase from Euphorbia characias latex

Tyramine, an important plant intermediate, was found to be a substrate for two proteins, a copper amine oxidase and a peroxidase from Euphorbia characias latex. The oxidation of tyramine took place by two different mechanisms: oxidative deamination to p-hydroxyphenylacetaldehyde by the amine oxidase and formation of di-tyramine by the peroxidase. The di-tyramine was further oxidized at the two amino groups by the amino oxidase, whereas p-hydroxyphenylacetaldehyde was transformed to di-p-hydroxyphenylacetaldehyde by the peroxidase. Data obtained in this study indicate a new interesting scenario in the metabolism of tyramine.

Metabolomics analysis and modeling suggest a lysophosphocholines-PAF receptor interaction in fibromyalgia.

Fibromyalgia Syndrome (FMS) is a chronic disease characterized by widespread pain, and difficult to diagnose and treat. We analyzed the plasma metabolic profile of patients with FMS by using a metabolomics approach combining Liquid Chromatography-Quadrupole-Time Of Flight/Mass Spectrometry (LC-Q-TOF/MS) with multivariate statistical analysis, aiming to discriminate patients and controls. LC-Q-TOF/MS analysis of plasma (FMS patients: n = 22 and controls: n = 21) identified many lipid compounds, mainly lysophosphocholines (lysoPCs), phosphocholines and ceramides. Multivariate statistical analysis was performed to identify the discriminating metabolites. A protein docking and molecular dynamic (MD) study was then performed, using the most discriminating lysoPCs, to validate the binding to Platelet Activating Factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) Receptor (PAFr). Discriminating metabolites between FMS patients and controls were identified as 1-tetradecanoyl-sn-glycero-3-phosphocholine [PC(14∶0/0∶0)] and 1-hexadecanoyl-sn-glycero-3-phosphocholine [PC(16∶0/0∶0)]. MD and docking indicate that the ligands investigated have similar potentialities to activate the PAFr receptor. The application of a metabolomic approach discriminated FMS patients from controls, with an over-representation of PC(14∶0/0∶0) and PC(16∶0/0∶0) compounds in the metabolic profiles. These results and the modeling of metabolite-PAFr interaction, allowed us to hypothesize that lipids oxidative fragmentation might generate lysoPCs in abundance, that in turn will act as PAF-like bioactivators. Overall results suggest disease biomarkers and potential therapeutical targets for FMS.

Tyrosine-like condensed derivatives as tyrosinase inhibitors

Objectives  We report the pharmacological evaluation of a new series of 3‐aminocoumarins differently substituted with hydroxyl groups, which have been synthesized because they include in their structures the tyrosine fragment (tyrosine‐like compounds), with the aim of discovering structural features necessary for tyrosinase inhibitory activity.

New insights into highly potent tyrosinase inhibitors based on 3-heteroarylcoumarins: Anti-melanogenesis and antioxidant activities, and computational molecular modeling studies

Melanogenesis is a physiological pathway for the formation of melanin. Tyrosinase catalyzes the first step of this process and down-regulation of its activity is responsible for the inhibition of melanogenesis. The search for molecules capable of controlling hyperpigmentation is a trend topic in health and cosmetics. A series of heteroarylcoumarins have been synthesized and evaluated. Compounds 4 and 8 exhibited higher tyrosinase inhibitory activities (IC50=0.15 and 0.38μM, respectively), than the reference compound, kojic acid (IC50=17.9μM). Compound 4 acts as competitive, while compound 8 as uncompetitive inhibitor of mushroom tyrosinase. Furthermore, compounds 2 and 8 inhibited tyrosinase activity and melanin production in B16F10 cells. In addition, compounds 2-4 and 8 proved to have an interesting antioxidant profile in both ABTS and DPPH radicals scavenging assays. Docking experiments were carried out in order to study the interactions between these heteroarylcoumarins and mushroom tyrosinase.