Synthesis and evaluation of 3-hydroxyquinolin-2(1H)-one derivatives as inhibitors of tyrosinase.

The tyrosinase (TYR) enzyme catalyses sequential reactions in the melanogenesis pathway: l-tyrosine is oxidised to yield L-3,4-dihydroxyphenylalanine (l-dopa), which in turn is converted to dopaquinone. These two reactions are the first two steps of melanin biosynthesis and are rate limiting. The accumulation or overproduction of melanin may cause skin hyperpigmentation and inhibitors of TYR are thus of interest to the cosmeceutical industry. Several TYR inhibitors are used to treat skin hyperpigmentation, however, some are ineffective and possess questionable safety profiles. This emphasises the need to develop novel TYR inhibitors with better safety and efficacy profiles. The small molecule, 3-hydroxycoumarin, has been reported to be a good potency TYR inhibitor (IC50 = 2.49 µM), and based on this, a series of eight structurally related 3-hydroxyquinolin-2(1H)-one derivatives were synthesised with the aim to discover novel TYR inhibitors. The results showed that four of the derivatives inhibited TYR from the champignon mushroom Agaricus bisporus (abTYR) with IC50 < 6.11 µM. The most potent inhibitor displayed an IC50 value of 2.52 µM. Under the same conditions, the reference inhibitors, thiamidol and kojic acid, inhibited abTYR with IC50 values of 0.130 and 26.4 µM, respectively. Based on the small molecular structures of the active 3-hydroxyquinolin-2(1H)-one inhibitors which are amenable to structure optimisation, it may be concluded that this class of compounds are good leads for the design of TYR inhibitors for cosmeceutical applications.

Hematoxylin, an Alternative Substrate of Tyrosinase.

Mushroom tyrosinase from Agaricus bisporus (abTYR) is often used during the development of tyrosinase inhibitors for medicinal and cosmetic purposes. In the search for novel tyrosinase inhibitors, this study identified hematoxylin as an alternative substrate for abTYR. The interaction of hematoxylin with abTYR was investigated through spectrophotometric and chromatographic analyses. The results showed that hematoxylin acted as an abTYR substrate and exhibited Michaelis-Menten kinetic behaviour at concentrations below 1.25 mM. The substrate properties of hematoxylin were similar to the natural tyrosinase substrate, L-3,4-dihydroxyphenylalanine (L-DOPA), with regards to Km, while Vmax was eightfold lower. The main oxidation product formed during the reaction of abTYR with hematoxylin was identified as hematein. This is the first report of the interaction of hematoxylin with abTYR.

Overview of popular cosmeceuticals in dermatology.

The eternal pursuit to prevent ageing and maintain a youthful appearance has resulted in a rapidly expanding cosmeceutical industry. Cosmeceutical products, particularly of natural origin, are in high demand due to claims of efficacy for signs of ageing and other skin conditions. Consumers often include cosmeceutical products in their skin care regime as they are readily available, and a more affordable option compared to prescription products. However, many cosmeceutical ingredients lack clinical evidence regarding their efficacy and safety as these products are not regulated by the U.S. Food and Drug Administration. This review provides a brief overview of several popular cosmeceutical ingredients with regards to their potential indications, targets and mechanisms of action.

A Multitarget Approach against Neuroinflammation: Alkyl Substituted Coumarins as Inhibitors of Enzymes Involved in Neurodegeneration.

Neurodegenerative disorders (NDs) include a large range of diseases characterized by neural dysfunction with a multifactorial etiology. The most common NDs are Alzheimer's disease and Parkinson's disease, in which cholinergic and dopaminergic systems are impaired, respectively. Despite different brain regions being affected, oxidative stress and inflammation were found to be common triggers in the pathogenesis and progression of both diseases. By taking advantage of a multi-target approach, in this work we explored alkyl substituted coumarins as neuroprotective agents, capable to reduce oxidative stress and inflammation by inhibiting enzymes involved in neurodegeneration, among which are Carbonic Anhydrases (CAs), Monoamine Oxidases (MAOs), and Cholinesterases (ChEs). The compounds were synthesized and profiled against the three targeted enzymes. The binding mode of the most promising compounds (7 and 9) within MAO-A and -B was analyzed through molecular modeling studies, providing and explanation for the different selectivities observed for the MAO isoforms. In vitro biological studies using LPS-stimulated rat astrocytes showed that some compounds were able to counteract the oxidative stress-induced neuroinflammation and hamper interleukin-6 secretion, confirming the success of this multitarget approach.