Determination of metabolic profiles of new chemical entities is a key step in the process of drug discovery, since it influences pharmacokinetic characteristics of therapeutic compounds. One of the main challenges of medicinal chemistry is not only to design compounds demonstrating beneficial activity, but also molecules exhibiting favourable pharmacokinetic parameters. Chemical compounds can be divided into those which are metabolized relatively fast and those which undergo slow biotransformation. Rapid biotransformation reduces exposure to the maternal compound and may lead to the generation of active, non-active or toxic metabolites. In contrast, high metabolic stability may promote interactions between drugs and lead to parent compound toxicity. In the present paper, issues of compound metabolic stability will be discussed, with special emphasis on its significance, in vitro metabolic stability testing, dilemmas regarding in vitro-in vivo extrapolation of the results and some aspects relating to different preclinical species used in in vitro metabolic stability assessment of compounds.

Hyperpigmentation disorders constitute important medical and aesthetical conditions. Dark areas or dark spots on the skin result from inappropriate amount and/or deposition of skin pigments - melanins. Several depigmenting agents, such as kojic acid, arbutin, aloesin, ellagic acid, resveratrol, azelaic acid, niacinamide, tretinoin, glycolic acid, lactic acid, and citric acid, have already been identified and are used in topical drugs or cosmetic formulations for the treatment of hyperpigmentations. However, these compounds are characterized by insufficient effectiveness and multiple adverse effects. As a result, there is still a need for searching for new active substances. The current paper summarizes strategies for searching for novel melanogenesis inhibitors. In the review, they are divided according to approach, into in silico, in vitro and in vivo experiments. In silico research includes computational studies with models of tyrosinase and di-copper complexes. The in vitro approach is based on tests using tyrosinase (a key enzyme in melanin biosynthesis), cell cultures, cell co-cultures, pigmented human skin equivalents or Streptomyces bikiniensis model. In vivo studies involve zebrafish, rodents or humans. Examples of protocols and laboratory procedures are presented, with a focus on utilization of various models for evaluation of mechanisms of action of tested compounds. The potential limitations of the methods are also discussed, together with future perspectives in the field of searching for melanogenesis inhibitors.

Fungal mycelium cultures are an alternative to natural sources in order to obtain valuable research materials. They also enable constant control and adaptation of the process, thereby leading to increased biomass growth and accumulation of bioactive metabolites. The present study aims to assess the biosynthetic potential of mycelial cultures of six Ganoderma species: G. adspersum, G. applanatum, G. carnosum, G. lucidum, G. pfeifferi, and G. resinaceum. The presence of phenolic acids, amino acids, indole compounds, sterols, and kojic acid in biomass extracts was determined by HPLC. The antioxidant and cytotoxic activities of the extracts and their effects on the inhibition of selected enzymes (tyrosinase and acetylcholinesterase) were also evaluated. The total content of phenolic acids in the extracts ranged from 5.8 (G. carnosum) to 114.07 mg/100 g dry weight (d.w.) (G. pfeifferi). The total content of indole compounds in the extracts ranged from 3.03 (G. carnosum) to 11.56 mg/100 g d.w. (G. lucidum) and that of ergosterol ranged from 28.15 (G. applanatum) to 74.78 mg/100 g d.w. (G. adspersum). Kojic acid was found in the extracts of G. applanatum and G. lucidum. The tested extracts showed significant antioxidant activity. The results suggest that the analyzed mycelial cultures are promising candidates for the development of new dietary supplements or pharmaceutical preparations.

The study aimed to examine whether usnic acid—a lichen compound with UV-absorbing properties—can be considered as a prospective photoprotective agent in cosmetic products. Moreover, a comparison of two usnic acid enantiomers was performed to preselect the more effective compound. To meet this aim, an in vitro model was created, comprising the determination of skin-penetrating properties via skin-PAMPA assay, safety assessment to normal human skin cells (keratinocytes, melanocytes, fibroblasts), and examination of photostability and photoprotective properties. Both enantiomers revealed comparable good skin-penetrating properties. Left-handed usnic acid was slightly more toxic to keratinocytes (IC₅₀ 80.82 and 40.12 µg/mL, after 48 and 72 h, respectively) than its right-handed counterpart. The latter enantiomer, in a cosmetic formulation, was characterized by good photoprotective properties and photostability, comparable to the UV filter octocrylene. Perhaps most interestingly, (+)-usnic acid combined with octocrylene in one formulation revealed enhanced photoprotection and photostability. Thus, the strategy can be considered for the potential use of (+)-usnic acid as a UV filter in cosmetic products. Moreover, the proposed model may be useful for the evaluation of candidates for UV filters.

Cinnamic acid and its natural derivatives were primarily used in cosmetics as fragrance materials as well as skin and hair conditioners. Nowadays, not only natural but also synthetic cinnamic acid derivatives are used as active ingredients of cosmetic formulations. They still serve as fragrance ingredients but also as active ingredients supporting the treatment of selected dermatoses such as acne vulgaris, atopic dermatitis, and hyperpigmentation. They are also commonly used in anti-aging cosmetic formulations. On the other hand, several cinnamic acid derivatives used as fragrances in cosmetic products are classified as potential allergens which can cause contact dermatitis. The main mechanisms of action proved for various cinnamic acid derivatives include antioxidant, antimicrobial, anti-inflammatory, and antimelanogenic properties. Most commonly used cinnamic acid derivatives in cosmetics products are hydroxy acids such as ferulic acid, caffeic acid, p-coumaric acid, and sinapic acid. Chemical synthesis led to several modified acids, esters, and amides, which also showed the potential to be used in cosmetic formulations.