# Skin Depigmenting Agents in Anti-Aging Cosmetics: A Medicinal Perspective on Emerging Ingredients
## 3 Results and Discussion
### Medicinal Chemistry Perspective of New Skin Depignetting Ingredients in Anti-Aging Products
#### 3.2.3 4-Butylresorcinol  
4-Butylresorcinol, also known as rucinol, is a highly effective resorcinol derivative that inhibits both tyrosinase and tyrosinase-related protein-1 (TRP-1) [10]. Although knowledge of the hypopigmenting properties of this agent dates back to 1995 [41], several in vitro and in vivo studies have documented its efficacy and action over the last years [10]. In fact, in vitro assays on the inhibition of human tyrosinase activity have revealed the superiority of 4-butylresorcinol when compared to kojic acid, hydroquinone, and arbutin [42]. A study aimed at providing a convenient screening method to differentiate phenolic skin tyrosinase inhibitors from leukoderma-inducing phenols concluded that leukoderma-inducing phenols (rhododendrol, raspberry ketone, 4-methoxyphenylol, 4-benzylol, 4-_tert_-butylphenol, and 4-_tert_-butylcatechol) were readily oxidized by mushroom tyrosinase to form _ortho_-quinones while phenolic skin tyrosinase inhibitors (ellagic acid, 4-_n_-butylresorcinol, potassium 4-methoxysalicylate, and 2,20-dihydroxy-5,50-di-_n_-propylphenyl) were not oxidized by mushroom tyrosinase, while arbutin was only slowly oxidized [43]. This study highlighted that there is a necessity that tyrosinase inhibitors should also be examined as substrates if they are phenolic compounds since leukoderma-inducing phenols are readily oxidized by tyrosinase to form reactive _ortho_-quinone species [43]. The superiority of 4-butylresorcinol over other depigmenting agents is translated in the number of patents approved over the last years reporting studies on cosmetic formulations containing this agent. As an example, in the year 2021, at least 14 patents were approved related to the incorporation of 4-butylresorcinol in a composition of a depigmenting cream [44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57]. A pilot clinical study aimed at evaluating the efficacy and safety of a skin depigmenting serum applied twice daily combined with a spot-preventing SPF50+ sunscreen in healthy female subjects with melasma hyperpigmentation was recently reported [58]. The studied serum contained niacinamide, hydroxyphenoxy propionic acid, dipotassium glycyrrhizate,glycolic acid, and 4-\(n\)-butylresorcinol, and was applied twice a day combined with a spot-preventing SPF50+ sunscreen for treatment of melasma [58]. The skin depigmenting serum has shown a rapid clinical efficacy in reducing melasum hyperpigmentation in adult women, with good tolerability. However, randomized and controlled studies with a large sample size need to be performed in order to validate this experiment [58]. Another interesting study was developed by [PERSON] et al. towards the assessment of efficacy, safety, and tolerability of 4-\(n\)-butylresorcinol 0.3% cream [10]. This study was aimed at evaluating the use of a 0.3% 4-\(n\)-butylresorcinol cream instead of the widely studied, and available in the literature, 0.1% cream in Indian skin, which is more prone to irritation with hypopigmenting agents. This study explored the efficacy, safety, and tolerability of 4-\(n\)-butylresorcinol 0.3% cream in fifty-two Indian subjects (90.38% females, mean age of patients: 38.5 \(\pm\) 7.8 years) with melasma. The treatment was well tolerated by all the study subjects with a twice a day application of 4-\(n\)-butylresorcinol 0.3% cream for 8 weeks over the areas of melasma. Since no adverse reactions were reported throughout the study period, it was possible to conclude that 4-\(n\)-butylresorcinol 0.3% cream is safe, effective, and well tolerated in Indian patients with melasma [10]. Noteworthy, although this ingredient has been used in several anti-aging cosmetic products in 2018, only two clinical studies demonstrating its efficacy for aging-induced pigmentation have been found [59]. Volunteers with senile hyperpigmentation on the forearm were treated twice daily with a formula containing 0.3% 4-\(n\)-butylresorcinol, 0.5% phenylethylresorcinol, or a vehicle.