IDENTIFICATION OF NEW TYROSINASE INHIBITORS VIA COMPUTATIONAL STUDIES, SYNTHESIS AND STRUCTURAL CHARACTERIZATION

Tys (EC 1.14.18.1) are metalloenzymes, existing in all life domains, involved in the mammal biosynthesis of melanin. An excessive production of melanin can cause serious skin diseases. Thus, Tys inhibition is an established strategy to avoid these side effects and the development of TyIs gained high interest in the therapy of skin pathologies, as well as, in dermocosmetic treatments. Over the past 30 years several TyIs such as hydroquinone and kojic acid were developed, but unfortunately they showed relevant human toxicity. For this reason, there is still an urgent needing for new derivatives with better pharmacological characteristics. A web-research performed using the most popular database, PubMed, highlighted how the interest of this target, related to the treatment of skin diseases, is increased during the years considering the growing of the number of scientific publications from 1987 to date. Thus, the purpose of my PhD project was the development of new synthetic TyIs with better pharmacological profile. Starting from a “lead compound” previously identified by my research group, a rational approach was employed to design new derivatives with various structural modifications clarifying the structure-activity relationships (SARs). In particular, a combination of crystallographic and docking studies were used and the so planned compounds were then synthetized and their biological activity was evaluated.