Synthesis and assessment of novel 1,4-diaryl-piperazine derivatives as tyrosinase inhibitors

• Grant number: 23/17755-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2024
• End date: March 31, 2025
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: João Paulo dos Santos Fernandes
• Grantee: Mariana Aparecida Siegl Breno
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil

Abstract

Melanin is the main biological pigment involved in skin pigmentation that, due to its antioxidant properties, protects against possible damage caused by ultraviolet rays. However, melanin is also produced in the CNS and by other organisms than animals, such as fungi and plants. Melanogenesis is a bioprocess that occurs from phenolic substrates such as L-tyrosine, L-DOPA and dopamine itself, initiated and controlled by the enzyme tyrosinase, the limiting step in the process. The abnormal accumulation of melanin is related to several changes and, therefore, the search for agents capable of regulating melanogenesis has been the target of pharmacological interest. Our group has been developing a series of anti-melanogenic compounds with proven efficacy in ex-vivo models of human skin and with inhibitory activity superior to known inhibitors. New piperazine compounds have shown increased activity with superiority in relation to solubility and drug-likeness, and thus, this project proposes the preparation and evaluation of a new series of derivatives to clarify some structure-activity relationships that guide the design of novel analogues even further effective as anti-melanogenic agents. Furthermore, opportunities for multitarget strategies with these inhibitors could be explored for the treatment of various pathologies involving melanogenesis, including melasma, fungal infections and melanoma.