Exploiting the 1-(4-fluorobenzyl)piperazine fragment for the development of novel tyrosinase inhibitors as anti-melanogenic agents: Design, synthesis, structural insights and biological profile

Abstract

The development of Tyrosinase inhibitors (TYRIs) could represent an efficacious strategy for pharmacological intervention on skin pathologies related to aberrant production of melanin. Based on in silico studies we designed and tested a library of twenty-four compounds bearing the 4-(4-fluorobenzyl) piperazin-1-yl]-fragment. As result, we identified several compounds with excellent inhibit effects at low micromolar concentration against TYR from Agaricus bisporus (TyM). Among them, compound 25 (IC 50 ¼ 0.96 mM) proved to be~20-fold more potent than the reference compound kojic acid (IC 50 ¼ 17.76 mM) having wide applications in the cosmetics and pharmaceutical industries. The mode of interaction of active inhibitor 25 was deciphered by means of crystallography as well as molecular docking and these results were consistent with kinetic experiments. Moreover, the identified compound 25 exhibited no considerable cytotoxicity and showed anti-melanogenic effects on B16F10 melanoma cells. Therefore, a combination of computational and biochemical approaches could represent a rational guidelines for further structural modification of this class of compounds as future anti-melanogenic agents.

4‐Fluorobenzylpiperazine‐Containing Derivatives as Efficient Inhibitors of Mushroom Tyrosinase

“…In particular, we designed a further series of 4-fluorobenzylpi-perazine compounds, in which the benzoyl moiety was properly decorated. As result, we obtained improved inhibitory activity toward Agaricus bisporus tyrosinase up to sub-micromolar range as showed by compounds 1 b and 1 c (0.5 and 1 μM; Figure 1), [17] thus confirming our computational hypotheses.…”

“…Docking simulation was performed by using the same protocol as reported in our previous paper. [17] Briefly, the binding site was defined in order to contain the residues within 15 Å from the position of the ligand in the X-ray structure. A scaffold constraint was applied to restrict the solutions in which the 4-fluorophenyl fragment matches its binding pose upon the cocrystal structure of the active portion of inhibitors.…”

“…[12,15,16] Experimental and theoretical structural investigations carried out on tyrosinases from Bacillus megaterium and Agaricus bisporus allowed us to identify 4-(4-fluorobenzyl)piperazin-1-yl] (2-methylphenyl)methanone (1 a) as promising agent (IC 50 = 5 μM) showing higher potency than the reference compound kojic acid (IC 50 = 18 μM; Figure 1). [12] As shown in Figure 2A, the docking studies [17] on mushroom tyrosinase revealed that 1 a was accommodated in the catalytic cavity through π/π stacking interactions with His263 as well as hydrophobic contacts with Val283, Met257, Val284 and Phe264. In turn, the binding pose was used as starting point for the generation of Apo-site pharmacophore grids ( Figure 2B), which suggested suitable hydrophobic and hydrophilic substituents.…”

Melanins as Sustainable Resources for Advanced Biotechnological Applications

“…Bioinformatic studies have been used to examine functional and structural genomics (genetics, [ 551,552 ] gene expression of tyrosinase‐induced melanogenesis, [ 553 ] albinism‐associated single nucleotide polymorphisms reported in oculocutaneous albinism, [ 554–557 ] identification of potential inhibitors against Rab38 and melanoma cancer [ 558 ] ), proteomics (protein conformations and interactions (e.g., melanin‐concentrating hormone; [ 559–564 ] melanin‐concentrating hormone receptors [ 563,565–567 ] and their antagonists; [ 563,566,568–570 ] structure–function relationships of tyrosinase mutants, [ 571–574 ] substances that inhibit tyrosinase activity; [ 550,575–599 ] the role of melanocortin 1 Receptor (MC1R) in skin tanning with potential to resolve pigmentary disorders, [ 600 ] physiology, [ 601–605 ] and pathology. [ 94,606–608 ] Such studies can offer insight into intermolecular interactions with melanins, [ 609–611 ] drug pharmacokinetics, [ 94,612–614 ] and antibody targeting for anticancer treatments.…”

Biological Evaluation and Synthesis of Thiazole Schiff Base Derivatives

“…1,2 Tyrosinase is a key enzyme for melanin pigment biosynthesis, it can catalyze two different reactions, including the conversion of monophenols to o-diphenols (monophenolase) and the conversion of o-diphenols to o-quinones (diphenolase). 3,4 Tyrosinase plays an important role in the formation of melanin in bacteria, fungi, plants and animals. Normal melanin production cannot only protect human skin from ultraviolet rays, but also reduce the damage of many toxic and harmful substances.…”