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

Abstract

Tyrosinase is a type‐3 copper protein involved in the biosynthesis of melanin pigments; therefore, the inhibition of its enzymatic activity represents a promising strategy for the treatment of hyperpigmentation‐related disorders. To address this point, we previously designed a class of 4‐(4‐fluorobenzyl)piperazin‐1‐yl‐based compounds, which proved to be more active inhibitors against tyrosinase from mushroom Agaricus bisporus than the positive control kojic acid. Herein, we report the synthesis of further series of 4‐(4‐fluorobenzyl)piperazin‐1‐yl analogues bearing a (hetero)aromatic fragment as key feature to improve protein affinity. The newly synthesized compounds were assayed in vitro and proved to be potent inhibitors in the low‐micromolar range. The active 2‐thienyl and 2‐furyl derivatives were selected for further modification to allow their binding mode to be analyzed by docking studies and to give satisfactory safety profiles.

Interaction mechanism of pelargonidin against tyrosinase by multi‐spectroscopy and molecular docking

“…High tyrosinase activity could produce melanin, 3‐6 however, excessive melanin could generally lead to many diseases, such as freckles, malignant melanoma, 7,8 urticaria pigmentosa, 9,10 melasma, age spots 11,12 and parkinson 's disease 13,14 . Thus, inhibition of tyrosinase activity was an effective way to block melanin synthesis 15‐17 . Although several tyrosinase inhibitors, such as kojic acid and arbutin exhibited strong inhibitory activity on tyrosinase, the continuous administration usually caused cytotoxicity 18‐20 .…”

Colla corii asini–derived peptides as tyrosinase inhibitors: identification, inhibitory activity and molecular mechanism

“…It catalyses the ortho‐hydroxylation of L ‐tyrosine to L ‐dopa and then catalyses the oxidation of L ‐dopa to dopaquinone; the latter is converted into melanin via a series of reactions (Song et al ., 2020). Tyrosinase is recognised as the only rate‐limiting enzyme in melanin pigment synthesis; hence, inhibiting the tyrosinase activity is a promising strategy for reducing the synthesis of melanin (Vittorio et al ., 2020).…”

Evaluation of 4‐(4‐Fluorobenzyl)piperazin‐1‐yl]‐Based Compounds as Competitive Tyrosinase Inhibitors Endowed with Antimelanogenic Effects

“…Here, we report the design of a new series of twenty‐six analogs in which the 4‐fluorobenzylpiperazine fragment was maintained as primary building block bearing second key feature that was selected to engage ancillary hydrophobic/hydrophilic interactions with the top region of the catalytic site as suggested by X‐ray and docking studies. [ 14 , 17 , 18 , 19 , 20 ] All new designed and synthesized compounds were preliminary tested for in vitro inhibiting AbTYR thus upgrading our knowledge about structural affinity relationship (SAR) information for this class of compounds. For selected potent inhibitors we also deciphered the mode of inhibition in kinetic assays.…”