Chemical exploration of 4-(4-fluorobenzyl)piperidine fragment for the development of new tyrosinase inhibitors.
Tyrosinase is involved in the production of melanin through the hydroxylation of monophenols to o-diphenols. The role of this enzyme was extensively studied in order to identify new therapeutics preventing skin pigmentation and melanoma. In this work we initially identified the 3-(4-benzylpiperidin-1-yl)-1-(1H-indol-3-yl)propan-1-one (1a) as promising mushroom tyrosinase inhibitor (IC50= 252 μM). Then, several chemical modifications were performed and new analogues related to compound 1a were synthesized. Biochemical assays demonstrated that several obtained compounds proved to be effective inhibitors showing IC50values lower both than "lead compound" 1a and reference inhibitor kojic acid, as a well-known tyrosinase inhibitor. The inhibition kinetics analyzed by Lineweaver-Burk plots revealed that compounds 2 a-c and 10b act as non-competitive inhibitors while the most active inhibitor 2d (IC50= 7.56 μM) is a mixed-type inhibitor. Furthermore, experimental and computational structural studies were performed in order to clarify the binding mode of the derivative 2d.
Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali (CHIBIOFARAM) Polo Universitario SS. Annunziata, Università di Messina, Viale Annunziata I-98168 Messina, Italy. Electronic address: sferro@unime.it.
Stefania
S
Ferro
Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali (CHIBIOFARAM) Polo Universitario SS. Annunziata, Università di Messina, Viale Annunziata I-98168 Messina, Italy.
Laura
L
De Luca
Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali (CHIBIOFARAM) Polo Universitario SS. Annunziata, Università di Messina, Viale Annunziata I-98168 Messina, Italy.
Maria Paola
MP
Germanò
Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali (CHIBIOFARAM) Polo Universitario SS. Annunziata, Università di Messina, Viale Annunziata I-98168 Messina, Italy.
Maria Rosa
MR
Buemi
Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali (CHIBIOFARAM) Polo Universitario SS. Annunziata, Università di Messina, Viale Annunziata I-98168 Messina, Italy.
Laura
L
Ielo
Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali (CHIBIOFARAM) Polo Universitario SS. Annunziata, Università di Messina, Viale Annunziata I-98168 Messina, Italy; Fondazione Prof. Antonio Imbesi, Piazza Pugliatti 1, 98100 Messina, Italy.
Giovanna
G
Certo
Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, 3200003, Israel.
Margarita
M
Kanteev
Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, 3200003, Israel.
Ayelet
A
Fishman
Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali (CHIBIOFARAM) Polo Universitario SS. Annunziata, Università di Messina, Viale Annunziata I-98168 Messina, Italy.
Antonio
A
Rapisarda
Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali (CHIBIOFARAM) Polo Universitario SS. Annunziata, Università di Messina, Viale Annunziata I-98168 Messina, Italy.
Rosaria
R
Gitto
D000363:Agaricales / Q000201:enzymology; D001667:Binding, Competitive; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008545:Melanoma / Q000188:drug therapy; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D012880:Skin Pigmentation / Q000187:drug effects; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D010880:Piperidines; D014442:Monophenol Monooxygenase
Crystallography; Docking studies; Kinetic mechanism; SARs; Synthesis; Tyrosinase inhibitors