2‐Aminothiazole‐Oxadiazole Bearing N‐Arylated Butanamides: Convergent Synthesis, Tyrosinase Inhibition, Kinetics, Structure‐Activity Relationship, and Binding Conformations

Abstract

A multi-step synthesis of novel bi-heterocyclic N-arylated butanamides was consummated through a convergent strategy and the structures of these medicinal scaffolds, 7a-h, were corroborated using spectral techniques. The in vitro analysis of these hybrid molecules revealed their potent tyrosinase inhibition as compared to the standard used. The kinetics mechanism was investigated through Lineweaver-Burk plots which exposed that, 7f, inhibited tyrosinase enzyme non-competitively by forming the enzyme-inhibitor complex. The inhibition constants K i calculated from Dixon plots for this compound was 0.025 μM. Their binding conformations were ascertained by in silico computational studies whereby these molecules disclosed good binding energy values (kcal/mol). So, it was anticipated from the current research that these bi-heterocyclic butanamides might be probed as imperative therapeutic agents for melanogenesis.

Design of potent tyrosinase inhibiting N-arylated-4-yl-benzamides bearing 2-aminothiazole-triazole bi-heterocycles: mechanistic insight through enzyme inhibition, kinetics and computational studies

“…A series of experiments were performed to determine the inhibition kinetics of 9c by following the already reported methods. 41,42 The inhibitor concentrations for 9c were 0.00, 0.004, 0.008, 0.016 and 0.032 μM. Substrate l -DOPA concentrations were between 0.125 and 2 mM in all kinetic studies.…”

Heterocyclic Compounds as Synthetic Tyrosinase Inhibitors: Recent Advances

“…Dockin studies revealed good interactions with the main amino acids of the catalytic pocket. A new class of 2-aminothiazole-oxadiazole bi-heterocyclic hybrids characterized by a butanamide moiety was reported by Kim and co-workers as TYRIs [58]. The synthesized compounds (46, Figure 27) showed IC 50 values in the range of 0.031-1.61 µM: lower in comparison to the standard, kojic acid (5, IC 50 = 16.83 µM).…”

Design, synthesis, in vitro, and in silico evaluations of kojic acid derivatives linked to amino pyridine moiety as potent tyrosinase inhibitors

“…Tyrosinase inhibitors are now commercially available from natural or synthetic sources [ 6 ]. Various potent tyrosinase inhibitors have recently been developed, including chalcone [ 7 ], thiazole-oxadiazol [ 8 ], benzylidenethiazol [ 9 ], thioquinoline [ 10 ], tetralone [ 11 ], benzothiazepine [ 12 ], 2-phenylchromone [ 13 , 14 ], flavone-based hydrazone [ 15 ], 2-arylchromone-4-thione [ 16 ], and aurone [ 17 ] ( Fig. 1 ).…”