tris‐ Schiff Base Derivatives Containing Flurbiprofen as Potential Tyrosinase Inhibitors: Synthesis, In Vitro Evaluation, Molecular Docking, DFT and Dynamics Simulations

ABSTRACT A novel series of tris ‐Schiff bases of flurbiprofen has been synthesised via multi‐step reactions, structures were deduced by means of HR‐ESI‐MS, 13 C‐ and 1 H‐NMR spectroscopy and screened for their in vitro tyrosinase inhibitory potential. All the synthetic derivatives attributed noteworthy inhibition except compounds (11 , 14 and 16) , while eight compounds ( 5 , 6 , 7 , 8 , 19 , 24 , 22 and 18 ) were found potent comparing them with the standard kojic acid. Furthermore, the remaining nine compounds showed good to less inhibitory activity. A para‐nitro containing compound 5 attributed the powerful tyrosinase inhibition through docking and normal mode analysis (NMA). It formed stable electrostatic interactions and hydrogen bonds that decline catalytic flexibility, as well as stabilising the enzyme in an inactive site. NMA showed disrupted strong intra‐domain coupling and global motions, signifying a broad stabilisation of the enzyme structure. Compared to kojic acid, compound 5 displayed enhanced binding stability, lower B‐factors and tighter packing. A robust correlation ( R 2 = 0.8754) among the IC 50 values and binding energy authenticated the computational model and its potential for rational inhibitor design.