ABSTRACT
Developing improved enzyme inhibitors is an effective therapy to counter various diseases. Aiming to build up biologically active templates, a new series of bis-diazoles conjugated with an aryl linker was designed and prepared through a convenient synthetic approach. Synthesized derivatives 6(a-m), having different substitutions at the 2nd position of the imidazole nucleus, depict the scope of present study. These compounds were characterized through spectroscopic methods and further examined for their in vitro enzyme inhibitory potentials against two selected enzymes: α-glucosidase and lipoxygenase (LOX). Overall, this series was found to be effective against α-glucosidase and moderately active against LOX enzyme. Compound 6k was the most potent α-glucosidase inhibitor with IC50 = 54.25 ± 0.67 µM as compared to reference drug acarbose (IC50 = 375.82 ± 1.76 µM). The docked conformation revealed the involvement of substituent's heteroatoms with amino acid residue Gly280 through hydrogen bonding. The most active LOX inhibitor was 6a with IC50 = 41.75 ± 0.04 µM as compared to standard baicalein (IC50 = 22.4 ± 1.3 µM). Docking model of 6a suggested the strong interaction of imidazole's nitrogen with iron atom of the active pocket of enzyme. Other features like lipophilicity, bulkiness of compounds, pi-pi interactions and/or pi-alkyl interactions also affected the inhibiting potentials of all prepared scaffolds.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Hydrocarbons, Aromatic/chemistry , Imidazoles/chemical synthesis , Lipoxygenase/metabolism , Pyrazoles/chemical synthesis , alpha-Glucosidases/metabolism , Amino Acid Sequence , Binding Sites , Enzyme Inhibitors/metabolism , Hydrogen Bonding , Imidazoles/metabolism , Inhibitory Concentration 50 , Molecular Conformation , Molecular Docking Simulation , Protein Binding , Pyrazoles/metabolism , Structure-Activity RelationshipABSTRACT
Herein, condensation of aryl(hetaryl)pyrazole-4-carbaldehydes 1(a-c) with substituted pyrazolones 2(a-d) lead to the corresponding arylidene-pyrazolones 3(a-l) which were tested against α-glucosidase enzyme. The synthesized compounds displayed moderate to good activity. Among these, a coumarin derivative 3k exhibited excellent results (IC50 2.10⯱â¯0.004⯵M) in comparison to clinical drug acarbose (IC50 37.38⯱â¯0.12⯵M). The ligand-protein interactions were identified through docking and stabilizing energy calculations.
