Synthesis of imidazole-pyrazole conjugates bearing aryl spacer and exploring their enzyme inhibition potentials

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: alpha-glucosidase and lipoxygenase (LOX). Overall, this series was found to be effective against alpha-glucosidase and moderately active against LOX enzyme. Compound 6k was the most potent alpha-glucosidase inhibitor with IC50 = 54.25 +/- 0.67 mu M as compared to reference drug acarbose (IC50 = 375.82 +/- 1.76 mu M). 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 mu M as compared to standard baicalein (IC50 = 22.4 +/- 1.3 mu M). 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.

Automated summary

Developing improved enzyme inhibitors is an effective therapy for various diseases. A new series of bis-diazoles conjugated with an aryl linker were found to be effective against alpha-glucosidase and moderately active against LOX enzyme. The inhibitory potentials of these compounds were influenced by factors such as lipophilicity, bulkiness, and specific interactions with enzyme active pockets.