Nicotinonitriles as potential inhibitors of α-glucosidase, tyrosinase, and urease enzymes: Synthesis, characterization, in vitro, and in silico studies

Abstract

In an effort to develop novel enzyme inhibitors with potent activity and high selectivity, a series of nicotinonitrile derivatives was synthesized. Cyano pyridone intermediates undergo nucleophilic substitution reactions with variously substituted phenacyl halides to yield the nicotinonitriles 1–20. All nicotinonitriles exhibited moderate to excellent in vitro enzyme inhibitory activities against α-glucosidase, tyrosinase, and urease. Compound 1 (IC50 = 27.09 ± 0.12 µM) selectively displayed more significant activity than the standard acarbose (IC50 = 40.00 ± 0.70 µM). Compound 1 also showed good urease inhibition (IC50 = 33.04 ± 0.70 µM); however, it exhibited activity less than the standard acetohydroxamic acid (IC50 = 27.00 ± 0.50 µM).Furthermore, the most effective compound of the series against tyrosinase compared to the standard kojic acid (IC50 = 16.9 ± 1.30 µM) was 16 with an IC50 value of 10.55 ± 0.08 µM. In contrast, this compound showed no activity against α-glucosidase and urease. DFT calculations were carried out to analyze electronic transitions and energy levels (HOMO and LUMO) in nicotinonitrile derivatives, offering insights into their chemical reactivity and stability. Molecular docking studies and molecular electrostatic potential (MEP) revealed the interactions of the active compounds with the amino acid residues at the active sites of the enzymes, thereby shedding light on the mechanism of enzyme inhibition. Therefore, compound 1 can be further studied as a promising α-glucosidase and urease inhibitor, while compound 16 is an effective tyrosinase inhibitor.