Synthesis, in vitro, and in silico study of novel pyridine based 1,3-diphenylurea derivatives as tyrosinase inhibitors

Tyrosinase inhibitors are studied in the cosmetics and pharmaceutical sectors as tyrosinase enzyme is involved in the biosynthesis and regulation of melanin, hence these inhibitors are beneficial for the management of melanogenesis and hyperpigmentation-related disorders. In the current work, a novel series of diphenyl urea derivatives containing a halo-pyridine moiety (5a-t) was synthesized via a multi-step synthesis. In vitro, tyrosinase inhibitory assay results showed that, except for two compounds, the derivatives were excellent inhibitors of human tyrosinase. The average IC50 value of the inhibitors (15.78 μM) is lower than that of kojic acid (17.3 μM) used as the reference compound, indicating that, on average, these molecules are more potent than the reference. Derivative 5a was identified as the most potent human tyrosinase inhibitor of the series, with an IC50 value of 3.5 ± 1.2  μM, approximately 5 times more potent than kojic acid. To get further insights into the nature of binding site interactions, molecular docking and molecular dynamics simulation studies were carried out. Moreover, the evaluation of in silico ADME properties showed a highly favorable profile for the synthesized compounds. These findings suggested that the further development of this class of compounds could be useful to get potent drug-like compounds that can target hyperpigmentation-related disorders

Molecular docking and glucosidase inhibition studies of novel N-arylthiazole-2-amines and Ethyl 2-[aryl(thiazol-2-yl)amino]acetates

This study describes an efficient synthesis of a series of novel ethyl 2-[aryl(thiazol-2-yl)amino]acetates (4a-l) from N-arylthiazole-2-amines (3a-l). The reaction conditions were optimized and the best results were obtained when ethyl chloroacetate was used as alkylating agent and NaH as base in THF. alpha-glucosidase and beta-glucosidase inhibition activities of N-arylthiazole-2-amines (3a-l) and ethyl 2-[aryl(thiazol-2-yl)amino]acetates (4a-l) were determined, which revealed that most of the compounds showed high percentage inhibition towards the enzymes. Among the synthesized compounds, 4e appeared to have the highest inhibition towards alpha-glucosidase having IC50 value of 150.4 +/- 1.9 mu M which was almost two folds as compared to acarbose (336.9 +/- 9.0 mu M) taken as standard. Molecular docking of the compounds 3g, 3f, 4a, and 4e was also performed which showed their bonding modes to the enzyme's active sites via amino and acetate groups, respectively.- A.F. Khan is thankful to Higher Education Commission, Pakistan for providing funding under NRPU project No. 1690 for this research.info:eu-repo/semantics/publishedVersio