In Vitro and In Silico Evaluation of Amylase, Tyrosinase, and Pancreatic Lipase Inhibitions of Novel Benzothiazole‐Sulfonate Derivatives

Abstract

AbstractThis paper provides a comprehensive account of the synthesis and assessment of newly developed aryl sulfonate derivatives based on benzothiazole as enzyme inhibitors, specifically focusing on their ability to target tyrosinase, amylase, and pancreatic lipase. The assessments were performed utilizing experimental (in vitro) and computational (in silico) methodologies. For this aim, nine different aryl sulfonate derivatives were synthesized. The synthesized compounds were subjected to structural characterizations by utilizing Nuclear Magnetic Resonance (1H NMR, 13C NMR) and High‐Resolution Mass Spectrometry (HRMS) studies, which provided confirmation of their structural properties. The inhibitory efficiency of the compounds was determined by measuring their 50 % inhibitory concentration (IC50) values and comparing them with the standard inhibitory compounds. According to the in vitro amylase activity, benzo[d]thiazol‐2‐yl 4‐methylbenzenesulfonate showed the best inhibition with the lowest IC50 value (43.31±4.3 μM) which was calculated to be at a close level to the IC50 value of standard acarbose (38.50±3.8 μM). Also, benzo[d]thiazol‐2‐yl 4‐bromobenzenesulfonate (22.73±4.15 μM) and benzo[d]thiazol‐2‐yl 4‐chlorobenzenesulfonate (25.28±1.95 μM) were calculated to have the lowest IC50 values and the most effective inhibition capacities against pancreatic lipase. Benzo[d]thiazol‐2‐yl 4‐fluorobenzenesulfonate and benzo[d]thiazol‐2‐yl 4‐methylbenzenesulfonate significantly exhibited superior tyrosinase inhibition compared to other derivatives and conventional kojic acid. In silico molecular docking affirmed that benzo[d]thiazol‐2‐yl naphthalene‐2‐sulfonate presented the highest binding affinities to the studied enzymes, with values of −7.8 kcal/mol for tyrosinase, −10.7 kcal/mol for pancreatic lipase, and −9.4 kcal/mol for α‐amylase. The pharmacokinetic characteristics and drug‐likeness of the synthesized sulfonate derivatives were also evaluated using absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction. Density Functional Theory (DFT) calculations were employed at the DFT/B3LYP/6‐311 g(d,p) level of theory to investigate the electronic characteristics of the compounds, therefore facilitating the comprehension of the reported enzyme inhibitory actions. In summary, our research highlights the potential of benzothiazole aryl sulfonate derivatives as effective enzyme inhibitors that hold promise for therapeutic applications.