Synthesis, characterization, and computational study of novel carvacrol-based 2-aminothiol and sulfonic acid derivatives as metabolic enzyme inhibitors

Eight new 2-aminothiols (69-96%) and three new sulfonic acids (51-76%) were synthesized and characterized by NMR and HRMS spectra. This study presents the inhibitory effects of a series of novel carvacrol-based 2-aminothiol and sulfonic acid derivatives (3a-f,4a-c) against human carbonic anhydrase I and II isozymes (hCA I and II) acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and alpha-glycosidase. Ki values were calculated as 12.52 +/- 3.61-335.65 +/- 60.56 nM for hCA I, 12.20 +/- 3.59-389.69 +/- 119.41 nM for hCA II, 1.79 +/- 0.56-84.86 +/- 23.34 nM for AChE, 6.57 +/- 2.54-88.05 +/- 21.05 nM for BChE and 14.63 +/- 4.76-116.39 +/- 33.70 nM alpha-glucosidase enzymes. Also, the inhibition effects of novel carvacrol-based 2-aminothiol (3a -h) and sulfonic acid derivatives (4a -c) were compared to standard and clinically used inhibitors of acetazolamide, Tacrine and acarbose, respectively. Molecular modeling studies of novel compounds, docking scores, and free binding energies were calculated. The activity results of the compounds were found to be compatible with the docking scores. Molecular dynamics studies were conducted with the best activity against CA I and CA II compounds, 4b (IC50: 4.76 nM) and 4a (IC50: 4.36 nM), respectively. In Dynamic Simulation studies, it was observed that the compounds remained stable at the active sites of the proteins.