Synthesis, characterization, evaluation of metabolic enzyme inhibitors and in silico studies of thymol based 2-amino thiol and sulfonic acid compounds

Eight new aminothiols (4a-g and 5) and three new sulfonic acid derivatives (6a-c) were synthesized, and their structures were characterized. Inhibitory effects of the obtained compounds on carbonic anhydrase I and II isoforms (hCA I and hCA II), butyrylcholinesterase (BChE) and acetylcholinesterase (AChE), enzymes were investigated. The newly synthesized compounds have inhibited hCA I with Kis ranging from 7.11 +/- 1.46 nM (6a) to 670.52 +/- 300.41 nM (4b) and, hCA II with Kis ranging from 16.83 +/- 5.72 nM (6a) to 453.34 +/- 208.56 nM (4c). Acetazolamide was employed as the positive control for both hCA isoforms (K-i for hCA I 198.81 +/- 14.13 nM and K-i for hCA II 211.42 +/- 13.10 nM), and among the new compounds obtained, it was observed that there were compounds that were active at much lower nM levels. All compounds were also evaluated for inhibition of AChE and BChE. They inhibited AChE and BChE enzymes in the range of Ki 5.24 +/- 2.27 (6c) -48.44 +/- 21.82 (4g) for AChE and 4.86 +/- 0.64 (6c) -51.75 +/- 12.56 (4a) for BChE, and the results were compared with the standard inhibitor Tacrine (K-i: 14.20 +/- 8.83 nM toward AChE and K-i: 3.39 +/- 1.91 nM for BChE). Cholinesterase (BChE and AChE) inhibitory abilities of all synthesized molecules were also performed in situ and molecular docking and molecular dynamics (MD) simulation studies. The molecular coupling scores of the compounds and the free binding energies calculated by MM/GBSA were found to be compatible. Examining the results obtained from this study shows that it may have the potential to develop new drugs to treat some global patients such as glaucoma and Alzheimer's disease (AD).