Sulfonyl thioureas with a benzo[d]thiazole ring as dual acetylcholinesterase/butyrylcholinesterase and human monoamine oxidase A and B inhibitors: An in vitro and in silico study

Abstract A series of sulfonyl thioureas 6a–q containing a benzo[ d ]thiazole ring with an ester functional group was synthesized from corresponding substituted 2‐aminobenzo[ d ]thiazoles 3a–q and p ‐toluenesulfonyl isothiocyanate. They had remarkable inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidase (MAO)‐A, and MAO‐B. Among thioureas, several compounds had notable activity in the order of 6k > 6 h > 6c (AChE), 6j > 6g > 6k (BChE), 6k > 6g > 6f (MAO‐A), and 6i > 6k > 6h (MAO‐B). Compound 6k was an inhibitor of interest due to its potent or good activity against all studied enzymes, with IC 50 values of 0.027 ± 0.008 μM (AChE), 0.043 ± 0.004 μM (BChE), 0.353 ± 0.01 μM (MAO‐A), and 0.716 ± 0.02 μM (MAO‐B). This inhibitory capacity was comparable to that of the reference drugs for each enzyme. Kinetic studies of two compounds with potential activity, 6k (against AChE) and 6j (against BChE), had shown that both 6k and 6j followed competitive‐type enzyme inhibition, with K i constants of 24.49 and 12.16 nM, respectively. Induced fit docking studies for enzymes 4EY7, 7BO4, 2BXR, and 2BYB showed active interactions between sulfonyl thioureas of benzo[ d ]thiazoles and the residues in the active pocket with ligands 6k, 6i , and 6j , respectively. The stability of the ligand–protein complexes while each ligand entered the active site of each enzyme (4EY7, 7BO4, 2BXR, or 2BYB) was confirmed by molecular dynamics simulations.