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 IC50 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 Ki 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.
Subject(s)
Acetylcholinesterase , Butyrylcholinesterase , Cholinesterase Inhibitors , Molecular Docking Simulation , Monoamine Oxidase Inhibitors , Monoamine Oxidase , Humans , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase/metabolism , Acetylcholinesterase/metabolism , Butyrylcholinesterase/metabolism , Structure-Activity Relationship , Molecular Structure , Thiourea/pharmacology , Thiourea/chemistry , Thiourea/chemical synthesis , Dose-Response Relationship, Drug , Benzothiazoles/pharmacology , Benzothiazoles/chemistry , Benzothiazoles/chemical synthesis , Thiazoles/pharmacology , Thiazoles/chemistry , Thiazoles/chemical synthesisABSTRACT
Some substituted thioureas (6a-i) containing a 1,3,4-thiadiazole ring were synthesized by the reaction of the corresponding substituted 2-amino-1,3,4-thiadiazoles 3a-i with p-toluenesulfonyl isocyanate in a one-pot procedure. The antibacterial and antifungal activities of these sulfonyl thioureas were estimated using a minimum inhibitory concentration protocol. Almost all the thioureas exhibited remarkable antimicrobial activity. Amongst the studied compounds, thioureas 6a, 6c, 6h, and 6i were better inhibitors against the bacterium S. aureus, with MIC values of 0.78-3.125 µg mL-1. These compounds were also tested for their inhibition against S. aureus enzymes, including enzymes of DNA gyrase, DNA topoisomerase IV (Topo IV), and dihydrofolate reductase. Amongst the compounds, 6h was a strong inhibitor, with IC50 values of 1.22, 53.78, and 0.23, respectively. Induced fit docking calculations were performed to observe the binding efficiency and steric interactions of these compounds. The obtained results showed that compound 6h was compatible with the active sites of S. aureus DNA gyrase 2XCS. This ligand interacted with residues ASP1083 (chain D), MET1121 (chain B), ARG1122 (chain D), and also with HOH2035, HOH2089, HOH2110, HOH2162. Molecular dynamics simulation in a water solvent system showed that the active interactions with residues ASP083 and MET1121 (chain B), along with ASP1083, MET1121, and ARG1122 (chain D), played an important role in stabilizing complex 6h/2XCS in the active pocket.
