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.

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.

Design, synthesis, inhibitory activity, and molecular simulations study for d-glucose-conjugated thioureas containing pyrimidine ring as multitarget inhibitors against α-amylase, α-glucosidase, DDP-4, and PTP1B in Type 2 diabetes mellitus.

A series of tetra-O-acetyl-α-d-glucopyranosyl thioureas 8a-l of substituted 2-aminopyrimidines 4a-l have been designed and synthesized. The latter were prepared from corresponding chalcones 3a-l of p-bromoacetophenone and appropriate substituted benzaldehydes by their reaction with guanidine. The target thiourea compounds 8a-l exhibited significant inhibitory activity in vitro against enzymes that were related to type 2 diabetes mellitus, including α-amylase, α-glucosidase, DPP-4, and PTP1B. Amongst these thioureas, compound 8k with an ortho-methoxy group was the most potential enzyme inhibitor against α-amylase with an IC50 value of 9.72 ± 0.34 µM. Its meta-isomer 8j was the strongest inhibitor against α-glucosidase with IC50 = 9.73 ± 0.72 µM. In the inhibition against DPP-4, compound 8f with a para-bromo substituent exhibited the strongest activity with an IC50 value of 2.53 ± 0.03 nM. In the inhibition against PTP1B, compound 8h with a para-isopropyl substituent had the strongest inhibitory activity with an IC50 value of 2.74 ± 0.03 µM. The enzyme kinetics of the most active compounds, including 8j, 8f and 8h against α-glucosidase, DPP-4, and PTP1B, respectively, were studied. The obtained results showed that 8j was a competitive α-glucosidase inhibitor with an inhibitory constant K I value of 9.31 µM. Compound 8f was a non-competitive inhibitor for DDP-4 with an inhibitory constant K I value of 12.57 µM. Compound 8h was also a non-competitive inhibitor for DDP-4 with an inhibitory constant K I value of 12.41 µM. The cytotoxicity of the most active compounds, including 8f and 8k (against α-amylase), 8i and 8j (against α-glucosidase), 8a, 8f, and 8g (against DPP-4), and 8d, 8f, and 8h (against PTP1B) was screened. The obtained cytotoxicity showed that all tested inhibitors were noncytotoxic to human normal cell line 3T3. Induced fit docking simulations of all synthesized compounds 8a-l were performed on four enzymes 4W93 (for α-amylase), 3TOP (for α-glucosidase), 3W2T (for DPP-4), and 1NNY (for PTP1B). Key interactions of each of these ligands with residues in the active pocket of each studied enzyme have been shown.

Synthesis, biological and molecular modelling for 1,3,4-thiadiazole sulfonyl thioureas: bacterial and fungal activity.

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.