Design, Synthesis, Pharmacological Activities, Structure-Activity Relationship, and In Silico Studies of Novel 5-Substituted-2-(morpholinoimino)-thiazolidin-4-ones.

This study is aimed to synthesize morpholine- and thiazolidine-based novel 5-(substituted)benzylidene)-2-(morpholinoimino)-3-phenylthiazolidin-4-ones ( 3 - 26 ) and characterized by molecular spectroscopy. The synthesized compounds were subjected to antioxidant activity with anticholinesterase, tyrosinase, and urease inhibition activities and evaluated the structure-activity relationship (SAR) of enzyme inhibition activities. Compound 11 was found to be the most active antioxidant. In anticholinesterase inhibition, compound 12 (IC 50 : 17.41 ± 0.22 μM) was the most active against AChE, while compounds 3 - 26 ( except 3 , 8 , and 17 ) showed notable activity against BChE. Compounds 17 (IC 50 : 3.22 ± 0.70 mM), 15 (IC 50 : 5.19 ± 0.03 mM), 24 (IC 50 : 7.21 ± 0.27 mM), 23 (IC 50 : 8.05 ± 0.11 mM), 14 (IC 50 : 8.10 ± 0.22 mM), 25 (IC 50 : 8.40 ± 0.64 mM), 26 (IC 50 : 8.76 ± 0.90 mM), and 22 (IC 50 : 9.13 ± 0.55 mM) produced higher tyrosinase inhibition activity. In urease inhibition activity, compounds 20 (IC 50 : 16.79 ± 0.19 μM), 19 (IC 50 : 18.25 ± 0.50 μM), 18 (IC 50 : 20.24 ± 0.77 μM), 26 (IC 50 : 21.51 ± 0.44 μM), 25 (IC 50 : 21.70 ± 0.06 μM), and 24 (IC 50 : 22.49 ± 0.11 μM) demonstrated excellent activities. Besides, the molecular docking study was applied to better understand the inhibitory mechanism between ( 1-26 ) compounds and enzymes at the molecular level. According to the results of this study, the synthesized compounds exhibited a better binding affinity toward these enzymes compared to the positive control. Further, molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) binding free energy and molecular dynamics (MD) simulation analyses were performed for AChE with compound 26 , which showed high inhibitory activity in silico and in vitro studies. In conclusion, novel morpholine and thiazolidine-based derivative compounds may be pharmacologically effective agents for AChE, BChE, tyrosinase, and urease enzymes.