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 (-) 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 was found to be the most active antioxidant. In anticholinesterase inhibition, compound (IC: 17.41 ± 0.22 μM) was the most active against AChE, while compounds - ( except , , and ) showed notable activity against BChE. Compounds (IC: 3.22 ± 0.70 mM), (IC: 5.19 ± 0.03 mM), (IC: 7.21 ± 0.27 mM), (IC: 8.05 ± 0.11 mM), (IC: 8.10 ± 0.22 mM), (IC: 8.40 ± 0.64 mM), (IC: 8.76 ± 0.90 mM), and (IC: 9.13 ± 0.55 mM) produced higher tyrosinase inhibition activity. In urease inhibition activity, compounds (IC: 16.79 ± 0.19 μM), (IC: 18.25 ± 0.50 μM), (IC: 20.24 ± 0.77 μM), (IC: 21.51 ± 0.44 μM), (IC: 21.70 ± 0.06 μM), and (IC: 22.49 ± 0.11 μM) demonstrated excellent activities. Besides, the molecular docking study was applied to better understand the inhibitory mechanism between () 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 , 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.