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

Abstract

This study is aimed to synthesize morpholine- and thiazolidine-based novel 5-(substituted)benzylidene)-2-(morpholinoimino)-3-phenylthiazolidin-4-ones (<b>3</b>-<b>26</b>) 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 <b>11</b> was found to be the most active antioxidant. In anticholinesterase inhibition, compound <b>12</b> (IC₅₀: 17.41 ± 0.22 μM) was the most active against AChE, while compounds <b>3</b>-<b>26</b> ( except <b>3</b>, <b>8</b>, and <b>17</b>) showed notable activity against BChE. Compounds <b>17</b> (IC₅₀: 3.22 ± 0.70 mM), <b>15</b> (IC₅₀: 5.19 ± 0.03 mM), <b>24</b> (IC₅₀: 7.21 ± 0.27 mM), <b>23</b> (IC₅₀: 8.05 ± 0.11 mM), <b>14</b> (IC₅₀: 8.10 ± 0.22 mM), <b>25</b> (IC₅₀: 8.40 ± 0.64 mM), <b>26</b> (IC₅₀: 8.76 ± 0.90 mM), and <b>22</b> (IC₅₀: 9.13 ± 0.55 mM) produced higher tyrosinase inhibition activity. In urease inhibition activity, compounds <b>20</b> (IC₅₀: 16.79 ± 0.19 μM), <b>19</b> (IC₅₀: 18.25 ± 0.50 μM), <b>18</b> (IC₅₀: 20.24 ± 0.77 μM), <b>26</b> (IC₅₀: 21.51 ± 0.44 μM), <b>25</b> (IC₅₀: 21.70 ± 0.06 μM), and <b>24</b> (IC₅₀: 22.49 ± 0.11 μM) demonstrated excellent activities. Besides, the molecular docking study was applied to better understand the inhibitory mechanism between (<b>1-26</b>) 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 <b>26</b>, 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.