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. 2023 Oct 4;8(41):38641-38657.
doi: 10.1021/acsomega.3c05928. eCollection 2023 Oct 17.

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

Yusuf Sıcak  1 , Bedriye Seda Kurşun Aktar  2 , Gizem Tatar Yılmaz  3 , Fatma Aydoğmuş Öztürk  1 , Mehmet Öztürk  4 , Tuğba Taşkın Tok  5 , Emine Elçin Oruç Emre  5
Affiliations

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

Yusuf Sıcak et al. ACS Omega. .

Abstract

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 (IC50: 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 (IC50: 3.22 ± 0.70 mM), 15 (IC50: 5.19 ± 0.03 mM), 24 (IC50: 7.21 ± 0.27 mM), 23 (IC50: 8.05 ± 0.11 mM), 14 (IC50: 8.10 ± 0.22 mM), 25 (IC50: 8.40 ± 0.64 mM), 26 (IC50: 8.76 ± 0.90 mM), and 22 (IC50: 9.13 ± 0.55 mM) produced higher tyrosinase inhibition activity. In urease inhibition activity, compounds 20 (IC50: 16.79 ± 0.19 μM), 19 (IC50: 18.25 ± 0.50 μM), 18 (IC50: 20.24 ± 0.77 μM), 26 (IC50: 21.51 ± 0.44 μM), 25 (IC50: 21.70 ± 0.06 μM), and 24 (IC50: 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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Synthetic Pathway of 5-Substituted-2-(substitute)imino-thiazolidin-4-one Derivatives (3–26)
Figure 1
Figure 1
COSY spectrum of compound 26.
Figure 2
Figure 2
HSQC spectrum of compound 26.
Figure 3
Figure 3
SAR of thiazolidine-4-one scaffold (3–26) as AChE and BChE inhibitors.
Figure 4
Figure 4
SAR finding of thiazoliodine-4-one scaffold (3–26) as tyrosinase inhibitors.
Figure 5
Figure 5
SAR evaluated as urease inhibitors of thiazoliodine-4-one scaffold (3–26).
Figure 6
Figure 6
2D analysis of the lowest energy binding conformations of AChE, BChE, tyrosinase, and urease and the most effective compound 26.
Figure 7
Figure 7
(A) 3D structure of AChE-compound 26 in the solvation box. (B) 2D analysis of the MD simulation conformations of AChE-compound 26. (C) Radius of gyration (Rg) analysis of in the complex structure during the 100 ns MD simulation time. (D) The RMSD trajectory of protein, compound 26, and complex structures. Red color indicates protein, black color indicates complex (protein and ligand), and green color indicates ligand (compound 26) structures. (E) The RMSF profile of AChE in the complex structures.
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References

    1. Burns J.; Gardner P. T.; Matthews D.; Duthie G. G.; Lean J.; Crozier A. Extraction of phenolics and changes in antioxidant activity of red wines during vilification. J. Agric. Food Chem. 2001, 49, 5797–5808. 10.1021/jf010682p. - DOI - PubMed
    1. Khan I.; Ali S.; Hameed S.; Rama N. H.; Hussain M. T.; Wadood A.; Uddin R.; Ul-Haq Z.; Khan A.; Ali S.; Choudhary M. I. Synthesis, antioxidant activities and urease inhibition of some new 1,2,4-triazole and 1,3,4-thiadiazole derivatives. Eur. J. Med. Chem. 2010, 45, 5200–5207. 10.1016/j.ejmech.2010.08.034. - DOI - PubMed
    1. Cadenas E.; Davies K. J. A. Mitochondrial free radical generation, oxidative stress, and aging. Free Radical Bio. Med. 2000, 29, 222–230. 10.1016/S0891-5849(00)00317-8. - DOI - PubMed
    1. Nijveldt R. J.; van Nood E.; van Hoorn D. E.; Boelens P. G.; van Norren K.; van Leeuwen P. A. Flavonoids: a review of probable mechanisms of action and potential applications. Am. J. Clin. Nutr. 2001, 74, 418–425. 10.1093/ajcn/74.4.418. - DOI - PubMed
    1. Neha K.; Haider M. R.; Pathak A.; Yar M. S. Medicinal prospects of antioxidants: A review. Eur. J. Med. Chem. 2019, 178, 687–704. 10.1016/j.ejmech.2019.06.010. - DOI - PubMed

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