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. 2024 Aug 30;10(17):e37147.
doi: 10.1016/j.heliyon.2024.e37147. eCollection 2024 Sep 15.

Bis-chalcones obtained via one-pot synthesis as the anti-neurodegenerative agents and their effect on the HT-22 cell line

Dorota Olender  1 , Jacek Kujawski  1 , Bartosz Skóra  2 , Ewa Baranowska-Wójcik  3 , Katarzyna Sowa-Kasprzak  1 , Anna Pawełczyk  1 , Lucjusz Zaprutko  1 , Dominik Szwajgier  3 , Konrad A Szychowski  2
Affiliations

Bis-chalcones obtained via one-pot synthesis as the anti-neurodegenerative agents and their effect on the HT-22 cell line

Dorota Olender et al. Heliyon. .

Abstract

In the area of research on neurodegenerative diseases, the current challenge is to search for appropriate research methods that would detect these diseases at the earliest possible stage, but also new active structures that would reduce the rate of the disease progression and minimize the intensity of their symptoms experienced by the patient. The chalcones are considered in the context of candidates for new drugs dedicated to the fight against neurodegenerative diseases. The synthesis of bis-chalcone derivatives (3a-3d), as aim molecules was performed. Their structures were established by applying 1H NMR, 13C NMR, MS, FT-IR and UV-Vis spectra. All bis-chalcones were synthesized from terephthalaldehyde and appropriate aromatic ketone as substrates in the Claisen-Schmidt condensation method and evaluated in the biological tests and in silico analysis. Compounds exerted antioxidant activity using the HORAC method (3a-3d) and decreased the activities of GPx, COX-2 (3b-3d), GR (3a-3c) and CAT (3a,3b). The high anti-neurodegenerative potential of all four bis-chalcones was observed by inhibition of acetyl- (AChE) and butyrylcholinesterase (BChE) and a positive effect on the mouse hippocampal neuronal HT-22 cell line (LDH release and PGC-1α, PPARγ and GAPDH protein expression). TD-DFT method (computing a number of descriptors associated with HOMO-LUMO electron transition: electronegativity, chemical hardness and potential, first ionization potential, electron affinity) was employed to study the spectroscopic properties. This method showed that the first excited state of compounds was consistent with their maximum absorption in the computed UV-Vis spectra, which showed good agreement with the experimental spectrum using PBE1PBE functional. Using in silico approach, interactions of bis-chalcones with selected targets (aryl hydrocarbon receptor (AhR) PAS-A Domain, ligand binding domain of human PPAR-γ, soman-aged human BChE-butyrylthiocholine complex, Torpedo californica AChE:N-piperidinopropyl-galanthamine complex and the COX-2-celecoxib complex) were characterized. Results obtained in in silico models were consistent with in vitro experiments.

Keywords: Anti-neurodegenerative activity; Bis-chalcones; Claisen-Schmidt reaction; Cytotoxicity; Molecular docking.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Naturally-occurring chalcone and its derivatives with biological activity.
Fig. 2
Fig. 2
The compounds bis-chalcone type.
Scheme 1
Scheme 1
Bis-chalcones (3a-d) synthesis path.
Fig. 3
Fig. 3
The structures compounds obtained.
Fig. 4
Fig. 4
Effect of increasing concentrations of tested: 3a (D), 3b (C), 3c (B), and 3d (A) compounds on the level of resazurin reduction after 24 h exposure of HT-22 cells. Data are expressed as mean ± SD of three independent experiments. *p < 0.05, **p < 0.01, and ***p < 0.001 vs. the control cells.
Fig. 5
Fig. 5
Effect of increasing concentrations of the compounds tested: 3a (D), 3b (C), 3c (B), and 3d (A) on LDH release after 24 h exposure of the HT-22 cells. Data are expressed as mean ± SD of three independent experiments. *p < 0.05, **p < 0.01, and ***p < 0.001 vs the control cells.
Fig. 6
Fig. 6
PGC-1α (A), PPARγ (B), IκBα (C), p(S32)-IκBα (D), and GAPDH protein expression of compounds tested after 24 h of exposure 3d and 3a in HT-22 cells. Data are expressed as mean ± SD of three independent experiments. *p < 0.05, **p < 0.01, and ***p < 0.001 vs the control cells.
Fig. 7
Fig. 7
ARNT (A), SOD1 (B), AhR (C), NF-κB (D), and GAPDH protein expression of compounds tested after 24 h of exposure compounds 3d and 3a in HT-22 cells. Data are expressed as mean ± SD of three independent experiments. *p < 0.05, **p < 0.01, and ***p < 0.001 vs the control cells.
Fig. 8
Fig. 8
Orbitals HOMO (A) and LUMO (B) of 3a.
Fig. 9
Fig. 9
Orbitals HOMO (A) and LUMO (B) of 3b.
Fig. 10
Fig. 10
Orbitals HOMO (A) and LUMO (B) of 3c.
Fig. 11
Fig. 11
Orbitals HOMO (A) and LUMO (B) of 3d.
Fig. 12
Fig. 12
Docked ligands: 3a (red), 3b (green), 3c (yellow), 3d (cyan); first poses; protein 3ln1.pdb. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 13
Fig. 13
Docked ligands: 3a (red), 3b (green), 3c (yellow), 3d (cyan); first poses; protein 3i6m.pdb. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 14
Fig. 14
Docked ligands: 3a (red), 3b (green), 3c (yellow), 3d (cyan); first poses; protein 1p0p.pdb. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 15
Fig. 15
Docked ligands: 3a (red), 3b (green), 3c (yellow), 3d (cyan); first poses; protein 4m4x.pdb. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 16
Fig. 16
Docked ligands: 3a (red), 3b (green), 3c (yellow), 3d (cyan); first poses; protein 2ath.pdb. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
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