Resveratrol–Maltol and Resveratrol–Thiophene Hybrids as Cholinesterase Inhibitors and Antioxidants: Synthesis, Biometal Chelating Capability and Crystal Structure

Mlakić, Milena; Fodor, Lajos; Odak, Ilijana; Horváth, Ottó; Lovrić, Marija Jelena; Barić, Danijela; Milašinović, Valentina; Molčanov, Krešimir; Marinić, Željko; Lasić, Zlata; Škorić, Irena

doi:10.3390/molecules27196379

Open AccessArticle

Resveratrol–Maltol and Resveratrol–Thiophene Hybrids as Cholinesterase Inhibitors and Antioxidants: Synthesis, Biometal Chelating Capability and Crystal Structure

by

Milena Mlakić

^1,†,

Lajos Fodor

^2,†

,

Ilijana Odak

^3,*

,

Ottó Horváth

²

,

Marija Jelena Lovrić

⁴,

Danijela Barić

⁴

,

Valentina Milašinović

⁵

,

Krešimir Molčanov

⁵

,

Željko Marinić

⁶,

Zlata Lasić

⁷ and

Irena Škorić

^1,*

¹

Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia

²

Department of General and Inorganic Chemistry, Institute of Chemistry, Faculty of Engineering, University of Pannonia, P.O. Box 158, H-8201 Veszprém, Hungary

³

Department of Chemistry, Faculty of Science and Education, University of Mostar, Matice hrvatske bb, 88000 Mostar, Bosnia and Herzegovina

⁴

Group for Computational Life Sciences, Division of Physical Chemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia

⁵

Division of Physical Chemistry, Rudjer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia

⁶

NMR Center, Rudjer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia

⁷

Teva api Analytical R&D, Pliva, Prilaz Baruna Filipovića 25, HR-10000 Zagreb, Croatia

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Molecules 2022, 27(19), 6379; https://doi.org/10.3390/molecules27196379

Submission received: 2 September 2022 / Revised: 20 September 2022 / Accepted: 21 September 2022 / Published: 27 September 2022

(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)

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Abstract

New resveratrol–thiophene and resveratrol–maltol hybrids were synthesized as cholinesterase inhibitors and antioxidants. As with photostability experiments, biological tests also found remarkable differences in the properties and behavior of thiophene and maltol hybrids. While resveratrol–thiophene hybrids have excellent inhibitory and antioxidant properties (similar to the activity of reference drug galantamine), maltols have been proven to be weaker inhibitors and antioxidants. The molecular docking of selected active ligands gave insight into the structures of docked enzymes. It enabled the identification of interactions between the ligand and the active site of both cholinesterases. The maltols that proved to be active cholinesterase inhibitors were able to coordinate Fe³⁺ ion, forming complexes of 1:1 composition. Their formation constants, determined by spectrophotometry, are very similar, lgK = 11.6–12.6, suggesting that Fe³⁺ binds to the common hydroxy-pyranone moiety and is hardly affected by the other aromatic part of the ligand. Accordingly, the characteristic bands in their individual absorption spectra are uniformly red-shifted relative to those of the free ligands. The crystal structures of two new resveratrol–maltol hybrids were recorded, giving additional information on the molecules’ intermolecular hydrogen bonds and packing. In this way, several functionalities of these new resveratrol hybrids were examined as a necessary approach to finding more effective drugs for complicated neurodegenerative diseases.

Keywords: cholinesterase inhibitory activity; molecular docking; pyran-4-ones; thienostilbenes

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MDPI and ACS Style

Mlakić, M.; Fodor, L.; Odak, I.; Horváth, O.; Lovrić, M.J.; Barić, D.; Milašinović, V.; Molčanov, K.; Marinić, Ž.; Lasić, Z.; et al. Resveratrol–Maltol and Resveratrol–Thiophene Hybrids as Cholinesterase Inhibitors and Antioxidants: Synthesis, Biometal Chelating Capability and Crystal Structure. Molecules 2022, 27, 6379. https://doi.org/10.3390/molecules27196379

AMA Style

Mlakić M, Fodor L, Odak I, Horváth O, Lovrić MJ, Barić D, Milašinović V, Molčanov K, Marinić Ž, Lasić Z, et al. Resveratrol–Maltol and Resveratrol–Thiophene Hybrids as Cholinesterase Inhibitors and Antioxidants: Synthesis, Biometal Chelating Capability and Crystal Structure. Molecules. 2022; 27(19):6379. https://doi.org/10.3390/molecules27196379

Chicago/Turabian Style

Mlakić, Milena, Lajos Fodor, Ilijana Odak, Ottó Horváth, Marija Jelena Lovrić, Danijela Barić, Valentina Milašinović, Krešimir Molčanov, Željko Marinić, Zlata Lasić, and et al. 2022. "Resveratrol–Maltol and Resveratrol–Thiophene Hybrids as Cholinesterase Inhibitors and Antioxidants: Synthesis, Biometal Chelating Capability and Crystal Structure" Molecules 27, no. 19: 6379. https://doi.org/10.3390/molecules27196379

APA Style

Mlakić, M., Fodor, L., Odak, I., Horváth, O., Lovrić, M. J., Barić, D., Milašinović, V., Molčanov, K., Marinić, Ž., Lasić, Z., & Škorić, I. (2022). Resveratrol–Maltol and Resveratrol–Thiophene Hybrids as Cholinesterase Inhibitors and Antioxidants: Synthesis, Biometal Chelating Capability and Crystal Structure. Molecules, 27(19), 6379. https://doi.org/10.3390/molecules27196379

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Resveratrol–Maltol and Resveratrol–Thiophene Hybrids as Cholinesterase Inhibitors and Antioxidants: Synthesis, Biometal Chelating Capability and Crystal Structure

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