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Synthesis and QSAR of Novel Ketoprofen–Chalcone-Amide Hybrides as Acetylcholinesterase (AChE) Inhibitors for Possible Treatment of Alzheimer Disease

Abstract

A new series of the anti-inflammatory drug ketoprofen derivatives bearing aryl chalcone-amide congeners were synthesized. The structures of the synthesized compounds were identified by the 1H NMR, 13C NMR, and EIMS spectroscopic methods. The inhibitory activity of the synthesized compounds on cholinesterase enzymes was investigated. Biological results revealed that five compounds displayed moderate activities against acetylcholinesterase (AChE) with IC50 values below 10 μM. Among the tested compounds, (BTPhP) was found to be the most potent against AChE (IC50 0.98 ± 0.02 μM), while the chalcone-amide analogues (MeOPh), (HydPh), (FPh), and (ChPh) exhibited moderate activities with IC50 values ranged between 5.19–9.61 μM. Molecular docking study showed that compound (BTPhP) could combine with the active site of acetylcholinesterase by the π–π between the ketoprofen phenyl groups is embedded in a cavity surrounded by two aromatic residues of Tyr334 and Trp279. The present results strongly suggest that the para-position of the D-ring should be a preferred modification site for further structural optimization design. Thus, compound (BTPhP) emerged as a promising lead for the development of new acetylcholinesterase inhibitor agent. The preliminary quantum structure-activity relationship (QSAR) among the newly synthesized congeners was obtained by Genetic Function Approximation (GFA).

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ACKNOWLEDGMENTS

The authors thank Department of Chemistry, University of Basrah for the technical facilities. This paper is dedicated to the soul of Dr. Suha Al-Mosawi who passed away recently.

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Correspondence to N. Al-Masoudi.

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This article does not contain any studies involving human participants performed by any of the authors and does not contain any studies involving animals performed by any of the author.

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Abbreviations: BTPhP, 2-(3-benzoylphenyl)-N-(4-(3-(4-tolyl)acryloyl)phenyl) propanamide; MePPh, 2-(3-benzoylphenyl)-N-(4-(3-(4-methoxyphenyl)acryloyl)phenyl)propanamide; HydPh, 2-(3-benzoylphenyl)-N-(4-(3-(4-hydroxyphenyl)acryloyl)phenyl)propanamide; FPh, 2-(3-benzoylphenyl)-N-(4-(3-(4-fluorophenyl)acryloyl)phenyl)propanamide; ChPh, 2-(3-benzoylphenyl)-N-(4-(3-(4-chlorophenyl)acryloyl)phenyl)propanamide.

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Al-Mosawi, S.K., Al-Hazam, H.A., Abbas, A.F. et al. Synthesis and QSAR of Novel Ketoprofen–Chalcone-Amide Hybrides as Acetylcholinesterase (AChE) Inhibitors for Possible Treatment of Alzheimer Disease. Russ J Bioorg Chem 48, 801–808 (2022). https://doi.org/10.1134/S1068162022040045

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  • DOI: https://doi.org/10.1134/S1068162022040045

Keywords:

  • alzheimer disease
  • acetylcholinesterase (AChE) inhibitors
  • chalcones
  • ketoprofen
  • molecular docking study