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Insight into the Crystal Structures and Potential of Two Newly Synthesized Naproxen-Based Hydrazide Derivatives as Potent COX-2 Inhibitors

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Abstract

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are medicines that are widely used to relieve pain, reduce inflammation, and bring down high temperature, literature confirmed that they still have harmful side effects. Most of their side effects are in the digestive system due to the carboxylic group. As naproxen is one of the NSAIDs, in this work, we try to mask the carboxylic group in naproxen with a relatively safe functional group. So, herein, we report the synthesis of new naproxen-based hydrazones derivatives, namely, (E)-N'-1-(4-chlorophenyl)ethylidene)-2-(6-methoxynaphthalen-2-yl)propane hydrazide (4a) and (E)-N'-(4-hydroxybenzylidene)-2-(6-methoxynaphthalen-2-yl)propane hydrazide ethanol solvate (4b). The compounds were confirmed by X-ray diffraction studies. Hirshfeld surface analyses and energy frameworks of 4a and 4b have been carried out and blind molecular docking studies of them to the COX-2 enzyme were undertaken to obtain binding affinities for judging whether the compounds could act as anti-inflammatory agents. The compounds interact with the key residues: Arg120, Val349, Leu352, Tyr355, Val523, Ala527, Ser530, and Leu531 of the active enzyme pocket. Molecular dynamics studies predicted that the complexes of 4a and 4b with COX-2 are structurally stable and no major conformational changes were observed. Confirmation of the docking and simulation data was achieved by a binding free energies analysis that indicated the dominance of van der Waals energy. The compounds are drug-like molecules as they obey all prominent drug-like rules and have acceptable pharmacokinetic profiles. To investigate the relationship between their intrinsic electronic properties and their possible similarities to actual drugs, the gas-phase DFT optimizations and NBO analyses were also performed in this study.

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Authors and Affiliations

  1. Chemistry and Environmental Division, Manchester Metropolitan University, Manchester, M1 5GD, England

    Shaaban K. Mohamed

  2. Chemistry Department, Faculty of Science, Minia University, El-Minia, 61519, Egypt

    Shaaban K. Mohamed

  3. Department of Health and Biological Sciences, Abasyn University, Peshawar, 25000, Pakistan

    Sajjad Ahmad

  4. Department of Chemistry, Kirkuk University, College of Science, Kirkuk, Iraq

    Mustafa R. Albayati

  5. Faculty of Science, Department of Biochemistry, Beni-Suef University, Beni-Suef, Egypt

    Sahar M. I. Elgarhy

  6. Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung, 40241, Taiwan

    Chin-Hung Lai

  7. Department of Medical Education, Chung Shan Medical University Hospital, Taichung, 402, Taiwan

    Chin-Hung Lai

  8. Department of Chemistry, Tulane University, New Orleans, LA, 70118, USA

    Joel T. Mague

  9. Department of Theoretical and Applied Chemistry, South Ural State University, Lenin prospect 76, Chelyabinsk, 454080, Russian Federation

    Youness El Bakri

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Mohamed, S.K., Ahmad, S., Albayati, M.R. et al. Insight into the Crystal Structures and Potential of Two Newly Synthesized Naproxen-Based Hydrazide Derivatives as Potent COX-2 Inhibitors. Appl Biochem Biotechnol 194, 5781–5807 (2022). https://doi.org/10.1007/s12010-022-04077-2

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