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Exploring azomethine ylides reactivity with acrolein through cycloaddition reaction and computational antiviral activity assessment against hepatitis C virus

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Abstract

Context

The regioselectivity and diastereoselectivity of the 1,3-dipolar cycloaddition reaction between azomethine ylides and acrolein were investigated. The DFT studies revealed that the favored pathway leads to the formation of cis-cycloadduct pyrrolidine and these computational findings align with experimental observations. The cis-cycloadduct pyrrolidine product serves as an advanced intermediate in the synthesis of a hepatitis C virus inhibitor. For this, the antiviral activity of cis-cycloadduct pyrrolidine against cyclophilin A, the co-factor responsible for hepatitis C virus, was also evaluated through molecular docking simulations which revealed intriguing interactions and a high C-score, which were further confirmed by molecular dynamics simulations, demonstrating stability over a 100-ns simulation period. Furthermore, the cis-cycloadduct pyrrolidine exhibits favorable drug-like properties and a better ADMET profile compared to hepatitis C virus inhibitor.

Methods

Chemical reactivity studies were performed using DFT method by the functional B3LYP at 6-31G (d, p) computational level by GAUSSIAN 16 program. Frontal molecular orbitals theory used to investigate HOMO/LUMO interactions between azomethine ylides and acrolein. Findings of this approach were confirmed by global reactivity indices and electron displacement was investigated based on Fukui functions. Furthermore, the activation energies were determined after frequency calculations using TS Berny algorithm and transition states were confirmed by the presence of a single imaginary frequency. Moreover, antiviral activity of cis-cycloadduct was explored through molecular docking using Surflex-Dock suite SYBYL X 2.0, and molecular dynamics simulation using GROMACS program. Finally, drug-like properties were investigated with SwissADME and ADMETlab 2.0.

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Acknowledgements

The authors express their gratitude to the “Association Marcaine des chimistes théoriciens” (AMCT) for technical support.

Author information

Authors and Affiliations

  1. Molecular Chemistry and Natural Substances Laboratory, Faculty of Sciences, Moulay Ismail University, 50000, Meknes, Morocco

    Oumayma Abdessadak, Kamal Tabti, Abdelouahid Sbai, Mohammed Aziz Ajana, Tahar Lakhlifi & Mohammed Bouachrine

  2. Department of Chemistry, National Institute of Technology, Dehradun, Uttarakhand, 246174, India

    Pankaj Kandwal

  3. Basic Science Department, Prince Al Hussein bin Abdullah II Academy for Civil Protection, Al-Balqa Applied University, Al-Salt, 19117, Jordan

    Marwa Alaqarbeh

  4. EST Khenifra, Sultan Moulay Sliman University, 23000, Beni-Mellal, Morocco

    Mohammed Bouachrine

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  1. Oumayma Abdessadak
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Contributions

Data collection, material preparation, analysis, and writing by “Abdessadak O”; material preparation and analysis of DFT simulation part by “Kandwal P”; material and analysis of MD simulation part by “Alaqarbeh M”; material and analysis by “Tabti K”; data analysis, study justification and supervision by “Sbai A” data analysis, study justification and supervision by “Ajana M A”; supervision and project administration by “Lakhlifi T”; review, study justification and supervision by “Bouachrine M”.

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Correspondence to Mohammed Aziz Ajana.

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Abdessadak, O., Kandwal, P., Alaqarbeh, M. et al. Exploring azomethine ylides reactivity with acrolein through cycloaddition reaction and computational antiviral activity assessment against hepatitis C virus. J Mol Model 30, 23 (2024). https://doi.org/10.1007/s00894-023-05818-8

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