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Synthesis, molecular docking and dynamics study of novel epoxide derivatives of 1,2,4-trioxanes as antimalarial agents

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Abstract

Malaria infection continues to pose a substantial threat to human health in the twenty-first century. The parasites’ resistance against conventional antimalarial drugs creates an emerging demand to develop new and efficient therapeutics against this mosquito-borne infection. Artemisinin, a sesquiterpene lactone, is a potent antimalarial drug found in nature. However, the lack of desirable physicochemical properties actuates researchers to develop new therapeutics based upon this compound. The 1,2,4-trioxane ring system of this natural product was identified as a crucial moiety for exhibiting antimalarial property. A related scientific investigation demonstrates that 1,2,4-trioxane derivatives bind to Plasmodium falciparum dihydrofolate reductase enzymes. The present work reports the synthesis of novel epoxide derivatives of 1,2,4-trioxanes and assesses their receptor binding profile towards Pf-DHFR employing molecular docking and dynamics experiments. The epoxides of 1,2,4-trioxane were synthesized using m-chloroperbenzoic acid and characterized by 1H & 13C NMR spectroscopy and mass spectrometry methods. The Pf-DHFR binding profile of epoxide derivatives of 1,2,4-trioxanes was evaluated utilizing in silico methods like Swiss ADME software. Various parameters calculated from 100 ns atomistic molecular dynamics trajectory, including MM-GBSA binding energy calculation, depict a good binding profile of synthesized compounds against this protein.

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Experimental details and spectral data of all the compounds are available in the attached electronic supplementary information (ESI).

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Acknowledgements

Authors acknowledge Dr. Ravi Kumar Muttineni, Founder & CSO of Immunocure Discovery Solutions Pvt Ltd, Hyderabad, Telangana, India, 500101, for conducting MM/GBSA experiments by providing software facilities in his establishment.

Funding

Ved Prakash Verma thanks the Department of Science and Technology, New Delhi, India, for the research grant. This research work was financially supported by DST-SERB File number: EEQ /2019/000078.

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Authors and Affiliations

  1. Department of Chemistry, Banasthali University, Newai-304022, Rajasthan, India

    Akriti Kumari, Manvika Karnatak & Ved Prakash Verma

  2. BCDA College of Pharmacy & Technology, Hridaypur, Kolkata, West, Bengal-700127, India

    Debanjan Sen

  3. Faculty of Exact Sciences, School of Chemistry, Tel Aviv University, Tel Aviv-6997801, Israel

    Varun Rawat

  4. Department of Chemistry, Prince College Sikar, Rajasthan-332001, Sikar, India

    Shahnawaz Khan

Authors
  1. Akriti Kumari
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  2. Manvika Karnatak
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  3. Debanjan Sen
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  4. Varun Rawat
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Contributions

All authors contributed to the study conception & design. The manuscript was written through contributions of all authors. Akriti Kumari and Manvika Karnatak, conducted experiments related to chemical synthesis, purification, and characterization of organic compounds. Varun Rawat and Ved Prakash Verma conceptualized the synthetic work and contributed in manuscript preparation. Debanjan Sen conducted molecular dynamics simulation and contributed in manuscript preparation. Shahnawaz Khan participated in the interpretation of data.

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Correspondence to Debanjan Sen, Varun Rawat or Ved Prakash Verma.

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Kumari, A., Karnatak, M., Sen, D. et al. Synthesis, molecular docking and dynamics study of novel epoxide derivatives of 1,2,4-trioxanes as antimalarial agents. Struct Chem 33, 907–919 (2022). https://doi.org/10.1007/s11224-022-01885-4

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  • DOI: https://doi.org/10.1007/s11224-022-01885-4

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