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Design, Synthesis, Molecular Docking, Drug-Likeness/ADMET and Molecular Dynamics Studies of Thiazolyl Benzenesulfonamide Carboxylates as Antimalarial Agents

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Abstract

In this work, nine novel thiazole derivatives of substituted benzenesulfonamide carboxylate were designed, synthesized and characterized (1H NMR, 13C NMR and Mass Spectra) for their possible development as antimalarial agents. All synthesized compounds were subjected to molecular docking, drug-likeness, ADMET properties and molecular dynamics studies by in silico methods using Biovia Discovery Studio (DS) 2020 software. The molecular docking study of all the synthesized compounds was carried out against Plasmodium falciparum cysteine protease falcipain 2 (FP-2, 3BPF) and falcipain 3 (FP-3, 3BPM) enzymes using the CDocker program of DS. Further, the best docked compound was studied by molecular dynamics simulation method followed by MM-PBSA calculation. In molecular docking studies, the synthesized thiazolyl benzenesulfonamides exhibited remarkable binding affinity against FP-2 and FP-3 enzymes. Molecular dynamics studies further confirmed the antimalarial potential of the compounds with the formation of well-defined and stable receptor-ligand interactions against both the falcipain enzymes. One derivative, ethyl 4-methyl-2-(4-methyl-2-(4-methylphenylsulfonamido)pentanamido) thiazole-5-carboxylate possesses promising inhibitory potential against both P. falciparum falcipain 2 and falcipain 3 enzymes. Based upon present findings, the thiazolyl benzenesulfonamide-5-carboxylates can be further evaluated for in vitro and in vivo antimalarial effectiveness towards possible development as antimalarial lead molecules and/ or potent antimalarial drug candidates.

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Acknowledgements

Dr. James Anayochukwu Ezugwu expresses his sincere gratitude to The World Academy of Sciences (TWAS) and the Council for Science and Industrial Research (CSIR), New Delhi for the joint sponsorship of the experimental work at CSIR-India Institute of Chemical Technology, Hyderabad, Telangana, India under the 2017 CSIR-TWAS Postgraduate Fellowship Award (Grant/Award number: 22/FF/CSIR‐TWAS/2017).

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Authors and Affiliations

  1. Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka, 410001, Enugu State, Nigeria

    James A. Ezugwu, Uchechukwu C. Okoro, Mercy. A. Ezeokonkwo, David. I. Ugwu, Florence U. Eze, Leonard E. Onyeyilim & Solomon I. Attah

  2. Organic Synthesis and Process Chemistry Division, CSIR-India Institute of Chemical Technology, Hyderabad, Telangana, 500007, India

    James A. Ezugwu & Kurma S. Hariprasad

  3. Department of Pharmaceutical Sciences, School of Biotechnology and Pharmaceutical Sciences, Vignan’s Foundation for Science, Technology & Research (Deemed to be University), Guntur, Andhra Pradesh, 522213, India

    Mithun Rudrapal

  4. Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, 786004, India

    Neelutpal Gogoi & Dipak Chetia

  5. Natural Science Unit, School of General Studies, University of Nigeria, Nsukka, 410001, Enugu State, Nigeria

    Cosmas C. Eze

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  1. James A. Ezugwu
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Correspondence to James A. Ezugwu, Uchechukwu C. Okoro or Mithun Rudrapal.

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Ezugwu, J.A., Okoro, U.C., Ezeokonkwo, M.A. et al. Design, Synthesis, Molecular Docking, Drug-Likeness/ADMET and Molecular Dynamics Studies of Thiazolyl Benzenesulfonamide Carboxylates as Antimalarial Agents. Chemistry Africa (2024). https://doi.org/10.1007/s42250-024-00904-7

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