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Molecular docking studies and biological evaluation of isoxazole-carboxamide derivatives as COX inhibitors and antimicrobial agents

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Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are considered one of the most commonly used medications globally. Seventeen isoxazole-containing compounds with various functional groups were evaluated in this work to identify which one was the most potent and which group was most selective toward COX-1 and COX-2 by using an in vitro COX inhibition assay kit. Their cytotoxicity was evaluated on the normal hepatic cell line (LX-2) utilizing the MTS assay. Moreover, these molecules' antibacterial and antifungal activities were evaluated using a microdilution assay against several bacterial and fungal species. In addition, molecular docking studies were conducted to identify the possible binding interactions between these compounds and their biological targets by using the X-ray crystal structure of the human COX enzyme and different proteins of bacterial and fungal strains. At the same time, the QiKProp module was used for ADME-T analysis. The results showed that all evaluated isoxazole derivatives showed moderate to potent activities against COX enzymes. The most potent compound against COX-1 and COX-2 enzymes was A13, with IC50 values of 64 and 13 nM, respectively, and a significant selectivity ratio of 4.63. It was clear that the 3,4-dimethoxy substitution on the first phenyl ring and the Cl atom on the other phenyl pushed the 5-methyl-isoxazole ring toward the secondary binding pocket and created the ideal binding interactions with the COX-2 enzyme in comparison with the other compounds. Compound A8 showed antibacterial and antifungal activities against Pseudomonas aeruginosa, Klebsiella pneumonia, and Candida albicans with MIC values of 2 mg/ml. In fact, this compound showed possible binding interactions with the elastase in P. aeruginosa and KPC-2 carbapenemase in K. pneumonia. Furthermore, for better understanding, molecular dynamics simulations were undertaken to study the change in dynamicity of the protein backbone and ligand after the ligand binds to the protein and to ensure the stability of ligand–protein complexes.

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The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank An-Najah National University's Faculty of Medicine and Health Sciences for their support.

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Authors and Affiliations

  1. Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine

    Mohammed Hawash, Nidal Jaradat, Murad Abualhasan, Yara Joudeh, Zeina Jaber, Majd Sawalmeh & Mohammed Arar

  2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330, Etiler, Ankara, Turkey

    Mohammed T. Qaoud

  3. Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, 00970, Nablus, Palestine

    Abdulraziq Zarour & Ahmed Mousa

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  1. Mohammed Hawash
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Hawash, M., Jaradat, N., Abualhasan, M. et al. Molecular docking studies and biological evaluation of isoxazole-carboxamide derivatives as COX inhibitors and antimicrobial agents. 3 Biotech 12, 342 (2022). https://doi.org/10.1007/s13205-022-03408-8

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