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Understanding the enzymatic inhibition of intestinal alkaline phosphatase by aminophenazone-derived aryl thioureas with aided computational molecular dynamics simulations: synthesis, characterization, SAR and kinetic profiling

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Abstract

The work presented in this paper aims toward the synthesis of aryl thiourea derivatives 4a–l of pyrazole based nonsteroidal anti-inflammatory drug named 4-aminophenazone, as potential inhibitors of intestinal alkaline phosphatase enzyme. The screening of synthesized target compounds 4a–l for unraveling the anti-inflammatory potential against calf intestinal alkaline phosphatase gives rise to lead member 4c possessing IC50 value 0.420 ± 0.012 µM, many folds better than reference standard used (KH2PO4 IC50 = 2.8 ± 0.06 µM and l-phenylalanine IC50 = 100 ± 3.1 µM). SAR for unfolding the active site binding pocket interaction along with the mode of enzyme inhibition based on kinetic studies is carried out which showed non-competitive binding mode. The enzyme inhibition studies were further supplemented by molecular dynamic simulations for predicting the protein behavior against active inhibitors 4c and 4g during docking analysis. The preliminary toxicity of the synthesized compounds was determined by using brine shrimp assay. This work also includes detailed biochemical analysis along with RO5 parameters for all the newly synthesized drug derivatives 4a–l.

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Authors and Affiliations

  1. Department of Chemistry, Quaid-I-Azam University, Islamabad, 45320, Pakistan

    Asma Khurshid & Aamer Saeed

  2. Department of Chemistry, Allama Iqbal Open University, Islamabad, 44000, Pakistan

    Zaman Ashraf

  3. Department of Physiology, University of Sindh, Jamshoro, Pakistan

    Qamar Abbas

  4. Department of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan

    Mubashir Hassan

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  1. Asma Khurshid
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  2. Aamer Saeed
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  4. Qamar Abbas
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Correspondence to Asma Khurshid or Aamer Saeed.

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Khurshid, A., Saeed, A., Ashraf, Z. et al. Understanding the enzymatic inhibition of intestinal alkaline phosphatase by aminophenazone-derived aryl thioureas with aided computational molecular dynamics simulations: synthesis, characterization, SAR and kinetic profiling. Mol Divers 25, 1701–1715 (2021). https://doi.org/10.1007/s11030-020-10136-9

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