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Synthesis, computational studies and biological evaluation of new 1-acetyl-3-aryl thiourea derivatives as potent cholinesterase inhibitors

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Abstract

A new series of 1-acetyl-3-aryl thioureas (3f1–15) was synthesized by the reaction of acetyl isothiocyanate with a variety of suitably substituted aromatic anilines. The acetyl isothiocyanate was freshly prepared by reaction of corresonding acid chloride with potassium thiocyanate. The structural confirmation of all compounds was carried out by spectroscopic techniques and in case of 3a by X-ray diffraction study. The newly prepared compounds were subjected to computational studies and evaluated for their cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibition studies. Except 3f9 and 3f15, all the derivatives were found as selective inhibitor of acetylcholinesterase. Compound 3f2 (IC50 ± SEM = 1.99 ± 0.11 µM) was found to be the most potent inhibitor of acetylcholinesterase exhibited ≈11 times greater inhibitory potential than reference inhibitor i.e. neostigmine (IC50 ± SEM = 22.2 ± 3.2 µM). Compound 3f9 was found to be most potent butyrylcholinesterase inhibitor (IC50 ± SEM = 1.33 ± 0.11 µM), exhibiting ≈four times greater selectivity for butyrylcholinesterase over acetylcholinesterase. Molecular docking studies were carried out to determine the binding site interactions of these potent inhibitors with cholinesterases and also supported the experimental observations.

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Acknowledgments

J. Iqbal is thankful to the Organization for the Prohibition of Chemical Weapons (OPCW), The Hague, The Netherlands and Higher Education Commission of Pakistan for the financial support through Project No. 20-3733/NRPU/R&D/14/520 for the financial support.

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Authors and Affiliations

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

    Aamer Saeed, Fayaz Ali Larik & Pervaiz Ali Channar

  2. Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan

    Muhammad Shakil Shah, Shafi Ullah Khan & Jamshed Iqbal

  3. Division of Analytical Chemistry, Institute of Chemical Science, Bahauddin Zakariya University, 60800, Multan, Pakistan

    Muhammad Shakil Shah

  4. Department Chemie, Fakultätfür Naturwissenschaften, Universität Paderborn, Warburgerstrasse 100, 33098, Paderborn, Germany

    Ulrich Flörke

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  1. Aamer Saeed
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  2. Muhammad Shakil Shah
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  3. Fayaz Ali Larik
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  4. Shafi Ullah Khan
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  5. Pervaiz Ali Channar
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  6. Ulrich Flörke
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  7. Jamshed Iqbal
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Correspondence to Aamer Saeed or Jamshed Iqbal.

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Saeed, A., Shakil Shah, M., Ali Larik, F. et al. Synthesis, computational studies and biological evaluation of new 1-acetyl-3-aryl thiourea derivatives as potent cholinesterase inhibitors. Med Chem Res 26, 1635–1646 (2017). https://doi.org/10.1007/s00044-017-1829-6

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  • DOI: https://doi.org/10.1007/s00044-017-1829-6

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