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  3. Microwave-Assisted Organic Synthesis, structure-activity relationship, kinetics and molecular docking studies of non-cytotoxic benzamide derivatives as selective butyrylcholinesterase inhibitors

Microwave-Assisted Organic Synthesis, structure-activity relationship, kinetics and molecular docking studies of non-cytotoxic benzamide derivatives as selective butyrylcholinesterase inhibitors

  • Bioorg Med Chem. 2019 Sep 15;27(18):4030-4040. doi: 10.1016/j.bmc.2019.07.015.
Sheeba Wajid 1,  Asma Khatoon 1,  Maria Aqeel Khan 1,  Humaira Zafar 2,  Shama Kanwal 1,  Atta-Ur-Rahman 1,  M Iqbal Choudhary 3,  Fatima Z Basha 4
Affiliations

Affiliations

  • 1 H. E. J. Research Institute of Chemistry, International Center for Chemical and Biology Science, University of Karachi, Karachi 75270, Pakistan.
  • 2 Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
  • 3 H. E. J. Research Institute of Chemistry, International Center for Chemical and Biology Science, University of Karachi, Karachi 75270, Pakistan; Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address: iqbal.choudhary@iccs.edu.
  • 4 H. E. J. Research Institute of Chemistry, International Center for Chemical and Biology Science, University of Karachi, Karachi 75270, Pakistan. Electronic address: fatima.basha@iccs.edu.
PMID: 31378596 DOI: 10.1016/j.bmc.2019.07.015
Abstract

A series of benzamide derivatives 1-12 with various functional groups (-H, -Br, -F, -OCH3, -OC2H5, and -NO2) was synthesized using an economic, and facile Microwave-Assisted Organic Synthesis, and evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity in vitro. Structure-activity relationship showed that the substitution of -Br group influenced the inhibitory activity against BChE enzyme. Synthesized compounds were found to be selective inhibitors of BChE. In addition, all compounds 1-12 were found to be non-cytotoxic, as compared to the standard cycloheximide (IC50 = 0.8 ± 0.2 µM). Among them, compound 3 revealed the most potent BChE inhibitory activity (IC50 = 0.8 ± 0.6 µM) when compared with the standard galantamine hydrobromide (IC50 = 40.83 ± 0.37 µM). Enzyme kinetic studies indicated that compounds 1, 3-4, and 7-8 showed a mixed mode of inhibition against BChE, while compounds 2, 5-6 and 9 exhibited an uncompetitive pattern of inhibition. Molecular docking studies further highlighted the interaction of these inhibitors with catalytically important amino acid residues, such as Glu197, Hip438, Phe329, and many Others.

Keywords

Acetylcholinesterase; Alzheimer disease; Benzamides; Butyrylcholinesterase; Enzyme inhibition; Green chemistry; Microwave-Assisted Organic Synthesis.

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