2. Academic Validation
  3. Design, Synthesis, biological investigations and molecular interactions of triazole linked tacrine glycoconjugates as Acetylcholinesterase inhibitors with reduced hepatotoxicity

Design, Synthesis, biological investigations and molecular interactions of triazole linked tacrine glycoconjugates as Acetylcholinesterase inhibitors with reduced hepatotoxicity

  • Bioorg Chem. 2022 Jan;118:105479. doi: 10.1016/j.bioorg.2021.105479.
Harmandeep Kaur Gulati 1,  Sushil Choudhary 2,  Nitish Kumar 3,  Ajaz Ahmed 4,  Kavita Bhagat 1,  Jatinder Vir Singh 1,  Atamjit Singh 1,  Ajay Kumar 5,  Preet Mohinder Singh Bedi 3,  Harbinder Singh 1,  Debaraj Mukherjee 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
  • 2 PK-PD Toxicology Division, CSIR-IIIM, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR-IIIM), Jammu 180001, India.
  • 3 Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India; Drug and Pollution Testing Laboratory, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
  • 4 Natural Product Chemistry Division, CSIR-IIIM, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR-IIIM), Jammu 180001, India.
  • 5 PK-PD Toxicology Division, CSIR-IIIM, Jammu 180001, India.
  • 6 Natural Product Chemistry Division, CSIR-IIIM, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR-IIIM), Jammu 180001, India. Electronic address: dmukherjee@iiim.ac.in.
PMID: 34801945 DOI: 10.1016/j.bioorg.2021.105479
Abstract

Tacrine is a known Acetylcholinesterase (AChE) inhibitors having hepatotoxicity as main liability associated with it. The present study aims to reduce its hepatotoxicity by synthesizing tacrine linked triazole glycoconjugates via Huisgen's [3 + 2] cycloaddition of anomeric azides and terminal acetylenes derived from tacrine. A series of triazole based glycoconjugates containing both acetylated (A-1 to A-7) and free sugar hydroxyl groups (A-8 to A-14) at the amino position of tacrine were synthesized in good yield taking aid from molecular docking studies and evaluated for their in vitro AChE inhibition activity as well as hepatotoxicity. All the hybrids were found to be non-toxic on HePG2 cell line at 200 μM (100 % cell viability) as compared to tacrine (35 % cell viability) after 24 h of incubation period. Enzyme kinetic studies carried out for one of the potent hybrids in the series A-1 (IC50 0.4 μM) revealed its mixed inhibition approach. Thus, compound A-1 can be used as principle template to further explore the mechanism of action of different targets involved in Alzheimer's disease (AD) which stands as an adequate chemical probe to be launched in an AD drug discovery program.

Keywords

Enzyme Kinetics; Glyco-conjugates; Hepatotoxicity; Molecular docking; Molecular dynamics.

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