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Design of reversible cholinesterase inhibitors: Fine-tuning of enzymatic activity by PAMAM-calix-dendrimers. | LitMetric

AI Article Synopsis

  • * The study introduces new "fine-tuned" ChE inhibitors called PAMAM-calix-dendrimers, which were designed and synthesized with varying terminal fragments.
  • * Experimental results show that these dendrimers effectively inhibit human acetylcholinesterase and butyrylcholinesterase, with their activity linked to their structure, paving the way for future drug development.

Article Abstract

Reversible cholinesterase (ChE) inhibitors are widely used drugs for the therapy of various cognitive and neurodegenerative disorders. The development of a "universal drug" with easily tunable ChE inhibition activity is a relevant interdisciplinary problem. Here we propose for the first time the design of novel "fine-tuned" ChE inhibitors based on dendrimers with a thiacalix[4]arene core (PAMAM-calix-dendrimers). A series of first-generation PAMAM-calix-dendrimers with different terminal fragments were designed and synthesized. The human acetylcholinesterase and butyrylcholinesterase inhibition by PAMAM-calix-dendrimers was confirmed by molecular docking and in vitro studies. PAMAM-calix-dendrimers were found to have IC values for acetylcholinesterase and butyrylcholinesterase in the range of 0.076-5400 μM. Relationships between the structure of PAMAM-calix-dendrimers and the ChE inhibitory activity were established. The conformation of the macrocyclic core and the nature of the terminal groups were found to exert a direct impact on the inhibitory activity of dendrimers. We anticipate our study to be a starting point for creation of "universal drug" with tunable ChE inhibitory activity to specific therapeutic targets, and more sophisticated in vivo studies of such systems.

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Source
http://dx.doi.org/10.1016/j.ijbiomac.2024.138503DOI Listing

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