Silicon incorporated tacrine: design, synthesis, and evaluation of biological and pharmacokinetic parameters

  • RSC Med Chem. 2025 Mar 7;16(6):2603-2614. doi: 10.1039/d5md00019j.
Akshay S Kulkarni  1  2 ,  Sreenivasa Rao Ramana  1 ,  Vijay K Nuthakki  2  3 ,  Shipra Bhatt  2  4 ,  Ashiya Jamwal  2  4 ,  Laxman D Nandawadekar  2  5 ,  Anshika Jotshi  2  4 ,  Ajay Kumar  2  4 ,  Utpal Nandi  2  4  6 ,  Sandip B Bharate  2  3  7 ,  D Srinivasa Reddy  1  2  3  5
Affiliations
  • 1. Organic Chemistry Division, CSIR-National Chemical Laboratory Dr. Homi Bhabha Road Pune 411008 India.
  • 2. Academy of Scientific and Innovative Research (AcSIR) Ghaziabad 201002 India.
  • 3. Natural Products & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine Canal Road Jammu 180001 India.
  • 4. Pharmacology Division, CSIR-Indian Institute of Integrative Medicine Canal Road Jammu 180001 India.
  • 5. Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology Tarnaka Hyderabad-500007 India [email protected].
  • 6. Bose Institute Unified Academic Campus Kolkata 700091 India [email protected].
  • 7. Department of Natural Products & Medicinal Chemistry, CSIR-Indian Institute of Chemical Technology Tarnaka Hyderabad-500007 India [email protected].
PMID: 40177641 DOI: 10.1039/d5md00019j
Abstract

Tacrine, an orally bioavailable cholinesterase inhibitor, was previously used to treat Alzheimer's Disease but was withdrawn due to Hepatotoxicity. The unique structural features of tacrine have once again captured the interest of medicinal chemists. However, the blood-brain barrier (BBB) permeability hampered the development of the majority of its new analogs. Herein, we employed a silicon switch approach for improving the BBB permeability of CNS drugs with tacrine as a tool compound. The replacement of C2 methylene of tacrine with dimethyl silicon yielded 'sila-tacrine' that inhibits acetylcholinesterase as well as butyrylcholinesterase with IC50 values of 3.18 and 6.09 μM, respectively. Sila-tacrine competitively inhibits acetylcholinesterase while it is a non-competitive inhibitor of butyrylcholinesterase. The molecular docking results corroborated with the in vitro cholinesterase inhibition activity of tacrine vs. sila-tacrine. Sila-tacrine demonstrated metabolic stability in HLM and MLM and exhibited superior plasma exposure in an oral pharmacokinetic study in Swiss albino mice. However, tissue distribution studies revealed lower-than-expected brain levels due to efflux pump-mediated transport. This study offers a proof-of-concept for the silicon switch approach in improving the BBB permeability of CNS-active compounds.

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