02244nas a2200253   4500008004100000245011300041210006900154260000800223300001400231490000700245520136600252100002501618700002801643700002401671700001801695700001901713700002901732700002001761700001601781700001701797700002401814700002101838856013101859       2025                        eng d00aSilicon incorporated tacrine: design, synthesis, and evaluation of biological and pharmacokinetic parameters0 aSilicon incorporated tacrine design synthesis and evaluation of   cJUN  a2603-26140 v163 a<p>
	Tacrine, an orally bioavailable cholinesterase inhibitor, was previously used to treat Alzheimer's disease but was withdrawn due to hepatotoxicity.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 mu M, 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.</p>
1 aKulkarni, Akshay, S.1 aRamana, Sreenivasa, Rao1 aNuthakki, Vijay, K.1 aBhatt, Shipra1 aJamwal, Ashiya1 aNandawadekar, Laxman, D.1 aJotshi, Anshika1 aKumar, Ajay1 aNandi, Utpal1 aBharate, Sandip, B.1 aReddy, Srinivasa  uhttps://library.ncl.res.in/content/silicon-incorporated-tacrine-design-synthesis-and-evaluation-biological-and-pharmacokinetic