| Abstract
| - Tacrine heterobivalent ligands were designed as novel and reversible inhibitors of cholinesterases. On the basis of the investigation of the active site gorge topology of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) and by using flexible docking procedures,molecular modeling studies formulated the hypothesis of extra interaction sites in the activegorge of hBuChE, namely, a mid-gorge interaction site and a peripheral interaction site. Thedesign strategy led to novel BuChE inhibitors, balancing potency and selectivity. Among thecompounds identified, the heterobivalent ligand 4m, containing an amide nitrogen and a sulfuratom at the 8-membered tether level, is one of the most potent and selective BuChE inhibitorsdescribed to date. The novel inhibitors, bearing postulated key features, validated the hypothesisof the presence of extra interaction sites within the hBuChE active site gorge.
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