A series of tryptophan-based selective nanomolar butyrylcholinesterase (BChE) inhibitors was designed and synthesized. Compounds were optimized in terms of potency, selectivity, and synthetic accessibility. The crystal structure of the inhibitor 18 in complex with BChE revealed the molecular basis for its low nanomolar inhibition (IC50 = 2.8 nM). The favourable in vitro results enabled a first-in-animal in vivo efficacy and safety trial, which demonstrated a positive impact on fear-motivated and spatial long-term memory retrieval without any concomitant adverse motor effects. Altogether, this research culminated in a handful of new lead compounds with promising potential for symptomatic treatment of patients with Alzheimers disease.
Representative scheme of BCHE structure and an image from PDBsum server
Databases
PDB-Sum
6XTA Previously Class, Architecture, Topology and Homologous superfamily - PDB-Sum server
FSSP
6XTAFold classification based on Structure-Structure alignment of Proteins - FSSP server
