20.500.12556/RUL-140000 From tryptophan-based amides to tertiary amines optimization of a butyrylcholinesterase inhibitor series Lead optimization of a series of tryptophan-based nanomolar butyrylcholinesterase (BChE) inhibitors led to tertiary amines as highly potent, achiral, sp$^3$-rich analogues with better synthetic accessibility and high selectivity over acetylcholinesterase (one to ten thousandfold). Taking it one step further, the introduction of a carbamate warhead on the well-explored reversible scaffold allowed conversion to pseudoirreversible inhibitors that bound covalently to BChE and prolonged the duration of inhibition (half-life of 14.8 h for compound 45a-carbamoylated enzyme). Additionally, N-hydroxyindole was discovered as a novel leaving group chemotype. The covalent mechanism of action was confirmed by time-dependency experiments, progress curve analysis, and indirectly by co-crystallization with the human recombinant enzyme. Two crystal structures of BChE-inhibitor complexes were solved and coupled with the supporting molecular dynamics simulations increased our understanding of the structure-activity relationship, while also providing the neccessary structural infromation for future optimization of this series. Overall, this research demonstates the high versatility and potential of this series of BChE inhibitors. cholinesterase inhibitors Alzheimer's disease butyrylcholinesterase carbamate pseudoirreversible inhibition zaviralci holinesteraze butirilholinesteraza karbamat psevdoireverzibilna inhibicija Alzheimerjeva bolezen farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2022-09-09 10:39:16 2022-09-09 10:39:21 2022-10-17 11:29:39 0000-00-00 00:00:00 2022 0 0 39 str. Vol. 234, art. 114248 2022 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54:616.894 0223-5234 10.1016/j.ejmech.2022.114248 100613379 1-s2.0-S0223523422001507-main_(3).pdf 1-s2.0-S0223523422001507-main_(3).pdf 1 F0C505D447C6B4AFA34CF53A546EC73A 64cee07fc3ffb9885a0ed8bc92b32b34c60f3f6c6d9637b1f790532f019ec30e bfb15d22-3025-11ed-92af-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=160666 https://www.sciencedirect.com/science/article/pii/S0223523422001507 1 d8e44db3-301a-11ed-92af-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=160656 Fakulteta za farmacijo Fakulteta za kemijo in kemijsko tehnologijo Medicinska fakulteta 0 0 0