Synthesis and biological evaluation of (-)- and (+)-debromoflustramine B and its analogues as selective butyrylcholinesterase inhibitors.
A series of pyrrolidinoindolines have been synthesized as debromoflustramine B (4a) analogues for their evaluation as cholinesterase inhibitors. Structure-activity studies of this series revealed the optimum pharmacophoric elements required for activity and resulted in the discovery of selective butyrylcholinesterase inhibitors with micromolar potency. Biological testing demonstrated that (-)-4a was 7500 times more potent than its enantiomer (+)-4b. The most active inhibitor against BChE in the series was demethyldebromoflustramine B (5a), with an IC50 value of 0.26 microM. X-ray crystallography of 15 and docking studies of selected compounds into human BChE (PDB 1POI) are presented. Molecular modeling studies showed that pi-hydrogen bond, classical hydrogen bond, and cation-pi interactions are critical for optimum potency.
Rivera-Becerril
Ernesto
E
Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado 14-740, México, DF, 07000 México.
Joseph-Nathan
Pedro
P
Pérez-Alvarez
Víctor M
VM
Morales-Ríos
Martha S
MS
D000470:Alkaloids / Q000138:chemical synthesis*; D002091:Butyrylcholinesterase / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis*; D018360:Crystallography, X-Ray; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D007211:Indoles; D011759:Pyrrolidines; C090331:debromoflustramine B; C057812:indoline; D002091:Butyrylcholinesterase; C032519:pyrrolidine