Debromofluustramine B (176), a prenylated pyrrolidinoindolinefound in the bryozoan Flustra foliacea. (-)-2 enantiomer (CID 10403152) has the lowest IC50 1.37 muM
Covering: Published between 1974 up to 2018Inhibition of cholinesterases is a common approach for the management of several disease states. Most notably, cholinesterase inhibitors are used to alleviate the symptoms of neurological disorders like dementia and Alzheimer's disease and treat myasthenia gravis and glaucoma. Historically, most drugs of natural origin have been isolated from terrestrial sources and inhibitors of cholinesterases are no exception. However, the last 50 years have seen a rise in the quantity of marine natural products with close to 25 000 reported in the scientific literature. A number of marine natural products with potent cholinesterase inhibitory properties have also been reported; isolated from a variety of marine sources from algae to ascidians. Representing a diverse range of structural classes, these compounds provide inspirational leads that could aid the development of therapeutics. The current paper aims to, for the first time, comprehensively summarize the literature pertaining to cholinesterase inhibitors derived from marine sources, including the first papers published in 1974 up to 2018. The review does not report bioactive extracts, only isolated compounds, and a specific focus lies on compounds with reported dose-response data. In vivo and mechanistic data is included for compounds where this is reported. In total 185 marine cholinesterase inhibitors and selected analogs have been identified and reported and some of the compounds display inhibitory activities comparable or superior to cholinesterase inhibitors in clinical use.
Title: In silico ligand-receptor docking of potentially selective butyrylcholinesterase inhibitors structurally related to the marine natural product debromoflustramine B Mitchell MO, Figliozzi RW, Guzel M Ref: Med Chem, 6:141, 2010 : PubMed
Selective human butyrylcholinesterase (BChE) inhibitors such as cymserine have shown considerable promise for restoring cognition in Alzheimer's disease. Recently, (-)-debromoflustramine B, 1, a hexahydropyrrolo-[2,3-b]indole natural product isolated from the marine bryozoan Flustra foliacea, has demonstrated micromolar potency as a selective BChE inhibitor. Since (+/-)-demethyldebromoflustramine B, (+/-)-2, has an even lower IC(50), and the active enantiomer is (-)-2, derivatives of (-)-2 were constructed in silico and docked into the active site of BChE. Several compounds exhibited improved inhibitor potency and could be candidates for future synthesis and in vitro enzyme inhibition study.
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.
