Away from Flatness: Unprecedented Nitrogen-Bridged Cyclopenta[a]indene Derivatives as Novel Anti-Alzheimer Multitarget Agents.
Alexander A TitovMaxim S KobzevMarco CattoModesto de CandiaNicola GambacortaNunzio DenoraLeonardo PisaniNicolotti OrazioTatiana N BorisovaAlexey V VarlamovLeonid G VoskressenskyCosimo D AltomarePublished in: ACS chemical neuroscience (2021)
Nature-inspired, bridged polycyclic molecules share low similarity with currently available drugs, containing preferentially planar and/or achiral moieties. This "Escape from Flatland" scenario, aimed at exploring pharmacological properties of atypical molecular scaffolds, finds interest in synthetic routes leading to tridimensional-shaped molecules. Herein we report on the synthesis of N-bridged cyclopenta[a]indene derivatives, achieved through microwave-assisted thermal rearrangement of allene 3-benzazecines with high diastereoselectivity. The biological evaluation disclosed selective inhibition of human acetylcholinesterase or butyrylcholinesterase, depending on the substitution around the molecular core, which was rationalized by means of docking simulations. The most potent BChE inhibitor 31 was effective in neuroprotection from glutamatergic excitotoxicity and displayed low intrinsic cytotoxicity and good brain penetration. Overall, compound 31 and its close congeners 34 and 35 acted as multitarget agents addressing different biological events involved in neurodegeneration, particularly in the progression of Alzheimer's disease.
Keyphrases
- molecular dynamics
- endothelial cells
- cognitive decline
- cerebral ischemia
- molecular dynamics simulations
- induced pluripotent stem cells
- brain injury
- single molecule
- structure activity relationship
- white matter
- pluripotent stem cells
- protein protein
- multiple sclerosis
- mild cognitive impairment
- anti inflammatory
- monte carlo
- blood brain barrier