期刊
FUTURE MEDICINAL CHEMISTRY
卷 9, 期 10, 页码 965-981出版社
FUTURE SCI LTD
DOI: 10.4155/fmc-2017-0049
关键词
antiaggregating agents; anticholinesterasic agents; antioxidants; BACE-1 inhibitors; molecular hybridization; multitarget agents
资金
- Ministerio de Economia y Competitividad (MINECO) [SAF2014-57094-R]
- Ramon y Cajal program [RYC-2011-07987]
- Generalitat de Catalunya (GC) [2014SGR52, 2014SGR1189, 2014SGR938]
- Italian Ministry of Education, University and Research - MIUR
- Juan de la Cierva program of MINECO [JCI-2012-12193]
- GC
- Ministerio de Educacion, Cultura y Deporte
- ICREA Academia
Aim: Simultaneous modulation of several key targets of the pathological network of Alzheimer's disease (AD) is being increasingly pursued as a promising option to fill the critical gap of efficacious drugs against this condition. Materials & methods: A short series of compounds purported to hit multiple targets of relevance in AD has been designed, on the basis of their distinct basicities estimated from high-level quantum mechanical computations, synthesized, and subjected to assays of inhibition of cholinesterases, BACE-1, and A beta 42 and tau aggregation, of antioxidant activity, and of brain permeation. Results: Using, as a template, a lead rhein-huprine hybrid with an interesting multitarget profile, we have developed second-generation compounds, designed by the modification of the huprine aromatic ring. Replacement by [1,8]-naphthyridine or thieno[3,2-e] pyridine systems resulted in decreased, although still potent, acetylcholinesterase or BACE-1 inhibitory activities, which are more balanced relative to their A beta 42 and tau antiaggregating and antioxidant activities. Conclusion: Second-generation naphthyridine-and thienopyridine-based rhein-huprine hybrids emerge as interesting brain permeable compounds that hit several crucial pathogenic factors of AD.
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