Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 88, Issue 4, Pages 498-510Publisher
WILEY
DOI: 10.1111/cbdd.12773
Keywords
Alzheimer's disease; cationic imino Diels-Alder reaction; cholinesterase inhibitors; docking and MM-GBSA simulations; N-Allyl; Propargyl tetrahydroquinolines
Funding
- COLCIENCIAS [RC-0908-2012]
- CONICYT-COLCIENCIAS [2012-005]
- Universidad Industrial de Santander (VIE-UIS) [1345]
- University of Talca (through PIEI-Quim-Bio Project)
- CONICYT-Chile
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New N-allyl/propargyl 4-substituted 1,2,3,4-tetrahydroquinolines derivatives were efficiently synthesized using acid-catalyzed three components cationic imino Diels-Alder reaction (70-95%). All compounds were tested in vitro as dual acetylcholinesterase and butyryl-cholinesterase inhibitors and their potential binding modes, and affinity, were predicted by molecular docking and binding free energy calculations (G) respectively. The compound 4af (IC50 = 72 m) presented the most effective inhibition against acetylcholinesterase despite its poor selectivity (SI = 2), while the best inhibitory activity on butyryl-cholinesterase was exhibited by compound 4ae (IC50 = 25.58 m) with considerable selectivity (SI = 0.15). Molecular docking studies indicated that the most active compounds fit in the reported acetylcholinesterase and butyryl-cholinesterase active sites. Moreover, our computational data indicated a high correlation between the calculated G and the experimental activity values in both targets.
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