- Design, synthesis, and in vitro evaluation of hydroxybenzimidazole-donepezil analogues as multitarget-directed ligands for the treatment of Alzheimer's disease
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A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzylpiperidine /-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer's disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Aβ-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD.
- Capriati, Vito,Cardoso, Sandra M.,Chaves, Sílvia,Costa, Marina,Gwizdala, Karolina,Josselin, Romane,Pereira-Santos, A. Raquel,Piemontese, Luca,Resta, Simonetta,Rinaldo, Federica,Santos, M. Amélia
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- Synthesis and structure-activity relationships of 4-amino-5-chloro-2- ethoxybenzamides with six- and seven-membered heteroalicycles as potential gastroprokinetic agents
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A new series of 4-amino-5-chloro-2-ethoxybenzamides 3b-f and 5-8 bearing six- and seven-membered heteroalicycles was prepared and evaluated for gastroprokinetic activity. Compounds 3b-e, derived by replacement of the morpholine oxygen of 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2- ethoxybenzamide (3a) with other atoms (sulfur, nitrogen and carbon), generally exhibited a potent gastric emptying activity. N-(4-Benzyl-3- morpholinyl)methylbenzamide (5a) and its analogues 5b-e had weaker activity. However, N-(4-benzyl-3-morpholinyl)ethylbenzamide 8 was as potent as 3a. Benzamides 6a-e, having seven-membered heteroalicycles, showed fairly potent activity. Molecular superimpositions of 5a, 6a and 8 upon 3a using computer graphics suggested that the direction of the N-benzyl group greatly influences the gastric emptying activity, whereas the location of the alicyclic nitrogen is less critical.
- Morie,Kato,Harada,Yoshida,Fujiwara,Matsumoto
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p. 1137 - 1147
(2007/10/02)
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