4553-21-3Relevant articles and documents
Propionamide Derivatives as Dual μ-Opioid Receptor Agonists and σ1Receptor Antagonists for the Treatment of Pain
García, Mónica,Llorente, Virginia,Garriga, Lourdes,Christmann, Ute,Rodríguez-Escrich, Sergi,Virgili, Marina,Fernández, Bego?a,Bordas, Magda,Ayet, Eva,Burgue?o, Javier,Pujol, Marta,Dordal, Albert,Portillo-Salido, Enrique,Gris, Georgia,Vela, José Miguel,Almansa, Carmen
, p. 10139 - 10154 (2021/07/28)
A new series of propionamide derivatives was developed as dual μ-opioid receptor agonists and σ1receptor antagonists. Modification of a high-throughput screening hit originated a series of piperazinylcycloalkylmethyl propionamides, which were e
Derivatives of tenuazonic acid as potential new multi‐target anti‐alzheimer’s disease agents
Poliseno, Viviana,Chaves, Sílvia,Brunetti, Leonardo,Loiodice, Fulvio,Carrieri, Antonio,Laghezza, Antonio,Tortorella, Paolo,Magalh?es, Jo?o D.,Cardoso, Sandra M.,Santos, M. Amélia,Piemontese, Luca
, p. 1 - 23 (2021/02/05)
Alzheimer’s disease (AD) is generally recognized as a multifactorial neurodegenerative pathology with an increasing impact on society. Tenuazonic acid (TA) is a natural compound that was recently identified as a potential multitarget ligand with anti‐cholinesterase, anti-amyloidogenic and antioxidant activities. Using its structure as a chemical scaffold, we synthesized and evaluated new derivatives (1–5), including tenuazonic‐donepezil (TA‐DNP) hybrids (4 and 5) due to the clinical importance of the anti‐AD drug donepezil. These novel compounds all achieved activity in the micromolar range towards all selected targets and demonstrated to be potentially orally absorbed. Moreover, a selected compound (1) was further investigated as a chelating agent towards copper (II), zinc (II) and iron (III) and showed good chelating ability (pFe = 16.6, pCu = 11.6, pZn = 6.0 at pH 7.4). Therefore, the TA motif can be considered an interesting building block in the search for innovative multi‐functional anti‐neurodegenerative drugs, as exemplified by hybrid 5, a promising non‐cytotoxic lead compound adequate for the early stages of AD, and capable of ameliorating the oxidative status of SH‐SY5Y human neuroblastoma cells.
Design, synthesis, and in vitro evaluation of hydroxybenzimidazole-donepezil analogues as multitarget-directed ligands for the treatment of Alzheimer's disease
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
, (2020/02/28)
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.
