de Oliveira MK

References (1)

Title : Design, synthesis, and biological evaluation of new thalidomide-donepezil hybrids as neuroprotective agents targeting cholinesterases and neuroinflammation - Cristancho_2022_RSC.Med.Chem_13_568
Author(s) : Cristancho Ortiz CJ , de Freitas Silva M , Pruccoli L , Fonseca Nadur N , de Azevedo LL , Kummerle AE , Guedes IA , Dardenne LE , Leomil Coelho LF , Guimaraes MJ , da Silva FMR , Castro N , Gontijo VS , Rojas VCT , de Oliveira MK , Vilela FC , Giusti-Paiva A , Barbosa G , Lima LM , Pinheiro GB , Veras LG , Mortari MR , Tarozzi A , Viegas C, Jr.
Ref : RSC Med Chem , 13 :568 , 2022
Abstract : A new series of eight multifunctional thalidomide-donepezil hybrids were synthesized based on the multi-target-directed ligand strategy and evaluated as potential neuroprotective, cholinesterase inhibitors and anti-neuroinflammatory agents against neurodegenerative diseases. A molecular hybridization approach was used for structural design by combining the N-benzylpiperidine pharmacophore of donepezil and the isoindoline-1,3-dione fragment from the thalidomide structure. The most promising compound, PQM-189 (3g), showed good AChE inhibitory activity with an IC(50) value of 3.15 microM, which was predicted by docking studies as interacting with the enzyme in the same orientation observed in the AChE-donepezil complex and a similar profile of interaction. Additionally, compound 3g significantly decreased iNOS and IL-1beta levels by 43% and 39%, respectively, after 24 h of incubation with lipopolysaccharide. In vivo data confirmed the ability of 3g to prevent locomotor impairment and changes in feeding behavior elicited by lipopolysaccharide. Moreover, the PAMPA assay evidenced adequate blood-brain barrier and gastrointestinal tract permeabilities with an Fa value of 69.8%. Altogether, these biological data suggest that compound 3g can treat the inflammatory process and oxidative stress resulting from the overexpression of iNOS and therefore the increase in reactive nitrogen species, and regulate the release of pro-inflammatory cytokines such as IL-1beta. In this regard, compound PQM-189 (3g) was revealed to be a promising neuroprotective and anti-neuroinflammatory agent with an innovative thalidomide-donepezil-based hybrid molecular architecture.
ESTHER : Cristancho_2022_RSC.Med.Chem_13_568
PubMedSearch : Cristancho_2022_RSC.Med.Chem_13_568
PubMedID: 35694691