de Freitas Silva M

References (5)

Title : Synthesis and biological evaluation of 4-hydroxy-methylpiperidinyl-N-benzyl-acylarylhydrazone hybrids designed as novel multifunctional drug candidates for Alzheimer's disease - Macedo_2022_Bioorg.Med.Chem_71_116952
Author(s) : Macedo Vaz S , de Freitas Silva M , Dos Reis Rosa Franco G , Jorge RGM , Motta RdSF , Goncalves Castro N , Alvim Guedes I , Dardenne LE , Amaral Alves M , Garrett da Costa R , Beserra Pinheiro G , Germino Veras L , Renata Mortari M , Pruccoli L , Tarozzi A , Viegas C, Jr.
Ref : Bioorganic & Medicinal Chemistry , 71 :116952 , 2022
Abstract : The search for new drug candidates against Alzheimer's disease (AD) remains a complex challenge for medicinal chemists due to its multifactorial pathogenesis and incompletely understood physiopathology. In this context, we have explored the molecular hybridization of pharmacophore structural fragments from known bioactive molecules, aiming to obtain a novel molecular architecture in new chemical entities capable of concomitantly interacting with multiple targets in a so-called multi-target directed ligands (MTDLs) approach. This work describes the synthesis of 4-hydroxymethyl)piperidine-N-benzyl-acyl-hydrazone derivatives 5a-l, designed as novel MTDLs, showing improved multifunctional properties compared to the previously reported parent series of N-benzyl-(3-hydroxy)piperidine-acyl-hydrazone derivatives 4. The new improved derivatives were studied in silico, regarding their mode of interaction with AChE enzyme, and in vitro, for evaluation of their effects on the selective inhibition of cholinesterases, cellular antioxidant, and neuroprotective activities as their cytotoxicity in human neuroblastoma (SH-SY5Y) cells. Overall, compound PQM-181 (5 k) showed the best balanced selective and non-competitive inhibition of AChE (IC(50) = 5.9 microM, SI > 5.1), with an additional antioxidant activity (IC(50) = 7.45 microM) against neuronal t-BOOH-induced oxidative stress and neuroprotective ability against neurotoxicity elicited by both t-BOOH and OAbeta(1-42), and a moderate ability to interfere in Abeta(1-42) aggregates, with low cytotoxicity and good predictive druggability properties, suggesting a multifunctional pharmacological profile suitable for further drug development against AD.
ESTHER : Macedo_2022_Bioorg.Med.Chem_71_116952
PubMedSearch : Macedo_2022_Bioorg.Med.Chem_71_116952
PubMedID: 35930852

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

Title : Design, Synthesis and Biological Evaluation of Novel Triazole N-acylhydrazone Hybrids for Alzheimer's Disease - de Freitas Silva_2020_Molecules_25_
Author(s) : de Freitas Silva M , Tardelli Lima E , Pruccoli L , Castro NG , Guimares MJR , F MRdS , Fonseca Nadur N , de Azevedo LL , Kummerle AE , Guedes IA , Dardenne LE , Gontijo VS , Tarozzi A , Viegas C
Ref : Molecules , 25 : , 2020
Abstract : Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves different pathogenic mechanisms. In this regard, the goal of this study was the design and synthesis of new compounds with multifunctional pharmacological activity by molecular hybridization of structural fragments of curcumin and resveratrol connected by an N-acyl-hydrazone function linked to a 1,4-disubstituted triazole system. Among these hybrid compounds, derivative 3e showed the ability to inhibit acetylcholinesterase activity, the intracellular formation of reactive oxygen species as well as the neurotoxicity elicited by Abeta(42) oligomers in neuronal SH-SY5Y cells. In parallel, compound 3e showed a good profile of safety and ADME parameters. Taken together, these results suggest that 3e could be considered a lead compound for the further development of AD therapeutics.
ESTHER : de Freitas Silva_2020_Molecules_25_
PubMedSearch : de Freitas Silva_2020_Molecules_25_
PubMedID: 32664425

Title : Design, synthesis and pharmacological evaluation of N-benzyl-piperidinyl-aryl-acylhydrazone derivatives as donepezil hybrids: Discovery of novel multi-target anti-alzheimer prototype drug candidates - Dias Viegas_2018_Eur.J.Med.Chem_147_48
Author(s) : Dias Viegas FP , de Freitas Silva M , Divino da Rocha M , Castelli MR , Riquiel MM , Machado RP , Vaz SM , Simoes de Lima LM , Mancini KC , Marques de Oliveira PC , Morais EP , Gontijo VS , da Silva FMR , D'Alincourt da Fonseca Pecanha D , Castro NG , Neves GA , Giusti-Paiva A , Vilela FC , Orlandi L , Camps I , Veloso MP , Leomil Coelho LF , Ionta M , Ferreira-Silva GA , Pereira RM , Dardenne LE , Guedes IA , de Oliveira Carneiro Junior W , Quaglio Bellozi PM , Pinheiro de Oliveira AC , Ferreira FF , Pruccoli L , Tarozzi A , Viegas C, Jr.
Ref : Eur Journal of Medicinal Chemistry , 147 :48 , 2018
Abstract : A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AbetaO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AbetaO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi-target drug prototype candidate for AD treatment.
ESTHER : Dias Viegas_2018_Eur.J.Med.Chem_147_48
PubMedSearch : Dias Viegas_2018_Eur.J.Med.Chem_147_48
PubMedID: 29421570

Title : Donepezil: an important prototype to the design of new drug candidates for Alzheimer's disease - Rodrigues_2014_Mini.Rev.Med.Chem_14_2
Author(s) : Rodrigues Simoes MC , Dias Viegas FP , Moreira MS , Freitas Silva M , Riquiel MM , da Rosa PM , Castelli MR , Dos Santos MH , Soares MG , Viegas C , de Freitas Silva M , Viegas C, Jr.
Ref : Mini Rev Med Chem , 14 :2 , 2014
Abstract : Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder, with a dramatic socioeconomic impact. The progress of AD is characterized by a severe loss in memory and cognition, leading to behavioral changing, depression and death. During the last decades, only a few anticholinergic drugs were launched in the market, mainly acetylcholinesterase inhibitors (AChEIs), with indications for the treatment of initial and moderate stages of AD. The search for new AChEIs, capable to overcome the limitations observed for rivastigmine and tacrine, led Sugimoto and co-workers to the discovery of donepezil. Besides its high potency, donepezil also exhibited high selectivity for AChE and a very low toxicity. In this review, we discuss the main structural and pharmacological attributes that have made donepezil the first choice medicine for AD, and a versatile structural model for the design of novel AChEIs, in spite of multipotent and multitarget-directed ligands. Many recent data from literature transdue great efforts worldwide to produce modifications in the donepezil structure that could result in new bioactive chemical entities with innovative structural pattern. Furthermore, multi-potent ligands have also been designed by molecular hybridization, affording rivastigmine-, tacrine- and huperzine-donepezil potent and selective AChEIs. In a more recent strategy, structural features of donepezil have been used as a model to design multitarget-directed ligands, aiming at the discovery of new effective drug candidates that could exhibit concomitant pharmacological activities as dual or multi- enzymatic inhibitors as genuine innovative therapeutic alternatives for the treatment of AD.
ESTHER : Rodrigues_2014_Mini.Rev.Med.Chem_14_2
PubMedSearch : Rodrigues_2014_Mini.Rev.Med.Chem_14_2
PubMedID: 24251806