Viegas C, Jr.

References (12)

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 : 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 : New multifunctional AChE inhibitor drug prototypes protect against Abeta-induced memory deficit - Bellozi_2020_Neurol.Sci_41_451
Author(s) : Bellozi PMQ , Campos AC , Viegas FPD , Silva MF , Machado RP , Vaz SM , Riquiel MM , Carneiro-Junior WO , Lima IVA , Saliba SW , Vaz GN , Viegas C, Jr. , de Oliveira ACP
Ref : Neurol Sci , 41 :451 , 2020
Abstract : Alzheimer's disease (AD) is the most incident neurodegenerative disorder, characterized by accumulation of extracellular amyloid-beta (Abeta), intracellular neurofibrillary tangles, and cognitive impairment. The current available treatments are mainly based on the use of reversible acetylcholinesterase (AChE) inhibitors, which only ameliorate the cognitive deficits. However, it is important to develop disease-modifying drugs with neuroprotective effects in order to hamper the progression of the disease. Here, we describe the effect of four promising new drugs with additional protective characteristics on AD-associated memory changes. C57Bl/6 mice treated with the compounds received an intra-hippocampal injection of Abeta1-40 and were submitted to the novel object recognition test, to evaluate memory recovery. All the compounds prevented memory loss. Compounds PQM-56 (4c) and PQM-67 (4g) showed the best profile of memory recovery, representing potential drug candidates for AD treatment.
ESTHER : Bellozi_2020_Neurol.Sci_41_451
PubMedSearch : Bellozi_2020_Neurol.Sci_41_451
PubMedID: 31506829

Title : PQM130, a Novel Feruloyl-Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer's Disease - Morroni_2019_Front.Pharmacol_10_658
Author(s) : Morroni F , Sita G , Graziosi A , Ravegnini G , Molteni R , Paladini MS , Dias KST , Dos Santos AF , Viegas C, Jr. , Camps I , Pruccoli L , Tarozzi A , Hrelia P
Ref : Front Pharmacol , 10 :658 , 2019
Abstract : Alzheimer's disease (AD) is the most frequent type of dementia in older people. The complex nature of AD calls for the development of multitarget agents addressing key pathogenic processes. Donepezil, an acetylcholinesterase inhibitor, is a first-line acetylcholinesterase inhibitor used for the treatment of AD. Although several studies have demonstrated the symptomatic efficacy of donepezil treatment in AD patients, the possible effects of donepezil on the AD process are not yet known. In this study, a novel feruloyl-donepezil hybrid compound (PQM130) was synthesized and evaluated as a multitarget drug candidate against the neurotoxicity induced by Abeta1-42 oligomer (AbetaO) injection in mice. Interestingly, PQM130 had already shown anti-inflammatory activity in different in vivo models and neuroprotective activity in human neuronal cells. The intracerebroventricular (i.c.v.) injection of AbetaO in mice caused the increase of memory impairment, oxidative stress, neurodegeneration, and neuroinflammation. Instead, PQM130 (0.5-1 mg/kg) treatment after the i.c.v. AbetaO injection reduced oxidative damage and neuroinflammation and induced cell survival and protein synthesis through the modulation of glycogen synthase kinase 3beta (GSK3beta) and extracellular signal-regulated kinases (ERK1/2). Moreover, PQM130 increased brain plasticity and protected mice against the decline in spatial cognition. Even more interesting is that PQM130 modulated different pathways compared to donepezil, and it is much more effective in counteracting AbetaO damage. Therefore, our findings highlighted that PQM130 is a potent multi-functional agent against AD and could act as a promising neuroprotective compound for anti-AD drug development.
ESTHER : Morroni_2019_Front.Pharmacol_10_658
PubMedSearch : Morroni_2019_Front.Pharmacol_10_658
PubMedID: 31244664

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 : Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer's disease - Dias_2017_Eur.J.Med.Chem_130_440
Author(s) : Dias KS , de Paula CT , Dos Santos T , Souza IN , Boni MS , Guimaraes MJ , da Silva FM , Castro NG , Neves GA , Veloso CC , Coelho MM , de Melo IS , Giusti FC , Giusti-Paiva A , da Silva ML , Dardenne LE , Guedes IA , Pruccoli L , Morroni F , Tarozzi A , Viegas C, Jr.
Ref : Eur Journal of Medicinal Chemistry , 130 :440 , 2017
Abstract : A novel series of feruloyl-donepezil hybrid compounds were designed, synthesized and evaluated as multitarget drug candidates for the treatment of Alzheimer's Disease (AD). In vitro results revealed potent acetylcholinesterase (AChE) inhibitory activity for some of these compounds and all of them showed moderate antioxidant properties. Compounds 12a, 12b and 12c were the most potent AChE inhibitors, highlighting 12a with IC50 = 0.46 muM. In addition, these three most promising compounds exhibited significant in vivo anti-inflammatory activity in the mice paw edema, pleurisy and formalin-induced hyperalgesy models, in vitro metal chelator activity for Cu2+ and Fe2+, and neuroprotection of human neuronal cells against oxidative damage. Molecular docking studies corroborated the in vitro inhibitory mode of interaction of these active compounds on AChE. Based on these data, compound 12a was identified as a novel promising drug prototype candidate for the treatment of AD with innovative structural feature and multitarget effects.
ESTHER : Dias_2017_Eur.J.Med.Chem_130_440
PubMedSearch : Dias_2017_Eur.J.Med.Chem_130_440
PubMedID: 28282613

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

Title : Anticholinesterasic, nematostatic and anthelmintic activities of pyridinic and pyrazinic compounds - Valli_2011_Curr.Med.Chem_18_3423
Author(s) : Valli M , Danuello A , Pivatto M , Saldana JC , Heinzen H , Dominguez L , Campos VP , Marqui SR , Young MC , Viegas C, Jr. , Silva DH , Bolzani VS
Ref : Curr Med Chem , 18 :3423 , 2011
Abstract : In the search for acetylcholinesterase inhibitors as a potential target for the discovery of anthelmintic drugs, a series of 27 pyridinic and pyrazinic compounds have been designed on the basis of molecular hybridization of two known AChE inhibitors, namely, tacrine and (-)-3-O-acetylspectaline, and on the concept of isosterism. The synthesized compounds generally presented moderate anticholinesterasic activities when compared with the positive control physostigmine, but one compound (ethyl 2-[(6-chloropyrazin-2-yl)sulfanyl] acetate) exhibited an in vitro ability to immobilize the root-knot nematode Meloidogyne incognita that was highly comparable to that of the positive control Temik. Moreover, in anthelmintic assays against the gastrointestinal parasitic nematode Nippostrongylus brasiliensis (L4), some of the compounds, such as (6-chloropyrazin-2-yl)sulfanyl ethanol (32, EC(5)(0) = 33 nM), presented activities that were considerably stronger than that of the positive control albendazole (EC(5)(0) = 340 nM). In the light of the positive results obtained in the anthelmintic evaluations, the acute oral toxicity of the representative compound diethyl 2,2'-[(3-nitropyridine-2,6-diyl) bissulfanediyl] diacetate was determined in rats, and the drug was shown to be non-toxic at a dose of 2000 mg/kg. These results, allied with the relatively simple structures of the active compounds and their facile synthesis, highlight their potential use as anthelmintic or nematicidic agents.
ESTHER : Valli_2011_Curr.Med.Chem_18_3423
PubMedSearch : Valli_2011_Curr.Med.Chem_18_3423
PubMedID: 21728957

Title : CNS-selective noncompetitive cholinesterase inhibitors derived from the natural piperidine alkaloid (-)-spectaline - Castro_2008_Eur.J.Pharmacol_580_339
Author(s) : Castro NG , Costa RS , Pimentel LS , Danuello A , Romeiro NC , Viegas C, Jr. , Barreiro EJ , Fraga CA , Bolzani VS , Rocha MS
Ref : European Journal of Pharmacology , 580 :339 , 2008
Abstract : LASSBio-767 [(-)-3-O-acetyl-spectaline] and LASSBio-822 [(-)-3-O-tert-Boc-spectaline] were recently described as cholinesterase inhibitors derived from the natural piperidine alkaloid (-)-spectaline, obtained from the flowers of Senna spectabilis (Fabaceae). We investigated their mechanism of inhibition of acetylcholinesterase and their efficacy in reversing scopolamine-induced amnesia. Competition assays with the substrate acetylthiocholine showed a concentration-dependent reduction in rat brain cholinesterase Vmax without changes in apparent Km. The kinetic data for LASSBio-767 and LASSBio-822 were best fit by a model of simple linear noncompetitive inhibition with Ki of 6.1 microM and 7.5 microM, respectively. A dilution assay showed a fast and complete reversal of inhibition, independent of incubation time. Simulated docking of the compounds into the catalytic gorge of Torpedo acetylcholinesterase showed interactions with the peripheral anionic site, but not with the catalytic triad. Anti-amnestic effects in mice were assessed in a step-down passive avoidance test and in the Morris water maze 30 min after injection of scopolamine (1 mg/kg i.p.). Saline, LASSBio-767, or LASSBio-822 was administered 15 min before scopolamine. Both compounds reversed the scopolamine-induced reduction in step-down latency at 0.1 mg/kg i.p. LASSBio-767 reversed scopolamine-induced changes in water maze escape latency at 1 mg/kg i.p. or p.o., while its cholinergic side effects were absent or mild up to 30 mg/kg i.p. (LD50 above 100 mg/kg i.p.). Thus, the (-)-spectaline derivatives are potent cholinergic agents in vivo, with a unique profile combining noncompetitive cholinesterase inhibition and CNS selectivity, with few peripheral side effects.
ESTHER : Castro_2008_Eur.J.Pharmacol_580_339
PubMedSearch : Castro_2008_Eur.J.Pharmacol_580_339
PubMedID: 18096154

Title : New selective acetylcholinesterase inhibitors designed from natural piperidine alkaloids - Viegas_2005_Bioorg.Med.Chem_13_4184
Author(s) : Viegas C, Jr. , Bolzani VS , Pimentel LS , Castro NG , Cabral RF , Costa RS , Floyd C , Rocha MS , Young MC , Barreiro EJ , Fraga CA
Ref : Bioorganic & Medicinal Chemistry , 13 :4184 , 2005
Abstract : Five new piperidine alkaloids were designed from natural (-)-3-O-acetyl-spectaline and (-)-spectaline that were obtained from the flowers of Senna spectabilis (sin. Cassia spectabilis, Leguminosae). Two semi-synthetic analogues (7 and 9) inhibited rat brain acetylcholinesterase, showing IC50 of 7.32 and 15.1 microM, and were 21 and 9.5 times less potent against rat brain butyrylcholinesterase, respectively. Compound 9 (1mg/kg, i.p.) was fully efficacious in reverting scopolamine-induced amnesia in mice. The two active compounds (7 and 9) did not show overt toxic effects at the doses tested in vivo.
ESTHER : Viegas_2005_Bioorg.Med.Chem_13_4184
PubMedSearch : Viegas_2005_Bioorg.Med.Chem_13_4184
PubMedID: 15878668

Title : New anti-Alzheimer drugs from biodiversity: the role of the natural acetylcholinesterase inhibitors - Viegas_2005_Mini.Rev.Med.Chem_5_915
Author(s) : Viegas C, Jr. , Bolzani Vda S , Barreiro EJ , Fraga CA
Ref : Mini Rev Med Chem , 5 :915 , 2005
Abstract : Alzheimer's disease (AD) is a progressive neurodegenerative pathology with severe economic and social impact. There is currently no cure, although cholinesterase inhibitors provide effective temporary relief of symptoms in some patients. Nowadays, drug research and development are based on the cholinergic hypothesis that supports the cognition improvement by regulation of the synthesis and release of acetylcholine in the brain. There are only four commercial medicines approved for treatment of AD, and natural products have played an important alternative role in the research for new acetylcholinesterase inhibitors, as exemplified through the discovery of galantamine. This profile conducts us to give in this paper an overview relating the several classes of natural products with anti-cholinesterasic activity as potential templates to the design of new selective and powerful anti-Alzheimer drugs.
ESTHER : Viegas_2005_Mini.Rev.Med.Chem_5_915
PubMedSearch : Viegas_2005_Mini.Rev.Med.Chem_5_915
PubMedID: 16250834

Title : Further bioactive piperidine alkaloids from the flowers and green fruits of Cassia spectabilis - Viegas_2004_J.Nat.Prod_67_908
Author(s) : Viegas C, Jr. , da SBV , Furlan M , Barreiro EJ , Young MC , Tomazela D , Eberlin MN
Ref : Journal of Natural Products , 67 :908 , 2004
Abstract : The flowers of Cassia spectabilis yielded three new piperidine alkaloids, (-)-3-O-acetylspectaline (1), (-)-7-hydroxyspectaline (2), and iso-6-spectaline (3), together with the known (-)-spectaline (4). The green fruits of this plant were also investigated, resulting in the isolation of 1 and 4. Their structures were elucidated using a combination of multidimensional NMR and MS techniques, and relative stereochemistries were established by NOESY correlations and analysis of coupling constants. The DNA-damaging activity of these compounds was evaluated using a mutant yeast, Saccharomyces cerevisiae, assay.
ESTHER : Viegas_2004_J.Nat.Prod_67_908
PubMedSearch : Viegas_2004_J.Nat.Prod_67_908
PubMedID: 15165164