RESUMO
Molecular hybridization between structural fragments from the structures of curcumin (1) and resveratrol (2) was used as a designing tool to generate a new N-acyl-cinnamoyl-hydrazone hybrid molecular architecture. Twenty-eight new compounds were synthesized and evaluated for multifunctional activities related to Parkinson's disease (PD), including neuroprotection, antioxidant, metal chelating ability, and Keap1/Nrf2 pathway activation. Compounds 3b (PQM-161) and 3e (PQM-164) were highlighted for their significant antioxidant profile, acting directly as induced free radical stabilizers by DPPH and indirectly by modulating intracellular inhibition of t-BOOH-induced ROS formation in neuronal cells. The mechanism of action was determined as a result of Keap1/Nrf2 pathway activation by both compounds and confirmed by different experiments. Furthermore, compound 3e (PQM-164) exhibited a significant effect on the accumulation of α-synuclein and anti-inflammatory activity, leading to an expressive decrease in gene expression of iNOS, IL-1ß, and TNF-α. Overall, these results highlighted compound 3e as a promising and innovative multifunctional drug prototype candidate for PD treatment.
Assuntos
Hidrazonas , Fármacos Neuroprotetores , Doença de Parkinson , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/síntese química , Hidrazonas/farmacologia , Hidrazonas/química , Hidrazonas/síntese química , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Relação Dose-Resposta a Droga , Desenho de Fármacos , Antioxidantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Animais , Cinamatos/farmacologia , Cinamatos/química , Cinamatos/síntese químicaRESUMO
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 (IC50 = 5.9 µM, SI > 5.1), with an additional antioxidant activity (IC50 = 7.45 µM) against neuronal t-BOOH-induced oxidative stress and neuroprotective ability against neurotoxicity elicited by both t-BOOH and OAß1-42, and a moderate ability to interfere in Aß1-42 aggregates, with low cytotoxicity and good predictive druggability properties, suggesting a multifunctional pharmacological profile suitable for further drug development against AD.
Assuntos
Doença de Alzheimer , Neuroblastoma , Fármacos Neuroprotetores , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Antioxidantes/farmacologia , Inibidores da Colinesterase/química , Desenho de Fármacos , Humanos , Hidrazonas/farmacologia , Hidrazonas/uso terapêutico , Ligantes , Estrutura Molecular , Neuroblastoma/tratamento farmacológico , Fármacos Neuroprotetores/química , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
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 Aß42 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.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Triazóis/química , Triazóis/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Células Cultivadas , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Inibidores da Colinesterase/farmacologia , Curcumina/farmacocinética , Curcumina/farmacologia , Humanos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Farmacocinética , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/farmacocinética , Resveratrol/farmacologia , Triazóis/farmacocinéticaRESUMO
Chalcones have shown a broad spectrum of biological activities with clinical potential against various diseases. The biological activities are mainly attributed to the presence in the chalcones of the α,ß-unsaturated carbonyl system, perceived as a potential Michael acceptor. Chalcones could activate the Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway through a Michael addition reaction with the cysteines of Keap1, which acts as a redox sensor and negative regulator of Nrf2. This modification allows the dissociation of Nrf2 from the cytoplasmic complex with Keap1 and its nuclear translocation. At this level, Nrf2 binds to the antioxidant response element (ARE) and activates the expression of several detoxification, antioxidant and anti-inflammatory genes as well as genes involved in the clearance of damaged proteins. In this regard, the Keap1/Nrf2â»ARE pathway is a new potential pharmacological target for the treatment of many chronic diseases. In this review we summarize the current progress in the study of Keap1/Nrf2â»ARE pathway activation by natural and synthetic chalcones and their potential pharmacological applications. Among the pharmacological activities highlighted, anti-inflammatory activity was more evident than others, suggesting a multi-target Michael acceptor mechanism for the chalcones involving key regulators of the Nrf2 and nuclear factor- κB (NF-κB) pathways.
Assuntos
Elementos de Resposta Antioxidante , Chalconas/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Chalconas/química , HumanosRESUMO
ABSTRACT: Based on the effectiveness of resveratrol and curcumin in carcinogenesis, (E)-3-(4-hydroxy-3-methoxyphenyl)-N'-((E)-4-methoxybenzylidene) acrylohydrazide (PQM-162), curcumin-resveratrol hybrid derivative, was designed by molecular hybridization using a hydrazone functionality as a spacer moiety between pharmacophoric fragments inspired by the parent compounds. OBJECTIVES: The present study aimed to evaluate the chemopreventive effects of the hybrid against pre-neoplastic lesions induced in the colon of rodents. METHODS: The doses were determined based on the reduction in DNA damage induced by doxorubicin [15 mg/kg body weight (b.w.)] in peripheral blood of Swiss mice. Doses of 8, 16, 32, and 64 mg/kg b.w. were antimutagenic. For the evaluation of pre-neoplastic lesions in the colon, Wistar rats were treated with PQM-162 at doses of 0.5, 1, and 2 mg/kg b.w. for 6 weeks using three approaches: simultaneous treatment, pre-treatment, and post-treatment. Pre-neoplastic lesions were induced with 1,2 dimethylhydrazine (160 mg/kg b.w.). KEY FINDINGS: PQM-162 reduced the formation of aberrant crypt foci in the simultaneous treatment and post-treatment. TNF-α and COX-2 mRNA levels decreased, while Nrf2 mRNA levels increased. PQM-162 also reduced the expression of COX-2, PCNA, and ß-catenin protein markers and increased Nrf2 expression. CONCLUSION: Our findings suggest a chemopreventive potential of PQM-162 in colorectal carcinogenesis, which acts on anti-inflammatory, antioxidant, and cell proliferation pathways.
RESUMO
Nowadays, neurodegenerative diseases (NDs), such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a great challenge in different scientific fields, such as neuropharmacology, medicinal chemistry, molecular biology and medicine, as all these pathologies remain incurable, with high socioeconomic impacts and high costs for governmental health services. Due to their severity and multifactorial pathophysiological complexity, the available approved drugs for clinic have not yet shown adequate effectiveness and exhibited very restricted options in the therapeutic arsenal; this highlights the need for continued drug discovery efforts in the academia and industry. In this context, natural products, such as curcumin (1), resveratrol (2) and cannabidiol (CBD, 3) have been recognized as important sources, with promising chemical entities, prototype models and starting materials for medicinal organic chemistry, as their molecular architecture, multifunctional properties and single chemical diversity could facilitate the discovery, optimization and development of innovative drug candidates with improved pharmacodynamics and pharmacokinetics compared to the known drugs and, perhaps, provide a chance for discovering novel effective drugs to combat NDs. In this review, we report the most recent efforts of medicinal chemists worldwide devoted to the exploration of curcumin (1), resveratrol (2) and cannabidiol (CBD, 3) as starting materials or privileged scaffolds in the design of multi-target directed ligands (MTDLs) with potential therapeutic properties against NDs, which have been published in the scientific literature during the last 10 years of research and are available in PubMed, SCOPUS and Web of Science databases.
Assuntos
Canabidiol , Curcumina , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Curcumina/farmacologia , Curcumina/uso terapêutico , Desenho de Fármacos , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Resveratrol/farmacologia , Resveratrol/uso terapêuticoRESUMO
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 IC50 value of 3.15 µM, 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-1ß 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-1ß. 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.
RESUMO
Neurodegenerative Diseases (NDs) are progressive multifactorial neurological pathologies related to neuronal impairment and functional loss from different brain regions. Currently, no effective treatments are available for any NDs, and this lack of efficacy has been attributed to the multitude of interconnected factors involved in their pathophysiology. In the last two decades, a new approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDLs) strategy, has emerged and has been used in the design and for the development of a variety of hybrid compounds capable to act simultaneously in diverse biological targets. Based on the polypharmacology concept, this new paradigm has been thought as a more secure and effective way for modulating concomitantly two or more biochemical pathways responsible for the onset and progress of NDs, trying to overcome low therapeutical effectiveness. As a complement to our previous review article (Curr. Med. Chem. 2007, 14 (17), 1829-1852. https://doi.org/10.2174/092986707781058805), herein we aimed to cover the period from 2008 to 2019 and highlight the most recent advances of the exploitation of Molecular Hybridization (MH) as a tool in the rational design of innovative multifunctional drug candidate prototypes for the treatment of NDs, specially focused on AD, PD, HD and ALS.
Assuntos
Desenho de Fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Animais , HumanosRESUMO
Alzheimer's disease (AD) is a progressive multifactorial neurodegenerative disorder. Currently, no effective treatment is available and this is due to multiple factors involved in pathophysiology and severity of AD. A recent approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDL) strategy, has been used to develop a variety of hybrid compounds capable to act simultaneously in diverse biological targets. The discovery of drug candidates capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. This review is a complement to another review article, recently published by our group, which covered the previous period of 2005-2012, and highlights recent advances and examples of the exploitation of MTDLs approach in the rational design of novel drug candidate prototypes for the treatment of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Fármacos Neuroprotetores/farmacologia , Humanos , Ligantes , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/químicaRESUMO
Curcumin (1) and resveratrol (2) are bioactive natural compounds that display wide pharmacological properties, including antitumor activity. However, their clinical application has been limited due to their low solubility and bioavailability. Nevertheless, independent studies have considered these compounds as interesting prototypes for developing new chemical structures useful for anticancer therapy. Here in, we report the synthesis of novel curcumin-like hydrazide analogues (3a and 3b), and a series of curcumin-resveratrol hybrid compounds (4a-f), and the evaluation of their cytotoxic potential on three tumor cell lines MCF-7 (breast), A549 (lung), and HepG2 (liver). Cell viability was significantly reduced in all tested cell lines when compounds 4c-4e were used. The IC50 values for these compounds on MCF-7 cells were lower than those for curcumin, resveratrol, or curcumin combined with resveratrol. We evidenced that 4c promoted a drastic increase of G2/M population. The accumulation of cells in mitosis onset in treated cultures was due to, at least in part, the ability of 4c to modulate nuclear kinase proteins, which orchestrate important events in mitosis progression. We have also observed significant reduction of the relative RNAm abundance of CCNB1, PLK1, AURKA, AURKB in samples treated with 4c, with concomitant increase of CDKN1A (p21). Thus, compound 4c is a promising multi-target antitumor agent that should be considered for further in vivo studies.
Assuntos
Antineoplásicos/farmacologia , Curcumina/farmacologia , Estilbenos/farmacologia , Células A549 , Apoptose/efeitos dos fármacos , Aurora Quinase A/genética , Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular , Sobrevivência Celular , Ciclina B1/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Combinação de Medicamentos , Estrogênios/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Células MCF-7 , Mitose/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Resveratrol , Quinase 1 Polo-LikeRESUMO
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 (AßO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AßO-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.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores da Colinesterase/farmacologia , Descoberta de Drogas , Hidrazonas/farmacologia , Indanos/farmacologia , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Donepezila , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Hidrazonas/química , Indanos/síntese química , Indanos/química , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
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.