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BACKGROUND: Test the ability of Mirasol Pathogen Reduction Technology (PRT, Terumo BCT, Lakewood Co, USA) treatment with riboflavin and ultraviolet light (R + UV) in reducing SARS-CoV-2 infectivity while maintaining blood product quality. MATERIAL AND METHODS: SARS-CoV-2 strains were isolated and titrated to prepare cell free virus for plasma units infection. The units were then under treatment with Mirasol PRT. The infectious titers were determined before and after treatment with an in house microtitration assay on Vero E6 cells. Thirty-six plasma pool bags underwent PRT treatment. RESULTS: In all the experiments, the measured titer following riboflavin and UV treatment was below the limit of detection of microtitration assay for all the different SARS-CoV-2 strains. Despite the high copies number detected by RT-PCR for each viral strain after treatment, viruses were completely inactivated and not able to infect VERO E6 cells. CONCLUSION: Riboflavin and UV light treatment effectively reduced the virus titers of human plasma to the limit of detection in tissue culture, regardless of the strain. These data suggest that pathogen reduction in blood products highlight the safety of CP therapy procedures for critically ill COVID-19 patients, while maintaining blood product quality.
Assuntos
Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Humanos , Riboflavina/farmacologia , Raios UltravioletaRESUMO
The major cause of bacterial resistance to ß-lactams is the production of hydrolytic ß-lactamase enzymes. Nowadays, the combination of ß-lactam antibiotics with ß-lactamase inhibitors (BLIs) is the main strategy for overcoming such issues. Nevertheless, particularly challenging ß-lactamases, such as OXA-48, pose the need for novel and effective treatments. Herein, we describe the screening of a proprietary compound collection against Klebsiella pneumoniae OXA-48, leading to the identification of several chemotypes, like the 4-ideneamino-4H-1,2,4-triazole (SC_2) and pyrazolo[3,4-b]pyridine (SC_7) cores as potential inhibitors. Importantly, the most potent representative of the latter series (ID2, AC50 = 0.99 µM) inhibited OXA-48 via a reversible and competitive mechanism of action, as demonstrated by biochemical and X-ray studies; furthermore, it slightly improved imipenem's activity in Escherichia coli ATCC BAA-2523 ß-lactam resistant strain. Also, ID2 showed good solubility and no sign of toxicity up to the highest tested concentration, resulting in a promising starting point for further optimization programs toward novel and effective non-ß-lactam BLIs.
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Everolimus (Eve) is an immunosuppressive macrolide that is being analyzed in various biological matrices and fluids. Its antitumor activity makes this drug suitable not only for organ transplantation but also for breast cancer treatments. In the attempt to reduce the incidence and severity of its side effects, Eve was loaded in H-ferritin (HFn), a natural biomolecule that is involved in specific cellular uptake pathways. Thus, Eve pre-complexed with Cu(II) and encapsulated in HFn resulted in an Eve nanoformulation, named HEve. The quantification of HEve was performed using a tailored pH-induced procedure to precipitate H-ferritin. This sample preparation was effective enough to reduce the ion suppression effect on the mass spectrometric responses of Eve in electrospray ionization (ESI). The ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-ESI-MS/MS) system operating in positive ionization mode showed to be a versatile technique in achieving more than 77 % recovery of Eve from the cytoplasmic compartment. This simple, selective and sensitive method enabled the quantification of Eve within the linear range of 2.5-100 ng/mL in matrix spiked with the isotope-labeled internal standard, EveD4. This method was validated according to FDA Guidance. The intracellular distribution of HEve and its accumulation at a cytoplasmic level were studied in breast cancer cell lines. As expected, HEve was more effective than free Eve on sensitive (i.e. BT474) and resistant cell lines, as a result of a better penetration into the target subcellular compartment.
Assuntos
Everolimo , Espectrometria de Massas em Tandem , Apoferritinas , Cromatografia Líquida de Alta Pressão , Imunossupressores , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Bipolar disorders still represent a global unmet medical need and pose a requirement for novel effective treatments. In this respect, glycogen synthase kinase 3ß (GSK-3ß) aberrant activity has been linked to the pathophysiology of several disease conditions, including mood disorders. Therefore, the development of GSK-3ß inhibitors with good in vivo efficacy and safety profile associated with high brain exposure is required. Accordingly, we have previously reported the selective indazole-based GSK-3 inhibitor 1, which showed excellent efficacy in a mouse model of mania. Despite the favorable preclinical profile, analog 1 suffered from activity at the hERG ion channel, which prevented its further progression. Herein, we describe our strategy to improve this off-target liability through modulation of physicochemical properties, such as lipophilicity and basicity. These efforts led to the potent inhibitor 14, which possessed reduced hERG affinity, promising in vitro ADME properties, and was very effective in a mood stabilizer in vivo model.
RESUMO
The interest of research groups and pharmaceutical companies to discover novel GSK-3ß inhibitors has increased over the years considering the involvement of this enzyme in many pathophysiological processes and diseases. Along this line, we recently reported on 1H-indazole-3-carboxamide (INDZ) derivatives 1-6, showing good GSK-3ß inhibition activity. However, they suffered from generally poor central nervous system (CNS) permeability. Here, we describe the design, synthesis, and in vitro characterization of novel imidazo[1,5-a]pyridine-1-carboxamide (IMID 1) and imidazo[1,5-a]pyridine-3-carboxamide (IMID 2) compounds (7-18) to overcome such liability. In detail, structure-based approaches and fine-tuning of physicochemical properties guided the design of derivatives 7-18 resulting in ameliorated absorption, distribution, metabolism, and excretion (ADME) properties. A crystal structure of 16 in complex with GSK-3ß enzyme (PDB entry 6Y9S) confirmed the in silico models. Despite the nanomolar inhibition activity, the new core compounds showed a reduction in potency with respect to INDZ derivatives 1-6. In this context, Molecular Dynamics (MD) and Quantum Mechanics (QM) based approaches along with NMR investigation helped to rationalize the observed structure activity relationship (SAR). With these findings, the key role of the acidic hydrogen of the central core for a tight interaction within the ATP pocket of the enzyme reflecting in good GSK-3ß affinity was demonstrated.
Assuntos
Inibidores Enzimáticos/síntese química , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Imidazóis/síntese química , Piridinas/química , Animais , Sítios de Ligação , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicogênio Sintase Quinase 3 beta/química , Imidazóis/química , Imidazóis/farmacologia , Células Madin Darby de Rim Canino , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Teoria Quântica , Relação Estrutura-AtividadeRESUMO
In this study, a drug discovery programme that sought to identify novel dual bacterial topoisomerase II inhibitors (NBTIs) led to the selection of six optimized compounds. In enzymatic assays, the molecules showed equivalent dual-targeting activity against the DNA gyrase and topoisomerase IV enzymes of Staphylococcus aureus and Escherichia coli. Consistently, the compounds demonstrated potent activity in susceptibility tests against various Gram-positive and Gram-negative reference species, including ciprofloxacin-resistant strains. The activity of the compounds against clinical multidrug-resistant isolates of S. aureus, Clostridium difficile, Acinetobacter baumannii, Neisseria gonorrhoeae, E. coli and vancomycin-resistant Enterococcus spp. was also confirmed. Two compounds (1 and 2) were tested in time-kill and post-antibiotic effect (PAE) assays. Compound 1 was bactericidal against all tested reference strains and showed higher activity than ciprofloxacin, and compound 2 showed a prolonged PAE, even against the ciprofloxacin-resistant S. aureus BAA-1720 strain. Spontaneous development of resistance to both compounds was selected for in S. aureus at frequencies comparable to those obtained for quinolones and other NBTIs. S. aureus BAA-1720 mutants resistant to compounds 1 and 2 had single point mutations in gyrA or gyrB outside of the quinolone resistance-determining region (QRDR), confirming the distinct site of action of these NBTIs compared to that of quinolones. Overall, the very good antibacterial activity of the compounds and their optimizable in vitro safety and physicochemical profile may have relevant implications for the development of new broad-spectrum antibiotics.
Assuntos
Antibacterianos/farmacologia , DNA Girase/efeitos dos fármacos , DNA Topoisomerases Tipo II/efeitos dos fármacos , Inibidores da Topoisomerase II/farmacologia , Animais , Células CHO , Ciprofloxacina/farmacologia , Cricetulus , DNA Topoisomerases Tipo II/metabolismo , DNA Bacteriano/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Células Hep G2 , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Testes de ToxicidadeRESUMO
The LIBRA compound library is a collection of 522 non-commercial molecules contributed by various Italian academic laboratories. These compounds have been designed and synthesized during different medicinal chemistry programs and are hosted by the Italian Institute of Technology. We report the screening of the LIBRA compound library against Trypanosoma brucei and Leishmania major pteridine reductase 1, TbPTR1 and LmPTR1. Nine compounds were active against parasitic PTR1 and were selected for cell-based parasite screening, as single agents and in combination with methotrexate (MTX). The most interesting TbPTR1 inhibitor identified was 4-(benzyloxy)pyrimidine-2,6-diamine (LIB_66). Subsequently, six new LIB_66 derivatives were synthesized to explore its Structure-Activity-Relationship (SAR) and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. The results indicate that PTR1 has a preference to bind inhibitors, which resemble its biopterin/folic acid substrates, such as the 2,4-diaminopyrimidine derivatives.
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Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Macrófagos/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Pirimidinas/química , Trypanosoma brucei brucei/enzimologia , Células A549 , Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos/química , Proliferação de Células , Sinergismo Farmacológico , Inibidores Enzimáticos/química , Humanos , Metotrexato/farmacologia , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Bacterial resistance is increasing rapidly, requiring urgent identification of new antibacterial drugs that are effective against multidrug-resistant pathogens. Novel bacterial topoisomerase inhibitors (NBTIs) provide a new strategy for investigating the well-validated DNA gyrase and topoisomerase IV targets while preventing cross-resistance issues. On this basis, starting from a virtual screening campaign and subsequent structure-based hit optimization guided by X-ray studies, a novel class of piperazine-like NBTIs with outstanding enzymatic activity against Staphylococcus aureus and Escherichia coli DNA gyrase and topoisomerase IV was identified. Notably, compounds (±)-33, (±)-35, and (±)-36 with potent and balanced multitarget enzymatic profiles exhibited excellent efficacy against selected Gram-positive and Gram-negative pathogens, as well as clinically relevant resistant strains. Overall, the new NBTI chemotype described herein, owing to the broad-spectrum antibacterial activity and favorable in vitro safety profile, might serve as a basis for the development of novel treatments against serious infections.
Assuntos
DNA Topoisomerase IV/antagonistas & inibidores , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Inibidores da Topoisomerase/farmacologia , Sequência de Aminoácidos , Infecções Bacterianas/microbiologia , Infecções Bacterianas/prevenção & controle , DNA Girase/genética , DNA Girase/metabolismo , DNA Topoisomerase IV/genética , DNA Topoisomerase IV/metabolismo , Escherichia coli/enzimologia , Escherichia coli/genética , Testes de Sensibilidade Microbiana , Modelos Químicos , Estrutura Molecular , Homologia de Sequência de Aminoácidos , Staphylococcus aureus/enzimologia , Staphylococcus aureus/genética , Relação Estrutura-Atividade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/químicaRESUMO
In the search for effective and sustainable drugs for human African trypanosomiasis (HAT), we developed hybrid compounds by merging the structural features of quinone 4 (2-phenoxynaphthalene-1,4-dione) with those of phenolic constituents from cashew nut shell liquid (CNSL). CNSL is a waste product from cashew nut processing factories, with great potential as a source of drug precursors. The synthesized compounds were tested against Trypanosoma brucei brucei, including three multidrug-resistant strains, T.â congolense, and a human cell line. The most potent activity was found against T.â b.â brucei, the causative agent of HAT. Shorter-chain derivatives 20 (2-(3-(8-hydroxyoctyl)phenoxy)-5-methoxynaphthalene-1,4-dione) and 22 (5-hydroxy-2-(3-(8-hydroxyoctyl)phenoxy)naphthalene-1,4-dione) were more active than 4, displaying rapid micromolar trypanocidal activity, and no human cytotoxicity. Preliminary studies probing their mode of action on trypanosomes showed ATP depletion, followed by mitochondrial membrane depolarization and mitochondrion ultrastructural damage. This was accompanied by reactive oxygen species production. We envisage that such compounds, obtained from a renewable and inexpensive material, might be promising bio-based sustainable hits for anti-trypanosomatid drug discovery.
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Trifosfato de Adenosina/biossíntese , Anacardium/química , Descoberta de Drogas , Mitocôndrias/efeitos dos fármacos , Extratos Vegetais/farmacologia , Tripanossomicidas/química , Tripanossomicidas/uso terapêutico , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase/tratamento farmacológico , Animais , Humanos , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/microbiologiaRESUMO
Our findings reported herein provide support for the benefits of including functional group complexity (FGC) within fragments when screening against protein targets such as Mycobacterium tuberculosis InhA. We show that InhA fragment actives with FGC maintained their binding pose during elaboration. Furthermore, weak fragment hits with functional group handles also allowed for facile fragment elaboration to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization.
Assuntos
Antituberculosos/química , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/química , Mycobacterium tuberculosis/enzimologia , Oxirredutases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Antituberculosos/síntese química , Proteínas de Bactérias/química , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Ligantes , Modelos Moleculares , Estrutura Molecular , Oxirredutases/química , Bibliotecas de Moléculas Pequenas/síntese química , Ressonância de Plasmônio de SuperfícieRESUMO
The amyloid hypothesis has long been the central dogma in drug discovery for Alzheimer's disease (AD), leading to many small-molecule and biological drug candidates. One major target has been the ß-site amyloid-precursor-protein-cleaving enzyme 1 (BACE-1), with many big pharma companies expending great resources in the search for BACE-1 inhibitors. The lack of efficacy of verubecestat in mild-to-moderate AD raises important questions about the timing of intervention with BACE-1 inhibitors, and anti-amyloid therapies in general, in AD treatment. It also suggests new possibilities for discovering BACE-1-targeted compounds with more complex mechanisms of actions and improved efficacy. Herein, we review the major advances in BACE-1 drug discovery, from single-target small molecule inhibitors to multitarget compounds. We discuss these compounds as innovative tools for better understanding the complexity of AD and for identifying efficacious drug candidates to treat this devastating disease.
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Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Terapia de Alvo Molecular/métodos , Inibidores de Proteases/farmacologia , Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/química , Animais , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Humanos , Inibidores de Proteases/uso terapêuticoRESUMO
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has recently gained attention as an antiprotozoan and anticancer drug target. We have previously identified 2-phenoxy-1,4-naphthoquinone as an inhibitor of both Trypanosoma brucei and human GAPDH. Herein, through multiple chemical, biochemical, and biological studies, and through the design of analogs, we confirmed the formation of a covalent adduct, we clarified the inhibition mechanism, and we demonstrated antitrypanosomal, antiplasmodial, and cytotoxic activities in cell cultures. The overall results lent support to the hypothesis that 2-phenoxy-1,4-naphthoquinone binds the GAPDH catalytic cysteine covalently through a phenolate displacement mechanism. By investigating the reactivity of 2-phenoxy-1,4-naphthoquinone and its analogs with four GAPDH homologs, we showed that the covalent inhibition is not preceded by the formation of a strong non-covalent complex. However, an up to fivefold difference in inactivation rates among homologs hinted at structural or electrostatic differences of their active sites that could be exploited to further design kinetically selective inhibitors. Moreover, we preliminarily showed that 2-phenoxy-1,4-naphthoquinone displays selectivity for GAPDHs over two other cysteine-dependent enzymes, supporting its suitability as a warhead starting fragment for the design of novel inhibitors.
Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Gliceraldeído-3-Fosfato Desidrogenases/antagonistas & inibidores , Naftoquinonas/química , Naftoquinonas/farmacologia , Plasmodium falciparum/enzimologia , Trypanosoma brucei brucei/enzimologia , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Humanos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacosRESUMO
The availability of suitable diverse fragment- and lead-oriented screening compounds is key for the identification of suitable chemical starting points for drug discovery programs. The physicochemical properties of molecules are crucial in determining the success of small molecules in clinical development, yet reports suggest that pharmaceutical and academic sectors often produce molecules with poor drug-like properties. We present a platform to design novel, high quality and diverse fragment- and lead-oriented libraries with appropriate physicochemical properties in a cost-efficient manner. This approach has the potential to assist the way libraries are constructed by significantly addressing the historical uneven exploration of chemical space for drug discovery. Additionally, this platform can teach undergraduates and graduates about compound library design.
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Desenho de Fármacos , Preparações Farmacêuticas/química , Preparações Farmacêuticas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/síntese química , Estabilidade de Medicamentos , Modelos Químicos , Estrutura Molecular , SolubilidadeRESUMO
The recent literature signals a growing paradigm shift toward integrating therapeutics and diagnostics rather than developing and deploying them separately. In this gradual move toward more effective and personalized medications, companion diagnostics are an intermediate stage. The next step may be "theranostics", in which single chemical entities are developed to deliver therapy and diagnosis simultaneously. This strategy has been successfully exploited in oncology and is now emerging as a possibility for Alzheimer's disease, where its feasibility has caught the attention of researchers from industry and academia. Medicinal chemists do not yet completely understand the nuances of theranostic action and consequently have not yet developed universally validated strategies for developing theranostic clinical applications against Alzheimer's disease. However, given the emerging indications of the potentially enormous benefits that theranostics may bring to the fight against this devastating disease, further rigorous research is warranted.
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Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Animais , Biomarcadores/análise , Corantes Fluorescentes , Humanos , Técnicas de Diagnóstico Molecular , Medicina de Precisão , Nanomedicina Teranóstica , Proteínas tau/metabolismoRESUMO
Multitarget drug discovery is one of the hottest topics and most active fields in the search for new molecules against Alzheimer's disease (AD). Over the last 20 years, many promising multitarget-directed ligands (MTDLs) have been identified and developed at a pre-clinical level. However, how to design them in a rational way remains the most fundamental challenge of medicinal chemists. This is related to the foundational question of achieving an optimized activity towards multiple targets of interest, while preserving drug-like properties. In this respect, large hybrid molecules and small fragments are poles apart. In this review article, our aim is to appraise what we have accomplished in the development of both hybrid- and fragment-like molecules directed to diverse AD targets (i.e., acetylcholinesterase, NMDA receptors, metal chelation, BACE-1 and GSK-3ß). In addition, we attempt to highlight what are the persistent needs that deserve to be improved and cared for, with the ultimate goal of moving an MTDL to AD clinical studies.
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Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Descoberta de Drogas , Acetilcolinesterase/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Humanos , Ligantes , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
We discovered a small series of hit compounds that show multitargeting activities against key targets in Alzheimer's disease (AD). The compounds were designed by combining the structural features of the anti-AD drug donepezil with clioquinol, which is able to chelate redox-active metals, thus decreasing metal-driven oxidative phenomena and ß-amyloid (Aß)-mediated neurotoxicity. The majority of the new hybrid compounds selectively target human butyrylcholinesterase at micromolar concentrations and effectively inhibit Aß self-aggregation. In addition, compounds 5-chloro-7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (1 b), 7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (2 b), and 7-(((1-benzylpiperidin-4-yl)amino)methyl)-5-chloro-8-hydroxyquinoline (3 a) are able to chelate copper(II) and zinc(II) and exert antioxidant activity inâ vitro. Importantly, in the case of 2 b, the multitarget profile is accompanied by high predicted blood-brain barrier permeability, low cytotoxicity in T67 cells, and acceptable toxicity in HUVEC primary cells.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Oxiquinolina/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/química , Antioxidantes/uso terapêutico , Antioxidantes/toxicidade , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quelantes/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Clioquinol/química , Clioquinol/uso terapêutico , Clioquinol/toxicidade , Cobre/química , Donepezila , Desenho de Fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Indanos/química , Indanos/uso terapêutico , Indanos/toxicidade , Oxiquinolina/uso terapêutico , Oxiquinolina/toxicidade , Piperidinas/química , Piperidinas/uso terapêutico , Piperidinas/toxicidade , Relação Estrutura-Atividade , Zinco/químicaRESUMO
INTRODUCTION: The importance of microglia in most neurodegenerative pathologies, from Parkinson's disease to amyotrophic lateral sclerosis and Alzheimer's disease, is increasingly recognized. Until few years ago, microglial activation in pathological conditions was considered dangerous to neurons due to its causing inflammation. Today we know that these glial cells also play a crucial physiological and neuroprotective role, which is altered in neurodegenerative conditions. AREAS COVERED: The neuroinflammatory hypothesis for neurodegenerative diseases has led to the trial of anti-inflammatory agents as therapeutics with largely disappointing results. New information about the physiopathological role of microglia has highlighted the importance of immunomodulation as a potential new therapeutic approach. This review summarizes knowledge on microglia as a potential therapeutic target in the most common neurodegenerative diseases, with focus on compounds directed toward the modulation of microglial immune response through specific molecular pathways. EXPERT OPINION: Here we support the innovative concept of targeting microglial cells by modulating their activity, rather than simply trying to counteract their inflammatory neurotoxicity, as a potential therapeutic approach for neurodegenerative diseases. The advantage of this therapeutic approach could be to reduce neuroinflammation and toxicity, while at the same time strengthening intrinsic neuroprotective properties of microglia and promoting neuroregeneration.
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Microglia/metabolismo , Doenças Neurodegenerativas/terapia , Animais , Anti-Inflamatórios/uso terapêutico , Humanos , Imunomodulação , Doenças Neurodegenerativas/metabolismoRESUMO
BACKGROUND: The main pathogenic event of prion disorders has been identified in the deposition of the disease-associated prion protein (PrP(Sc)), which is accompanied by metal dyshomeostasis. RESULTS: The multitarget-directed ligand 1, designed by combining a heteroaromatic prion recognition motif to an 8-hydroxyquinoline metal chelator, has been developed as a potential antiprion disease-modifying agent. Importantly, 1 was found to effectively clear PrP(Sc) from scrapie-infected cells, and, at the same time, inhibit metal-induced prion aggregation and reactive oxygen species generation. 1 was also characterized in terms of pharmacokinetic properties in a preliminary in vitro investigation. CONCLUSION: Compound 1 has emerged as a suitable lead candidate against prion diseases and as a good starting point for a further optimization process.
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Compostos Organometálicos/farmacologia , Oxiquinolina/farmacologia , Doenças Priônicas/tratamento farmacológico , Príons/antagonistas & inibidores , Desenho de Fármacos , Humanos , Ligantes , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Oxiquinolina/química , Doenças Priônicas/metabolismo , Príons/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
A small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives was initially developed to optimize the antitrypanosomatid profile of the multitarget hit compound B6 (1). The whole series was evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and two compounds (14 and 21) showed good activity, despite a concomitant mammalian cytotoxicity. Furthermore, a subset also inhibited the glycolytic TbGAPDH enzyme in vitro. In light of these results and aware of the antitumor properties of quinones, the anticancer potential of some selected derivatives was investigated. Intriguingly, the tested compounds displayed antitumor activity, while being less toxic against noncancerous cells. The observed cytotoxic potency was ascribed to a multitarget mechanism of action accounting for hGAPDH inhibition and mitochondrial toxicity. Overall, the development of further derivatives, able to finely modulate multiple pathways of cancer or parasite cell metabolism, might lead to more effective treatments against these devastating diseases.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/antagonistas & inibidores , Humanos , Leishmania donovani/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacosRESUMO
One of the main obstacles toward the discovery of effective anti-Alzheimer drugs is the multifactorial nature of its etiopathology. Therefore, the use of multitarget-directed ligands has emerged as particularly suitable. Such ligands, able to modulate different neurodegenerative pathways, for example, amyloid and tau cascades, as well as cognitive and neurogenic functions, are fostered to come. In this respect, we report herein on the first class of BACE-1/GSK-3ß dual inhibitors based on a 3,4-dihydro-1,3,5-triazin-2(1H)-one skeleton, whose hit compound 1 showed interesting properties in a preliminary investigation. Notably, compound 2, endowed with well-balanced potencies against the two isolated enzymes (IC50 of 16 and 7 µM against BACE-1 and GSK-3ß, respectively), displayed effective neuroprotective and neurogenic activities and no neurotoxicity in cell-based assays. It also showed good brain permeability in a pharmacokinetic assessment in mice. Overall, triazinone derivatives, thanks to the simultaneous modulation of multiple points of the diseased network, might emerge as suitable candidates to be tested in in vivo Alzheimer's disease models.