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1.
BMC Infect Dis ; 21(1): 379, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33892628

RESUMO

BACKGROUND: The Integrase (IN) strand transfer inhibitor (INSTI), Dolutegravir (DTG), has been given the green light to form part of first-line combination antiretroviral therapy (cART) by the World Health Organization (WHO). DTG containing regimens have shown a high genetic barrier against HIV-1 isolates carrying specific resistance mutations when compared with other class of regimens. METHODS: We evaluated the HIV-1 CRF02_AG IN gene sequences from Cameroon for the presence of resistance-associated mutations (RAMs) against INSTIs and naturally occurring polymorphisms (NOPs), using study sequences (n = 20) and (n = 287) sequences data derived from HIV Los Alamos National Laboratory database. The possible impact of NOPs on protein structure caused by HIV-1 CRF02_AG variations was addressed within the context of a 3D model of the HIV-1 IN complex and interaction analysis was performed using PyMol to validate DTG binding to the Wild type and seven mutant structures. RESULTS: We observed 12.8% (37/287) sequences to contain RAMs, with only 1.0% (3/287) of the sequences having major INSTI RAMs: T66A, Q148H, R263K and N155H. Of these,11.8% (34/287) of the sequences contained five different IN accessory mutations; namely Q95K, T97A, G149A, E157Q and D232N. NOPs occurred at a frequency of 66% on the central core domain (CCD) position, 44% on the C-terminal domain (CTD) position and 35% of the N-terminal domain (NTD) position. The interaction analysis revealed that DTG bound to DNA, 2MG ions and DDE motif residues for T66A, T97A, Q148H, N155H and R263K comparable to the WT structure. Except for accessory mutant structure E157Q, only one MG contact was made with DTG, while DTG had no MG ion contacts and no DDE motif residue contacts for structure D232N. CONCLUSIONS: Our analysis indicated that all RAM's that resulted in a change in the number of interactions with encompassing residues does not affect DTG binding, while accessory mutations E157Q and D232N could affect DTG binding leading to possible DTG resistance. However, further experimental validation is required to validate the in silico findings of our study.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Integrase de HIV/genética , HIV-1/enzimologia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Modelos Moleculares , Mutação , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Camarões/epidemiologia , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Integrase de HIV/química , Inibidores de Integrase de HIV/química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Oxazinas/química , Filogenia , Piperazinas/química , Polimorfismo Genético , Piridonas/química
2.
Eur J Med Chem ; 212: 113096, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33395621

RESUMO

Based on our previous work, a series of N-phenyl-3-methoxy-4-pyridinone derivatives were designed as orally bioavailable dual functional agents for therapy of Alzheimer's disease, through introducing alkyloxy moiety into 4-pyridinone ring to avoid the possible phase II metabolism of 3-hydroxy-4-pyridinone in lead compound 3-hydroxy-2-methyl-1-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-pyridin-4(1H)-one (4). In vitro studies indicated that most of these compounds exhibit excellent H3 receptor antagonistic activities and potent self-induced Aß1-40/Aß1-42 aggregation inhibitory activities. In particular, 3-methoxy-1-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-pyridin-4(1H)-one (7i) demonstrated IC50 value of 0.52 nM in H3R antagonism and good selectivity over other histamine receptor subtypes. The transmission electron microscopy (TEM) images showed that compound 7i can inhibit self-mediated Aß1-40/Aß1-42 aggregation efficiently. As expected, it exhibited desirable pharmacokinetic properties in plasma and good BBB permeability. Furthermore, compound 7i can efficiently block (R)-α-methylhistamine- induced dipsogenia and reverse scopolamine-induced learning deficits of rats. All above results indicated that compound 7i was a promising orally bioavailable dual functional agents with potential use in the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Antagonistas dos Receptores Histamínicos H3/farmacologia , Piridonas/farmacologia , Receptores Histamínicos H3/metabolismo , Administração Oral , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Antagonistas dos Receptores Histamínicos H3/química , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Agregados Proteicos/efeitos dos fármacos , Piridonas/administração & dosagem , Piridonas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
3.
Int J Mol Sci ; 22(3)2021 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-33498933

RESUMO

As catabolites of nicotinamide possess physiological relevance, pyridones are often included in metabolomics measurements and associated with pathological outcomes in acute kidney injury (AKI). Pyridones are oxidation products of nicotinamide, its methylated form, and its ribosylated form. While they are viewed as markers of over-oxidation, they are often wrongly reported or mislabeled. To address this, we provide a comprehensive characterization of these catabolites of vitamin B3, justify their nomenclature, and differentiate between the biochemical pathways that lead to their generation. Furthermore, we identify an enzymatic and a chemical process that accounts for the formation of the ribosylated form of these pyridones, known to be cytotoxic. Finally, we demonstrate that the ribosylated form of one of the pyridones, the 4-pyridone-3-carboxamide riboside (4PYR), causes HepG3 cells to die by autophagy; a process that occurs at concentrations that are comparable to physiological concentrations of this species in the plasma in AKI patients.


Assuntos
NAD/metabolismo , Niacinamida/metabolismo , Piridonas/metabolismo , Autofagia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Piridonas/química , Piridonas/farmacologia , Piridonas/uso terapêutico
4.
J Med Chem ; 64(1): 370-384, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33385210

RESUMO

Among a series of benzopyridone-based scaffolds investigated as human transient receptor potential vanilloid 1 (TRPV1) ligands, two isomeric benzopyridone scaffolds demonstrated a consistent and distinctive functional profile in which 2-oxo-1,2-dihydroquinolin-5-yl analogues (e.g., 2) displayed high affinity and potent antagonism, whereas 1-oxo-1,2-dihydroisoquinolin-5-yl analogues (e.g., 3) showed full agonism with high potency. Our computational models provide insight into the agonist-antagonist boundary of the analogues suggesting that the Arg557 residue in the S4-S5 linker might be important for sensing the agonist binding and transmitting signals. These results provide structural insights into the TRPV1 and the protein-ligand interactions at a molecular level.


Assuntos
Descoberta de Drogas , Piridonas/química , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Ureia/química
5.
Nucleic Acids Res ; 49(3): 1609-1618, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33469660

RESUMO

The endonuclease activity within the influenza virus cap-snatching process is a proven therapeutic target. The anti-influenza drug baloxavir is highly effective, but is associated with resistance mutations that threaten its clinical efficacy. The endonuclease resides within the N-terminal domain of the PA subunit (PAN) of the influenza RNA dependent RNA polymerase, and we report here complexes of PAN with RNA and DNA oligonucleotides to understand its specificity and the structural basis of baloxavir resistance mutations. The RNA and DNA oligonucleotides bind within the substrate binding groove of PAN in a similar fashion, explaining the ability of the enzyme to cleave both substrates. The individual nucleotides occupy adjacent conserved pockets that flank the two-metal active site. However, the 2' OH of the RNA ribose moieties engage in additional interactions that appear to optimize the binding and cleavage efficiency for the natural substrate. The major baloxavir resistance mutation at position 38 is at the core of the substrate binding site, but structural studies and modeling suggest that it maintains the necessary virus fitness via compensating interactions with RNA. These studies will facilitate the development of new influenza therapeutics that spatially match the substrate and are less likely to elicit resistance mutations.


Assuntos
Endorribonucleases/química , Vírus da Influenza A Subtipo H1N1/enzimologia , Proteínas Virais/química , Antivirais/química , DNA/química , Dibenzotiepinas/química , Endorribonucleases/metabolismo , Modelos Moleculares , Morfolinas/química , Piridonas/química , RNA/química , Especificidade por Substrato , Triazinas/química , Proteínas Virais/metabolismo
6.
Artigo em Inglês | MEDLINE | ID: mdl-32630027

RESUMO

This review summarizes our contributions during last decade on the synthesis of arylazopyridones that may be used as disperse dyes for hydrophobic fabrics utilizing an environmentally benign high temperature dyeing method. The review also discusses the advantages of select disperse dyes based on pyridone moieties as antioxidant, antimicrobial and anticancer agents.


Assuntos
Anti-Infecciosos , Corantes , Piridonas , Poliésteres , Piridonas/química , Têxteis
7.
J Med Chem ; 63(15): 8059-8068, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32643929

RESUMO

Pirfenidone is approved for the treatment of idiopathic pulmonary fibrosis. Idiosyncratic drug reactions, due to clinical application of pirfenidone, have been documented, even along with death cases resulting from acute liver failure. The present study aimed at the investigation of metabolic activation of pirfenidone possibly participating in the reported adverse reactions. Pirfenidone-derived glutathione/N-acetylcysteine (GSH/NAC) conjugates were detected in microsomal/primary hepatocyte incubations after exposure to pirfenidone. The GSH/NAC conjugates were also observed in bile and urine of rats given pirfenidone, respectively. The observation of the conjugates suggests the formation of a quinone methide intermediate derived from pirfenidone. The intermediate was possibly generated through two pathways. First, pirfenidone was directly metabolized to the quinone methide intermediate via dehydrogenation; second, pirfenidone was oxidized to 5-hydroxymethyl pirfenidone, followed by sulfation to a benzyl alcohol-sulfate derivative. The findings facilitate the understanding of the mechanisms of pirfenidone-induced idiosyncratic toxicity and assist medicinal chemists to minimize toxicities in the development of new pharmaceutical agents.


Assuntos
Anti-Inflamatórios não Esteroides/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Microssomos Hepáticos/metabolismo , Piridonas/metabolismo , Sulfotransferases/metabolismo , Animais , Anti-Inflamatórios não Esteroides/química , Sistema Enzimático do Citocromo P-450/química , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Piridonas/química , Piridonas/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Sulfotransferases/química
8.
J Med Chem ; 63(13): 7186-7210, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32453591

RESUMO

Acquired resistance to fulvestrant and palbociclib is a new challenge to treatment of estrogen receptor positive (ER+) breast cancer. ER is expressed in most resistance settings; thus, bromodomain and extra-terminal protein inhibitors (BETi) that target BET-amplified ER-mediated transcription have therapeutic potential. Novel pyrrolopyridone BETi leveraged novel interactions with L92/L94 confirmed by a cocrystal structure of 27 with BRD4. Optimization of BETi using growth inhibition in fulvestrant-resistant (MCF-7:CFR) cells was confirmed in endocrine-resistant, palbociclib-resistant, and ESR1 mutant cell lines. 27 was more potent in MCF-7:CFR cells than six BET inhibitors in clinical trials. Transcriptomic analysis differentiated 27 from the benchmark BETi, JQ-1, showing downregulation of oncogenes and upregulation of tumor suppressors and apoptosis. The therapeutic approach was validated by oral administration of 27 in orthotopic xenografts of endocrine-resistant breast cancer in monotherapy and in combination with fulvestrant. Importantly, at an equivalent dose in rats, thrombocytopenia was mitigated.


Assuntos
Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fulvestranto/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Piridonas/química , Piridonas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Neoplasias da Mama/metabolismo , Humanos , Células MCF-7 , Camundongos , Modelos Moleculares , Domínios Proteicos , Piridonas/farmacocinética , Receptores Estrogênicos/metabolismo , Distribuição Tecidual , Fatores de Transcrição/química , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Med Chem ; 63(13): 7008-7032, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32462873

RESUMO

Herein, we report the discovery of a series of JAK1-selective kinase inhibitors with high potency and excellent JAK family subtype selectivity. A fragment screening hit 1 with a pyrazolopyridone core and a JAK1 bias was selected as the starting point for our fragment-based lead generation efforts. A two-stage strategy was chosen with the dual aims of improving potency and JAK1 selectivity: Optimization of the lipophilic ribose pocket-targeting substituent was followed by the introduction of a variety of P-loop-targeting functional groups. Combining the best moieties from both stages of the optimization afforded compound 40, which showed excellent potency and selectivity. Metabolism studies in vitro and in vivo together with an in vitro safety evaluation suggest that 40 may be a viable lead compound for the development of highly subtype-selective JAK1 inhibitors.


Assuntos
Desenho de Fármacos , Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Piridonas/química , Piridonas/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Janus Quinase 1/química , Janus Quinase 1/metabolismo , Simulação de Acoplamento Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismo , Piridonas/metabolismo , Estereoisomerismo , Especificidade por Substrato
10.
J Nat Med ; 74(3): 545-549, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32236853

RESUMO

Fungal co-culture is a strategy to induce the production of secondary metabolites by activating cryptic genes. We discovered the production of a new compound, talarodone A (1), along with five known compounds 2-6 in co-culture of Talaromyces pinophilus and Paraphaeosphaeria sp. isolated from soil collected in Miyazaki Prefecture, Japan. Among them, the productions of penicidones C (2) and D (3) were enhanced 27- and sixfold, respectively, by the co-culture. The structure of 3 should be represented as a γ-pyridol form with the reported chemical shifts, but not as a γ-pyridone form, based on DFT calculation.


Assuntos
Piridonas/metabolismo , Saccharomycetales/metabolismo , Talaromyces/metabolismo , Técnicas de Cocultura , Japão , Piridonas/química , Saccharomycetales/crescimento & desenvolvimento , Saccharomycetales/isolamento & purificação , Microbiologia do Solo , Talaromyces/crescimento & desenvolvimento , Talaromyces/isolamento & purificação
11.
J Med Chem ; 63(8): 3956-3975, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32208600

RESUMO

The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold of ABBV-075, which recently entered Phase I clinical trials, enabled the generation of a series of highly potent BET bromodomain inhibitors. Further druggability optimization led to the discovery of compound 38 as a potential preclinical candidate. Significantly, compared with ABBV-075, which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound 38 demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300. Orally administered 38 achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.


Assuntos
Acetanilidas/química , Acetanilidas/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Descoberta de Drogas/métodos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Piridonas/química , Piridonas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Proteínas de Ciclo Celular/metabolismo , Cães , Relação Dose-Resposta a Droga , Proteína p300 Associada a E1A/antagonistas & inibidores , Proteína p300 Associada a E1A/metabolismo , Haplorrinos , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Domínios Proteicos/efeitos dos fármacos , Domínios Proteicos/fisiologia , Estrutura Secundária de Proteína , Ratos , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
12.
J Med Chem ; 63(8): 4215-4226, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32208614

RESUMO

Deferoxamine, deferiprone, and deferasirox are used for the treatment of systemic iron overload, although they possess limitations due to lack of oral activity, lower efficacy, and side effects. These limitations led to a search for an orally active iron chelator with an improved therapeutic index. The lower efficacy of deferiprone is due to rapid glucuronidation, leading to the formation of a nonchelating metabolite. Here, we demonstrate that the influence of metabolism can be reduced by introducing a sacrificial site for glucuronidation. A log P-guided investigation of 20 hydroxpyridinones led to the identification of CN128. The Fe(III) affinity and metal selectivity of CN128 are similar to those of deferiprone, the log P value is more lipophilic, and its iron scavenging ability is superior. Overall, CN128 was demonstrated to be safe in a range of toxicity assessments and is now in clinical trials for the treatment of ß-thalassemia after regular blood transfusion.


Assuntos
Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/química , Sobrecarga de Ferro/tratamento farmacológico , Piridonas/administração & dosagem , Piridonas/química , Administração Oral , Animais , Relação Dose-Resposta a Droga , Cobaias , Humanos , Sobrecarga de Ferro/sangue , Camundongos , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia
13.
Science ; 368(6489): 409-412, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32198291

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.


Assuntos
Amidas/química , Amidas/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Cisteína Endopeptidases/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/química , Amidas/metabolismo , Animais , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacocinética , Antivirais/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Cisteína Endopeptidases/metabolismo , Desenho de Fármacos , Meia-Vida , Humanos , Pulmão/metabolismo , Camundongos , Modelos Moleculares , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacocinética , Domínios Proteicos , Multimerização Proteica , Piridonas/química , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
14.
Pharm Res ; 37(3): 59, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32095934

RESUMO

PURPOSE: Evaluate fundamental parameters that dictate the effectiveness of drug loading. METHODS: A model water-soluble drug lacking ionizable groups, pirfenidone (PFD), was encapsulated through nanoprecipitation in poly(ethylene glycol)-poly(lactic acid) (PEG-PLA)-poly(lactic-co-glycolic acid) (PLGA) NPs. Firstly, the thermodynamic parameters predicting drug-polymer miscibility were determined to assess the system's suitability. Then, the encapsulation was evaluated experimentally by two different techniques, bulk and microfluidic (MF) nanoprecipitation. Additionally, the number of molecules that fit in a particle core were calculated and the loading determined experimentally for different core sizes. Lastly, the effect of co-encapsulation of α-lipoic acid (LA), a drug with complementary therapeutic effects and enhanced lipophilicity, was evaluated. RESULTS: The thermodynamic miscibility parameters predicted a good suitability of the selected system. MF manufacturing enhanced the encapsulation efficiency by 60-90% and achieved a 2-fold higher NP cellular uptake. Considering spatial constrictions for drug encapsulation and increasing the size of the PLGA core the number of PFD molecules per NP was raised from under 500 to up to 2000. More so, the co-encapsulation of LA increased the number of drug molecules per particle by 96%, with no interference with the release profile. CONCLUSIONS: Thermodynamic, spatial and methodological parameters should be considered to optimize drug encapsulation.


Assuntos
Antineoplásicos/administração & dosagem , Nanocápsulas/química , Polietilenoglicóis/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/análogos & derivados , Piridonas/administração & dosagem , Antineoplásicos/química , Liberação Controlada de Fármacos , Ácido Láctico/administração & dosagem , Ácido Láctico/química , Piridonas/química , Termodinâmica
15.
Molecules ; 25(3)2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033284

RESUMO

Nitro group is one of the most important functional groups in organic syntheses because its strongly electron-withdrawing ability activates the scaffold, facilitating the reaction with nucleophilic reagents or the Diels-Alder reaction. In this review, recent progress in the nitro-promoted direct functionalization of pyridones and quinolones is highlighted to complement previous reviews.


Assuntos
Nitrocompostos/química , Piridonas/química , Quinolonas/química , Reação de Cicloadição , Espectroscopia de Ressonância Magnética , Nitrocompostos/síntese química , Piridonas/síntese química , Quinolonas/síntese química
16.
Chem Pharm Bull (Tokyo) ; 68(1): 77-90, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902903

RESUMO

Novel 3,5-dimethylpyridin-4(1H)-one scaffold compounds were synthesized and evaluated as AMP-activated protein kinase (AMPK) activators. Unlike direct AMPK activators, this series of compounds showed selective cell growth inhibitory activity against human breast cancer cell lines. By optimizing the lead compound (4a) from our library, 2-[({1'-[(4-fluorophenyl)methyl]-2-methyl-1',2',3',6'-tetrahydro[3,4'-bipyridin]-6-yl}oxy)methyl]-3,5-dimethylpyridin-4(1H)-one (25) was found to have potent AMPK activating activity. Compound 25 also showed good aqueous solubility while maintaining the unique selectivity in cell growth inhibitory activity.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Piridonas/química , Proteínas Quinases Ativadas por AMP/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Piridonas/síntese química , Piridonas/farmacologia , Solubilidade , Relação Estrutura-Atividade
17.
Chem Asian J ; 15(3): 360-364, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31944607

RESUMO

A RhIII -catalyzed strategy was developed for the rapid construction of highly substituted 2-pyridone scaffolds using α,ß-unsaturated oximes and fluorinated diazomalonate. The reaction proceeds through direct, site-selective alkylation based on migratory insertion and subsequent cyclocondensation. A wide substrate scope with different functional groups was explored. The requirement of fluorinated diazomalonate was explored for this transformation. The developed methodology was further extended with the synthesis of the bioactive compound.


Assuntos
Diazometano/química , Piridonas/química , Ródio/química , Catálise , Halogenação , Cinética , Piridonas/síntese química
18.
Spectrochim Acta A Mol Biomol Spectrosc ; 230: 118064, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-31955124

RESUMO

Positional isomers of benzothiazole-pyridone and benzothiazole-pyrazole containing disperse azo dyes are reported. These heterocyclic azo dyes are decorated with 'separate ESIPT core' and show emission in seven solvents of different polarity. After application on polyester fabric, "very good to excellent" light and washing fastness properties were observed. Thermal stability of 'dyed fabric' was analysed by sublimation fastness test- and found 'very good to excellent' ratings at 210 °C. Ultraviolet Protection Factor (UPF) analysis of four 'dyed fabric' indicates the blocking 96-97% of UV radiation. Dyes were found effective on gram positive and negative bacteria by agar diffusion method and all the 'dyed fabrics' also showed more than 92% or 94% reduction of S. aureus or K. pneumoniae respectively by 'AATCC 100' method. Structures of the dyes were optimized using Density Functional Theory (DFT) to deduce stable tautomeric form. Calculated HOMO-LUMO gap is then compared with antibacterial activities. Electrophilicity index and lightfastness property were also compared and found to have very good correlation.


Assuntos
Compostos Azo/química , Benzotiazóis/química , Poliésteres/química , Piridonas/química , Têxteis , Antibacterianos/química , Humanos , Infecções por Klebsiella/prevenção & controle , Klebsiella pneumoniae/efeitos dos fármacos , Pirazóis/química , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/efeitos dos fármacos , Fator de Proteção Solar , Indústria Têxtil , Têxteis/análise
19.
Biochem Med (Zagreb) ; 30(1): 010702, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31839722

RESUMO

Introduction: Clinical application of rivaroxaban and apixaban does not require therapeutic monitoring. Commercial anti-activated factor X (anti-FXa) inhibition methods for all anti-FXa drugs are based on the same principle, so there are attempts to evaluate potential clinical application of heparin-calibrated anti-FXa assay as an alternative method for direct FXa inhibitors. We aimed to evaluate relationship between anti-FXa methods calibrated with low molecular weight heparin (LMWH) and with drug specific calibrators, and to determine whether commercial LMWH anti-FXa assay can be used to exclude the presence of clinically relevant concentrations of rivaroxaban and apixaban. Materials and methods: Low molecular weight heparin calibrated reagent (Siemens Healthineers, Marburg, Germany) was used for anti-FXa activity measurement. Innovance heparin (Siemens Healthineers, Marburg, Germany) calibrated with rivaroxaban and apixaban calibrators (Hyphen BioMed, Neuville-sur-Oise, France) was used for quantitative determination of FXa inhibitors. Results: Analysis showed good agreement between LMWH calibrated and rivaroxaban calibrated activity (κ = 0.76) and very good agreement with apixaban calibrated anti-Xa activity (κ = 0.82), respectively. Low molecular weight heparin anti-FXa activity cut-off values of 0.05 IU/mL and 0.1 IU/mL are suitable for excluding the presence of clinically relevant concentrations (< 30 ng/mL) of rivaroxaban and apixaban, respectively. Concentrations above 300 ng/mL exceeded upper measurement range for LMWH anti-FXa assay and cannot be determined by this method. Conclusion: Low molecular weight heparin anti-FXa assay can be used in emergency clinical conditions for ruling out the presence of clinically relevant concentrations of rivaroxaban and apixaban. However, use of LMWH anti-FXa assay is not appropriate for their quantitative determination as an interchangeable method.


Assuntos
Anticoagulantes/química , Testes de Coagulação Sanguínea/métodos , Heparina de Baixo Peso Molecular/química , Pirazóis/química , Piridonas/química , Rivaroxabana/química , Anticoagulantes/metabolismo , Área Sob a Curva , Testes de Coagulação Sanguínea/normas , Calibragem , Compostos Cromogênicos/química , Fator Xa/química , Fator Xa/metabolismo , Inibidores do Fator Xa/química , Inibidores do Fator Xa/metabolismo , Heparina de Baixo Peso Molecular/metabolismo , Humanos , Pirazóis/metabolismo , Piridonas/metabolismo , Curva ROC
20.
Eur J Med Chem ; 187: 111917, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31806536

RESUMO

Mechanical Allodynia (MA), a frequent chronic pain symptom caused by innocuous stimuli, constitutes an unmet medical need, as treatments using analgesics available today are not always effective and can be associated with important side-effects. A series of 3,5-disubstituted pyridin-2(1H)-ones was designed, synthesized and evaluated in vivo toward a rat model of inflammatory MA. We found that the series rapidly and strongly prevented the development of MA. 3-(2-Bromophenyl)-5-(phenylamino)pyridin-2(1H)-one 69, the most active compound of the series, was also able to quickly reverse neuropathic MA in rats. Next, when 69 was evaluated toward a panel of 50 protein kinases (PK) in order to identify its potential biological target(s), we found that 69 is a p38α MAPK inhibitor, a PK known to contribute to pain hypersensitivity in animal models. 3,5-Disubstituted pyridin-2(1H)-ones thus could represent a novel class of analgesic for the treatment of MA.


Assuntos
Analgésicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Piridonas/uso terapêutico , Analgésicos/síntese química , Analgésicos/química , Animais , Relação Dose-Resposta a Droga , Estrutura Molecular , Medição da Dor , Piridonas/síntese química , Piridonas/química , Ratos , Relação Estrutura-Atividade
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