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1.
J Med Chem ; 64(1): 719-740, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33395287

RESUMO

Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.


Assuntos
Antituberculosos/química , Pirimidinonas/química , Animais , Antituberculosos/metabolismo , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Meia-Vida , Humanos , Ferro/metabolismo , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Microssomos/metabolismo , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Pirazóis/química , Pirimidinonas/metabolismo , Pirimidinonas/farmacologia , Ratos , Relação Estrutura-Atividade
2.
J Mol Graph Model ; 102: 107763, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33069124

RESUMO

The molecular electronic density theory (MEDT) was invested to elucidate the chemo-, regio- and stereo-selectivity of the 1,3-dipolar cycloaddition between Diazomethane (DZM) and Psilostachyin (PSH). The DFT method at B3LYP/6-31 + G (d,p) level of theory was used. Reactivity indices, transition structures theory, IGM and ELF analysis were employed to reveal the mechanism of the reaction. The addition of DZM to PSH takes place through a one-step mechanism and an asynchronous transition states. Eight possible addition channels of reaction were investigated (addition of C (sp2) to Diazomethane at C4, C5, C6 or C7). The addition of C (sp2) at C5 leading to P1 product is the preferred channel. The addition of ether does not affect the chemo-, regio- and stereo-selectivity of the reaction. Analysis of transfer of charges along the IRC path associated with the P1 product shows a polar character for the studied reaction. We have also used the noncovalent interaction (NCI) which is very helpful to reveal the most favored addition channel of the reaction, by analyzing the weak interactions in different TSs. Finally, we investigate about the potential of inhibition of some pyrazoline compounds against COVID-19-Mpro by performing a molecular docking calculations.


Assuntos
Antivirais/química , Antivirais/farmacologia , Lactonas/química , Lactonas/farmacologia , /enzimologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/efeitos dos fármacos , /tratamento farmacológico , Reação de Cicloadição , Diazometano/química , Humanos , Simulação de Acoplamento Molecular , Pandemias , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Conformação Proteica , Pirazóis/química , Pirazóis/farmacologia , Eletricidade Estática
3.
Chemosphere ; 263: 127972, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32822938

RESUMO

Brazil is the largest producer of sugarcane, a crop largely dependent on chemical control for its maintenance. The insecticide fipronil and herbicide 2,4-D stand out among the most commonly used pesticides and, therefore, environmental consequences are a matter of concern. The present study aimed to investigate the toxicity mechanisms of Regent® 800 WG (a.i. fipronil) and DMA® 806 BR (a.i. 2,4-D) pesticides using forced and non-forced exposures through an integrative approach: firstly, to assess whether contamination by fipronil and 2,4-D can trigger the avoidance behavior of the fish Danio rerio (zebrafish) and Hyphessobrycon eques (serpae tetra or mato-grosso). Additionally, the effects on fish were analyzed considering the swimming behavior together with a biomarker of neurotoxicity, the activity of acetylcholinesterase (AChE). In avoidance tests with pesticide gradients, D. rerio avoided the highest concentrations of the two compounds and H. eques avoided only the highest concentration of 2,4-D. The swimming behavior (distance moved) was reduced and AChE was inhibited when D. rerio was exposed to fipronil. The 2,4-D affected the swimming (maximum speed) of H. eques, but AChE was not altered. Avoidance response seemed not to have been affected by possible effects of contaminants on swimming behavior and Ache activity. This study showed the importance of knowing the avoidance capacity, swimming behavior and neurotoxic effects of pesticides on fish in an integrated and realistic context of exposure in environments contaminated with pesticides and can be useful as ecologically relevant tools for ecological risk assessment.


Assuntos
Ácido 2,4-Diclorofenoxiacético/toxicidade , Comportamento Animal/efeitos dos fármacos , Pirazóis/química , Poluentes Químicos da Água/toxicidade , Acetilcolinesterase/metabolismo , Animais , Brasil , Herbicidas/farmacologia , Inseticidas/toxicidade , Praguicidas/toxicidade , Natação , Transmissão Sináptica , Peixe-Zebra/metabolismo , Peixe-Zebra/fisiologia
4.
J Med Chem ; 64(1): 840-844, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33352050

RESUMO

A series of 1-methyl-1H-pyrazole-5-carboxamides were synthesized as potent inhibitors of the parasitic nematode of sheep, Haemonchus contortus. These compounds did not show overt cytotoxicity to a range of mammalian cell lines under standard in vitro culture conditions, had high selectivity indices, and were progressed to an acute toxicity study in a rodent model. Strikingly, acute toxicity was observed in mice. Experiments measuring cellular respiration showed a dose-dependent inhibition of mitochondrial respiration. Under these conditions, potent cytotoxicity was observed for these compounds in rat hepatocytes suggesting that the potent acute mammalian toxicity of this chemotype is most likely associated with respiratory inhibition. In contrast, parasite toxicity was not correlated to acute toxicity or cytotoxicity in respiring cells. This paper highlights the importance of identifying an appropriate in vitro predictor of in vivo toxicity early on in the drug discovery pipeline, in particular assessment for in vitro mitochondrial toxicity.


Assuntos
Antiprotozoários/farmacologia , Haemonchus/efeitos dos fármacos , Pirazóis/química , Animais , Antiprotozoários/química , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Pirazóis/farmacologia , Ratos , Ovinos/parasitologia , Relação Estrutura-Atividade
5.
Chem Biol Interact ; 330: 109231, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32853594

RESUMO

Hetero mononuclear rhenium(I) metal complexes (I-V) using different substituted indole-pyrazoline based ligands were synthesized and characterized by spectroscopic and analytical methods. The binding of the rhenium complexes to Herring sperm DNA was monitored by UV spectroscopy, viscosity measurements, and molecular docking studies; groove binding was suggested as the most possible mode and the DNA-binding constants of the complexes were evaluated. In vivo and in vitro cytotoxicity of compounds were evaluated against the brine shrimp and S. cerevisiae cells. An antimicrobial study was carried out by estimating MIC (Minimum Inhibitory Concentration) against two Gram-positive and three Gram-negative bacteria. All synthesized complexes are biologically more active than the corresponding ligands. The anti-proliferation activity of complexes was evaluated on MCF-7, HCT116, and A549 cancer cells by MTT assay. The toxicity profile of synthesized compounds was confirmed by H2O2 production by reactive oxygen species. The increased concentration of lipid peroxidation end products increased free radicals, which enhancing the oxidative stress level in living organisms and results in cell death.


Assuntos
Complexos de Coordenação/farmacologia , Indóis/química , Pirazóis/química , Rênio/química , Animais , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Artemia/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Citotoxinas/toxicidade , DNA/metabolismo , Humanos , Ligantes , Peroxidação de Lipídeos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/toxicidade , Saccharomyces cerevisiae/efeitos dos fármacos
6.
Ann N Y Acad Sci ; 1475(1): 43-51, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32483859

RESUMO

There is a significant need to study the binding of active compounds to the specific sites on insect ryanodine receptors (RyRs) that are the targets of two novel classes of diamide insecticides to which insects are becoming increasingly resistant. Here, we describe a rapid assay to study the action of potential compounds on the flubendiamide (Flu) binding site of insect RyRs that uses a fluorescence polarization assay with the fluorescence probe Flu-R-L that we synthesized. The IC50 of Flu for inhibiting probe binding on insect RyR was 18.82 ng/mL. The binding of 86 novel phthalic diamide derivatives on insect RyRs was studied using this newly established assay, and the compounds that exhibited high-affinity binding in the assay also possessed in vivo insecticidal activity against Plutella xylostella. Thus, Flu-R-L is a highly selective and sensitive fluorescence probe for studying the binding affinity of novel compounds to the Flu binding site of insect RyRs. The assay based on Flu-R-L is a rapid, accurate, and sensitive method for the screening of potentially bioactive molecules that bind specifically to insect RyRs.


Assuntos
Corantes Fluorescentes/metabolismo , Mariposas/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Benzamidas/química , Sítios de Ligação , Bioensaio , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Cinética , Pirazóis/química , Reprodutibilidade dos Testes , Sulfonas/química , ortoaminobenzoatos/química
8.
J Med Chem ; 63(11): 6066-6089, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32421339

RESUMO

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) have been suggested to be effective anti-HBV agents in both preclinical and clinical studies. In addition to blocking HBV replication, CAMs could reduce the formation of covalently closed circular DNA (cccDNA), which accounts for the persistence of HBV infection. Here, we describe the discovery of (1H-indazole-5-yl)sulfonamides and (1H-pyrazolo[3,4-c]pyridin-5-yl)sulfonamides as new CAM chemotypes by constraining the conformation of the sulfamoylbenzamide derivatives. Lead optimization resulted in compound 56 with an EC50 value of 0.034 µM and good metabolic stability in mouse liver microsomes. To increase the solubility, the amino acid prodrug (65) and its citric acid salt (67) were prepared. Compound 67 dose dependently inhibited HBV replication in a hydrodynamic injection-based mouse model of HBV infection, while 56 did not show in vivo anti-HBV activity, likely owing to its suboptimal solubility. This class of compounds may serve as a starting point to develop novel anti-HBV drugs.


Assuntos
Antivirais/química , Capsídeo/metabolismo , Vírus da Hepatite B/fisiologia , Sulfonamidas/química , Animais , Antivirais/metabolismo , Antivirais/farmacologia , Sítios de Ligação , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Linhagem Celular , DNA Viral/metabolismo , Desenho de Fármacos , Farmacorresistência Viral/efeitos dos fármacos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Terciária de Proteína , Pirazóis/química , Piridinas/química , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Montagem de Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
9.
Sci Rep ; 10(1): 7623, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376995

RESUMO

Small-molecule agonism of peroxisome proliferator-activated receptor α (PPARα), a ligand-activated transcriptional factor involved in regulating fatty acid metabolism, is an important approach for treating dyslipidemia. Here, we determined the structures of the ligand-binding domain (LBD) of PPARα in complex with 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives, which were recently identified as PPARα-selective activators with markedly different structures from those of the well-known PPARα agonists fibrates. The crystal structures of the complexes showed that they form a canonical hydrogen-bond network involving helix 12 in the LBD, which is thought to be essential for PPARα activation, as also observed for fibrates. However, the phenyl side chain of the compounds occupies a small cavity between Ile272 and Ile354, which is rarely accessed by fibrates. This unique feature may be essential for subtype selectivity and combine with the well-characterized binding mode of fibrates to improve activity. These findings demonstrate the advantage of using 1H-pyrazolo-[3,4-b]pyridine as a skeleton of PPARα agonists and provide insight into the design of molecules for treating dyslipidemia.


Assuntos
PPAR alfa/metabolismo , Pirazóis/química , Piridinas/química , Piridinas/farmacologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , PPAR alfa/química , Domínios Proteicos , Piridinas/metabolismo
10.
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
11.
Chem Biol Interact ; 325: 109127, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32437695

RESUMO

Inhibition of mouse double minute 2 homolog (MDM2)-p53 interaction and reactivation of p53 signaling have been explored as effective anticancer therapeutic strategy. The potent and specific antitumor activity shown by Nutlins, first class of MDM2-p53 inhibitors discovered, has made these compounds potential antitumor candidates. To this end, we synthesized Nutlin-1 and Nutlin-2 analogs through molecular simplification and selected the compound with the most efficient antitumoral activity. Cytotoxicity of Nutlin-2 analog LQFM126 on B16F10 melanoma cells induced intense cytoplasmic vacuolization, reduction of cell size, chromatin condensation, cytoplasmic degeneration and nuclear fragmentation. LQFM126 antiproliferative effects mediated cell cycle retention in G0/G1 phase and increased the levels of cell cycle regulatory proteins p21 and p27. This Nutlin analog increased mitochondrial membrane potential, activated caspase-8, -9 and -3/7 and reduced VEGF levels in B16F10 cells. Therefore, LQFM126 promoted alterations suggestive of apoptosis, G0/G1 cell cycle arrest and suppression of angiogenesis through modulation of VEGF expression in B16F10 cells. Additionally, LQFM126 was classified as UN GHS category 4 (LD50 > 300-2000 mg/kg), suggesting it has low acute systemic toxicity. LQFM126 can be a promising prototype for anticancer therapy.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Melanoma Experimental/patologia , Pirazóis/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imidazóis/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Piperazinas/química , Pirazóis/síntese química , Pirazóis/química , Pirazóis/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
12.
PLoS One ; 15(5): e0233089, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32459810

RESUMO

Many drugs are promiscuous and bind to multiple targets. On the one hand, these targets may be linked to unwanted side effects, but on the other, they may achieve a combined desired effect (polypharmacology) or represent multiple diseases (drug repositioning). With the growth of 3D structures of drug-target complexes, it is today possible to study drug promiscuity at the structural level and to screen vast amounts of drug-target interactions to predict side effects, polypharmacological potential, and repositioning opportunities. Here, we pursue such an approach to identify drugs inactivating B-cells, whose dysregulation can function as a driver of autoimmune diseases. Screening over 500 kinases, we identified 22 candidate targets, whose knock out impeded the activation of B-cells. Among these 22 is the gene KDR, whose gene product VEGFR2 is a prominent cancer target with anti-VEGFR2 drugs on the market for over a decade. The main result of this paper is that structure-based drug repositioning for the identified kinase targets identified the cancer drug ibrutinib as micromolar VEGFR2 inhibitor with a very high therapeutic index in B-cell inactivation. These findings prove that ibrutinib is not only acting on the Bruton's tyrosine kinase BTK, against which it was designed. Instead, it may be a polypharmacological drug, which additionally targets angiogenesis via inhibition of VEGFR2. Therefore ibrutinib carries potential to treat other VEGFR2 associated disease. Structure-based drug repositioning explains ibrutinib's anti VEGFR2 action through the conservation of a specific pattern of interactions of the drug with BTK and VEGFR2. Overall, structure-based drug repositioning was able to predict these findings at a fraction of the time and cost of a conventional screen.


Assuntos
Reposicionamento de Medicamentos/métodos , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Linfócitos B/metabolismo , Humanos , Células Jurkat , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Suramina/química , Suramina/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
13.
Life Sci ; 252: 117643, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32298738

RESUMO

AIMS: Non-peptide ligands of oxytocin receptor (OTR) have promising potentialities as therapeutic agents with improved pharmacological properties. WAY-267,464 is a non-peptide agonist which loses its agonist activity when its resorcinol moiety is methylated, yielding a partial antagonist (denoted here, WAY-Methylated). This study attempts to rationalize these opposing activities by comparative analyses of structural dynamicsof OTR in complex with these ligands. MAIN METHODS: Glide extra precision (XP) docking with and without positional constraints was employed to probe alternative binding poses of both WAY-267,464 and WAY-Methylated. The more preferred configuration of each system was subjected to an extended 2 µs MD simulation and the physics-based Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding energy was used to rank the complexes with improved accuracy, in addition to empirical-based Glide docking score. Network analysis was performed, and the identified critical residues were cross-referenced with the experimental mutagenesis data. KEY FINDINGS: The added methyl groups in the antagonist WAY-Methylated enhanced hydrophobicity, resulting in a flipped binding pose deeper in the binding pocket. Interestingly, OTR responded to the methylation by stabilizing the initial inactive conformation, decreasing fluctuations and increasing the overall secondary structural composition. Conversely, the agonist WAY-267,464 produced larger fluctuations to allow the receptor to change from the default inactive state to a state of partial activation. These transitions were further supported by the identified critical residues overlapping with experimental mutagenesis data. SIGNIFICANCE: These findings provide insights into the activation mechanism of OTR by WAY-267.464 and its antagonism by WAY-Methylated.


Assuntos
Benzodiazepinas/farmacologia , Simulação de Dinâmica Molecular , Pirazóis/farmacologia , Receptores de Ocitocina/agonistas , Benzodiazepinas/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Metilação , Simulação de Acoplamento Molecular , Ligação Proteica , Pirazóis/química , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/metabolismo
14.
Mol Pharmacol ; 97(6): 409-422, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32241960

RESUMO

The microtubule-binding taxanes, docetaxel and cabazitaxel, are administered intravenously for the treatment of castration-resistant prostate cancer (CRPC) as the oral administration of these drugs is largely hampered by their low and highly variable bioavailabilities. Using a simple, rapid, and environmentally friendly microwave-assisted protocol, we have synthesized a number of 3,5-bis(styryl)pyrazoles 2a-l, thus allowing for their screening for antiproliferative activity in the androgen-independent PC3 prostate cancer cell line. Surprisingly, two of these structurally simple 3,5-bis(styryl)pyrazoles (2a and 2l) had concentrations which gave 50% of the maximal inhibition of cell proliferation (GI50) in the low micromolar range in the PC3 cell line and were thus selected for extensive further biologic evaluation (apoptosis and cell cycle analysis, and effects on tubulin and microtubules). Our findings from these studies show that 3,5-bis[(1E)-2(2,6-dichlorophenyl)ethenyl]-1H-pyrazole 2l 1) caused significant effects on the cell cycle in PC3 cells, with the vast majority of treated cells in the G2/M phase (89%); 2) induces cell death in PC3 cells even after the removal of the compound; 3) binds to tubulin [dissociation constant (Kd) 0.4 ± 0.1 µM] and inhibits tubulin polymerization in vitro; 4) had no effect upon the polymerization of the bacterial cell division protein FtsZ (a homolog of tubulin); 5) is competitive with paclitaxel for binding to tubulin but not with vinblastine, crocin, or colchicine; and 6) leads to microtubule depolymerization in PC3 cells. Taken together, these results suggest that 3,5-bis(styryl)pyrazoles warrant further investigation as lead compounds for the treatment of CRPC. SIGNIFICANCE STATEMENT: The taxanes are important components of prostate cancer chemotherapy regimens, but their oral administration is hampered by very low and highly variable oral bioavailabilities resulting from their poor absorption, poor solubility, high first-pass metabolism, and efficient efflux by P-glycoprotein. New chemical entities for the treatment of prostate cancer are thus required, and we report here the synthesis and investigation of the mechanism of action of some bis(styryl)pyrazoles, demonstrating their potential as lead compounds for the treatment of prostate cancer.


Assuntos
Antineoplásicos/uso terapêutico , Chumbo/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirazóis/uso terapêutico , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Humanos , Chumbo/química , Masculino , Microtúbulos/efeitos dos fármacos , Modelos Moleculares , Células PC-3 , Pirazóis/síntese química , Pirazóis/química
15.
Eur J Med Chem ; 192: 112161, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32155529

RESUMO

KDM5B (also known as PLU-1 and JARID1B) is 2-oxoglutarate and Fe2+ dependent oxygenase that acts as a histone H3K4 demethylase, which is a key participant in inhibiting the expression of tumor suppressors as a drug target. Here, we present the discovery of pyrazole derivatives compound 5 by structure-based virtual screening and biochemical screening with IC50 of 9.320 µM against KDM5B, and its subsequent optimization to give 1-(4-methoxyphenyl)-N-(2-methyl-2-morpholinopropyl)-3-phenyl-1H-pyrazole-4-carboxamide (27 ab), a potent KDM5B inhibitor with IC50 of 0.0244 µM. In MKN45 cells, compound 27 ab can bind and stabilize KDM5B and induce the accumulation of H3K4me2/3, bona fide substrates of KDM5B, while keep the amount of H3K4me1, H3K9me2/3 and H3K27me2 without change. Further biological study also indicated that compound 27 ab is a potent cellular active KDM5B inhibitor that can inhibit MKN45 cell proliferation, wound healing and migration. In sum, our finding gives a novel structure for the discovery of KDM5B inhibitor and targeting KDM5B may be a new therapeutic strategy for gastric cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Histona Desmetilases com o Domínio Jumonji , Estrutura Molecular , Proteínas Nucleares , Pirazóis/síntese química , Pirazóis/química , Proteínas Repressoras , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacos
16.
J Agric Food Chem ; 68(14): 4144-4154, 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32191457

RESUMO

In the current work, we synthesized two series of dehydroabietyl amide derivatives from natural product rosin and evaluated their antifungal effects on Valsa mali, Phytophthora capsici, Botrytis cinerea, Sclerotinia sclerotiorum, and Fusarium oxysporum. In vitro and in vivo antifungal activities results indicated that rosin-based amide compounds containing thiophene heterocycles had better inhibitory effects on B. cinerea. In particular, compound 5b (5-fluoro-2-thiophene dehydroabietyl amide) exhibited the excellent antifungal properties against B. cinerea with an EC50 of 0.490 mg/L, which was lower compared to the positive control penthiopyrad (0.562 mg/L). Physiological and biochemical studies showed that the primary action mechanism of compound 5b on B. cinerea changes mycelial morphology, increases cell membrane permeability, and inhibits the TCA pathway in respiratory metabolism. Furthermore, QSAR and SAR studies revealed that charge distribution of rosin-based amides derivatives have a key role in the antifungal activity through the hydrogen bonding, conjugation, and electrostatic interaction between the compounds and the receptors of the target. To sum up, this study contributes to the development of rosin-based antifungal agents with a novel structure and preferable biological activity.


Assuntos
Amidas/síntese química , Antifúngicos/química , Produtos Biológicos/química , Proteção de Cultivos/métodos , Resinas Vegetais/química , Antifúngicos/farmacologia , Ascomicetos/efeitos dos fármacos , Produtos Biológicos/farmacologia , Descoberta de Drogas , Fusarium/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Fungos Mitospóricos/efeitos dos fármacos , Estrutura Molecular , Phytophthora/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Resinas Vegetais/farmacologia , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologia
17.
J Med Chem ; 63(8): 4090-4106, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32202425

RESUMO

Fatty-acid binding protein 4 (FABP4) is a promising therapeutic target for immunometabolic diseases, while its potential for systemic inflammatory response syndrome treatment has not been explored. Here, a series of 2-(phenylamino)benzoic acids as novel and potent FABP4 inhibitors are rationally designed based on an interesting fragment that adopts multiple binding poses within FABP4. A fusion of these binding poses leads to the design of compound 3 with an ∼460-fold improvement in binding affinity compared to the initial fragment. A subsequent structure-aided optimization upon 3 results in a promising lead (17) with the highest binding affinity among all the inhibitors, exerting a significant anti-inflammatory effect in cells and effectively attenuating a systemic inflammatory damage in mice. Our work therefore presents a good example of lead compound discovery derived from the multiple binding poses of a fragment and provides a candidate for development of drugs against inflammation-related diseases.


Assuntos
Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/metabolismo , Descoberta de Drogas/métodos , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/metabolismo , Células 3T3 , Administração Oral , Animais , Anti-Inflamatórios/química , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Células CACO-2 , Relação Dose-Resposta a Droga , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Pirazóis/administração & dosagem , Pirazóis/química , Pirazóis/metabolismo , Resultado do Tratamento
18.
J Med Chem ; 63(7): 3538-3551, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32134266

RESUMO

The overaccumulation of glycogen appears as a hallmark in various glycogen storage diseases (GSDs), including Pompe, Cori, Andersen, and Lafora disease. Accumulating evidence suggests that suppression of glycogen accumulation represents a potential therapeutic approach for treating these GSDs. Using a fluorescence polarization assay designed to screen for inhibitors of the key glycogen synthetic enzyme, glycogen synthase (GS), we identified a substituted imidazole, (rac)-2-methoxy-4-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-phenyl-1H-imidazol-5-yl)phenol (H23), as a first-in-class inhibitor for yeast GS 2 (yGsy2p). Data from X-ray crystallography at 2.85 Å, as well as kinetic data, revealed that H23 bound within the uridine diphosphate glucose binding pocket of yGsy2p. The high conservation of residues between human and yeast GS in direct contact with H23 informed the development of around 500 H23 analogs. These analogs produced a structure-activity relationship profile that led to the identification of a substituted pyrazole, 4-(4-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrogallol, with a 300-fold improved potency against human GS. These substituted pyrazoles possess a promising scaffold for drug development efforts targeting GS activity in GSDs associated with excess glycogen accumulation.


Assuntos
Inibidores Enzimáticos/química , Glicogênio Sintase/antagonistas & inibidores , Imidazóis/química , Pirazóis/química , Animais , Caenorhabditis elegans/enzimologia , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Glicogênio Sintase/química , Glicogênio Sintase/metabolismo , Células HEK293 , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Cinética , Estrutura Molecular , Ligação Proteica , Pirazóis/síntese química , Pirazóis/metabolismo , Saccharomyces cerevisiae/enzimologia , Relação Estrutura-Atividade
19.
Pharmacol Rep ; 72(1): 36-46, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32016854

RESUMO

BACKGROUND/OBJECTIVES: 4-(Arylchalcogenyl)-1H-pyrazoles containing selenium or sulfur (0.001-50 mg/kg) were investigated regarding the intragastric route effect (ig) administration on nociception in mice. In this study, nociception and inflammation were induced by chemical agents such as formalin (0.92%), sodium L-glutamate 1-hydrate (20 µmol), croton oil (2.5%), acetic acid (1.6%) and thermic model with a hot plate test. RESULTS: Compounds 1a-c had the ability to reduce licking time in both phases (neurogenic and inflammatory) of the formalin test and glutamate. Only compounds 1a and 1b had the ability to reduce the number of abdominal writhes caused by acetic acid. The same was observed with the positive control celecoxib. To evaluate the possible anti-inflammatory activity of compounds 1a-c, the induction of paw edema by formalin and ear edema by croton oil was performed. For the inflammation induced by formalin, significant effects were observed from the dose of 0.1 mg/kg (1a-b) and 10 mg/kg (1c). In the ear edema test, it can be observed that only compound 1a had a significant effect. In the hotplate test, all the compounds had the ability to reduce the latency time. CONCLUSION: The results demonstrated that acute antinociceptive and anti-inflammatory effects of 4-(arylchalcogenyl)-1H-pyrazoles 1a is better than compared with the compound 1b and 1c in mice. This resulted in these molecules attracting the interest of researchers to perform future studies to develop new drugs to treat pain and inflammatory clinical conditions.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Pirazóis/farmacologia , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Celecoxib/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Pirazóis/administração & dosagem , Pirazóis/química , Selênio/química , Enxofre/química
20.
Dalton Trans ; 49(8): 2505-2516, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32022055

RESUMO

In this study, we designed and synthesized four novel multi-nuclear silver complexes (1-4) coordinated with pyrazole- or pyridine-functionalized N-heterocyclic carbene (NHC) ligands. The crystal structures of the silver-NHC complexes were confirmed by X-ray diffraction analysis. In vitro assays showed that the silver-NHC complexes effectively killed a broad range of cancer cells after short-term drug exposure, serving as fast-acting cytotoxic agents. Of note, in cisplatin-resistant A549 cancer cells, the silver complexes were not cross-resistant with the clinically used cisplatin agent. Detailed mechanistic studies revealed that complex 2 triggered caspase-independent cell necrosis associated with intracellular reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) depletion. By exploiting a facile nano-assembly process, silver-NHC complexes 1, 2 and 4 were successfully integrated into the hydrophobic cores of amphiphilic matrices (DSPE-PEG2K), enabling systemic injection. The silver complex-loaded nanotherapeutics (1-NPs, 2-NPs, and 4-NPs) showed high safety margins with reduced systemic drug toxicities relative to cisplatin in animals. Furthermore, in a xenograft model of human colorectal cancer, the administration of the nanotherapeutics resulted in a marked inhibition of tumor progression.


Assuntos
Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Metano/análogos & derivados , Nanopartículas/química , Pirazóis/química , Piridinas/química , Prata/química , Células A549 , Animais , Apoptose , Proliferação de Células , Neoplasias do Colo/patologia , Compostos Heterocíclicos/farmacologia , Humanos , Metano/química , Camundongos , Estrutura Molecular , Nanopartículas/administração & dosagem , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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