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1.
Int J Mol Sci ; 22(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34639113

RESUMO

Among the serotonin receptors, one of the most recently discovered 5-HT6 subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT6 receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT6 receptor. Thus, a broader pharmacological profile for 1-3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT6 receptor target.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Demência/tratamento farmacológico , Receptores de Serotonina/química , Antagonistas da Serotonina/farmacologia , Triazinas/farmacologia , Animais , Células CACO-2 , Humanos , Masculino , Estrutura Molecular , Ratos , Ratos Wistar , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/química , Relação Estrutura-Atividade , Triazinas/química
2.
J Gen Virol ; 102(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34661516

RESUMO

The polymerase acidic (PA) I38T substitution is a dominant marker of resistance to baloxavir. We evaluated the impact of I38T on the fitness of a contemporary influenza A(H3N2) virus. Influenza A/Switzerland/9715293/2013 (H3N2) wild-type (WT) virus and its I38T mutant were rescued by reverse genetics. Replication kinetics were compared using ST6GalI-MDCK and A549 cells and infectivity/contact transmissibility were evaluated in guinea pigs. Nasal wash (NW) viral titres were determined by TCID50 ml-1 in ST6GalI-MDCK cells. Competition experiments were performed and the evolution of viral population was assessed by droplet digital RT-PCR. I38T did not alter in vitro replication. I38T induced comparable titres vs the WT in guinea pigs NWs and the two viruses transmitted equally by direct contact. However, a 50 %:50 % mixture inoculum evolved to mean WT/I38T ratios of 71 %:29 % and 66.4 %:33.6 % on days 4 and 6 p.i., respectively. Contemporary influenza A(H3N2)-I38T PA variants may conserve a significant level of viral fitness.


Assuntos
Vírus da Influenza A Subtipo H3N2/fisiologia , Infecções por Orthomyxoviridae/virologia , RNA Polimerase Dependente de RNA/genética , Proteínas Virais/genética , Células A549 , Substituição de Aminoácidos , Animais , Antivirais/farmacologia , Dibenzotiepinas/farmacologia , Cães , Farmacorresistência Viral , Cobaias , Humanos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/patogenicidade , Células Madin Darby de Rim Canino , Morfolinas/farmacologia , Nariz/virologia , Infecções por Orthomyxoviridae/transmissão , Piridonas/farmacologia , RNA Polimerase Dependente de RNA/química , RNA Polimerase Dependente de RNA/metabolismo , Genética Reversa , Triazinas/farmacologia , Carga Viral , Proteínas Virais/química , Proteínas Virais/metabolismo , Replicação Viral
3.
PLoS One ; 16(10): e0258817, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34665844

RESUMO

Radiation is an important therapeutic strategy for hepatocellular (HCC). In this study, we evaluated the role of the dual PI3K/mTOR inhibitor, PKI-587, on radiosensitization of HCC and its possible mechanism. MTT, colony formation, flow cytometry, and immunofluorescence were used to analyze the proliferation, cell cycle, formation of residual γ-H2AX foci, and apoptosis of HCC cells. A SK-Hep1 xenograft HCC model was used to assess the effects of PKI-587 in combination with ionizing radiation in vivo. The activation levels of PI3K/AKT/mTOR and DNA damage repair pathways and their downstream effector molecules were detected with Western blot. It was found that PKI-587 sensitized HCC cells to radiation by increasing DNA damage, enhancing G0/G1 cell-cycle arrest, and inducing apoptosis. In vivo, the combination of radiation with PKI-587 significantly inhibited tumor growth. These findings suggest the usefulness of PKI-587 on radiosensitization of HCC cells by inhibiting the PI3K/AKT/mTOR and DNA damage repair pathways. The combination of ionizing radiation and PKI-587 may be a strategy to improve the efficacy of treating HCC.


Assuntos
Carcinoma Hepatocelular/terapia , Quimiorradioterapia/métodos , Neoplasias Hepáticas/terapia , Morfolinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Radiossensibilizantes/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Triazinas/administração & dosagem , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Radiossensibilizantes/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Triazinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Life Sci ; 285: 119994, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34592236

RESUMO

AIM OF THE STUDY: Breast cancer is caused by abnormal growth of the cells and progressed due to the over-expression of estrogen (ER) and progesterone (PR). The current study was designed to evaluate the anti-tumor activity of 2,4,6 tris-methyphenylamino1,3,5-triazine compound (MPAT) in N-nitroso, N-methyl urea (NMU)-induced mammary gland cancer. METHODS: Molecular docking and in-vitro studies were conducted before the in-vivo analysis. Female Albino rats were divided into 5 groups (n = 6). Group I received Carboxymethylcellulose (CMC) (1 mL/100 g). Group II (diseased group) received NMU 50 mg/kg. Group III (standard group) received tamoxifen (5 mg/kg). Group IV-V received MPAT at doses of 30 and 60 mg/kg respectively. All groups received NMU intraperitoneally except the control group at 3 weeks intervals for 12 weeks. After 12 weeks of NMU dosing, MPAT was given for 15 consecutive days. Biochemical, oxidative stress markers, hormonal profile, and inflammatory mediators were analyzed. KEY FINDINGS: MPAT showed significant interaction with the selected targets in docking studies. An over-expression of ER and PR was observed in NMU-treated rats which were restored significantly after MPAT administration. Nitrite and MDA levels were high in the diseased group and MPAT treatment attenuated the oxidative damage after treatment. Antioxidants such as superoxide dismutase (SOD), Catalase (CAT), total sulfhydryl (TSH), glutathione (GSH), and Lactate dehydrogenase (LDH) values were low in NMU-treated rats. SIGNIFICANCE: This study concluded that MPAT can be used as an anticancer agent due to its significant effects on down-regulating the hormonal profile and oxidative stress markers.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Estrogênios/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Progesterona/metabolismo , Triazinas/farmacologia , Animais , Antineoplásicos/química , Regulação para Baixo , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Células MCF-7 , Estresse Oxidativo/efeitos dos fármacos , Oxirredutases/metabolismo , Progesterona/antagonistas & inibidores , Ratos , Tamoxifeno/farmacologia , Triazinas/química
5.
Antiviral Res ; 194: 105158, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34363859

RESUMO

It is more than 20 years since the neuraminidase inhibitors, oseltamivir and zanamivir were approved for the treatment and prevention of influenza. Guidelines for global surveillance and methods for evaluating resistance were established initially by the Neuraminidase Inhibitor Susceptibility Network (NISN), which merged 10 years ago with the International Society for influenza and other Respiratory Virus Diseases (isirv) to become the isirv-Antiviral Group (isirv-AVG). With the ongoing development of new influenza polymerase inhibitors and recent approval of baloxavir marboxil, the isirv-AVG held a closed meeting in August 2019 to discuss the impact of resistance to these inhibitors. Following this meeting and review of the current literature, this article is intended to summarize current knowledge regarding the clinical impact of resistance to polymerase inhibitors and approaches for surveillance and methods for laboratory evaluation of resistance, both in vitro and in animal models. We highlight limitations and gaps in current knowledge and suggest some strategies for addressing these gaps, including the need for additional clinical studies of influenza antiviral drug combinations. Lessons learned from influenza resistance monitoring may also be helpful for establishing future drug susceptibility surveillance and testing for SARS-CoV-2.


Assuntos
Antivirais/uso terapêutico , Influenza Humana/tratamento farmacológico , Animais , Antivirais/efeitos adversos , Antivirais/farmacologia , Dibenzotiepinas/farmacologia , Farmacorresistência Viral , Inibidores Enzimáticos/farmacologia , Humanos , Influenza Humana/virologia , Conhecimento , Morfolinas/farmacologia , Neuraminidase/uso terapêutico , Oseltamivir/farmacologia , Piridonas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Triazinas/farmacologia , Replicação Viral/efeitos dos fármacos , Zanamivir/farmacologia
6.
Antimicrob Agents Chemother ; 65(11): e0031121, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34460304

RESUMO

Novel bis-1,2,4-triazine compounds with potent in vitro activity against Plasmodium falciparum parasites were recently identified. The bis-1,2,4-triazines represent a unique antimalarial pharmacophore and are proposed to act by a novel but as-yet-unknown mechanism of action. This study investigated the activity of the bis-1,2,4-triazine MIPS-0004373 across the mammalian life cycle stages of the parasite and profiled the kinetics of activity against blood and transmission stage parasites in vitro and in vivo. MIPS-0004373 demonstrated rapid and potent activity against P. falciparum, with excellent in vitro activity against all asexual blood stages. Prolonged in vitro drug exposure failed to generate stable resistance de novo, suggesting a low propensity for the emergence of resistance. Excellent activity was observed against sexually committed ring stage parasites, but activity against mature gametocytes was limited to inhibiting male gametogenesis. Assessment of liver stage activity demonstrated good activity in an in vitro P. berghei model but no activity against Plasmodium cynomolgi hypnozoites or liver schizonts. The bis-1,2,4-triazine MIPS-0004373 efficiently cleared an established P. berghei infection in vivo, with efficacy similar to that of artesunate and chloroquine and a recrudescence profile comparable to that of chloroquine. This study demonstrates the suitability of bis-1,2,4-triazines for further development toward a novel treatment for acute malaria.


Assuntos
Malária , Parasitos , Animais , Malária/tratamento farmacológico , Masculino , Plasmodium berghei , Triazinas/farmacologia
7.
Cells ; 10(8)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34440640

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disorder and results in severe neurodegeneration and progressive cognitive decline. Neurotrophins are growth factors involved in the development and survival of neurons, but also in underlying mechanisms for memory formation such as hippocampal long-term potentiation. Our aim was to identify small molecules with stimulatory effects on the signaling of two neurotrophins, the nerve growth factor (NGF) and the brain derived neurotrophic factor (BDNF). To identify molecules that could potentiate neurotrophin signaling, 25,000 molecules were screened, which led to the identification of the triazinetrione derivatives ACD855 (Ponazuril) and later on ACD856, as positive allosteric modulators of tropomyosin related kinase (Trk) receptors. ACD855 or ACD856 potentiated the cellular signaling of the neurotrophin receptors with EC50 values of 1.9 and 3.2 or 0.38 and 0.30 µM, respectively, for TrkA or TrkB. ACD855 increased acetylcholine levels in the hippocampus by 40% and facilitated long term potentiation in rat brain slices. The compounds acted as cognitive enhancers in a TrkB-dependent manner in several different behavioral models. Finally, the age-induced cognitive dysfunction in 18-month-old mice could be restored to the same level as found in 2-month-old mice after a single treatment of ACD856. We have identified a novel mechanism to modulate the activity of the Trk-receptors. The identification of the positive allosteric modulators of the Trk-receptors might have implications for the treatment of Alzheimer's diseases and other diseases characterized by cognitive impairment.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Nootrópicos/farmacologia , Receptores de Fator de Crescimento Neural/agonistas , Fatores Etários , Animais , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Linhagem Celular Tumoral , Disfunção Cognitiva/enzimologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Glicoproteínas de Membrana , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Proteínas Tirosina Quinases , Ratos Sprague-Dawley , Receptor trkA/agonistas , Receptor trkA/metabolismo , Receptor trkB/agonistas , Receptor trkB/metabolismo , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Transdução de Sinais , Bibliotecas de Moléculas Pequenas , Triazinas/farmacologia
8.
Biochem Biophys Res Commun ; 572: 185-190, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34375928

RESUMO

The pathogenesis of heart failure with preserved ejection fraction (HFpEF) in obese diabetic patients has been implicated in metainflammation. Increased expression of inducible nitric oxide synthase (iNOS) and dysfunction of the unfolded protein response (UPR), especially inositol-requiring enzyme 1α-X-box binding protein 1 (IRE1α-Xbp1s) signaling in the heart, have been associated with HFpEF. We investigated the effect of imeglimin, a potential new treatment for type 2 diabetes, on the pathogenesis of HFpEF. We induced obesity, impaired glucose tolerance, and cardiac hypertrophy with fibrosis, fat accumulation, and diastolic dysfunction in wild-type mice with a high-fat diet (HFD) and the nitric oxide synthase (NOS) inhibitor l-NAME for 16 weeks. Treatment with imeglimin starting at 10 weeks not only improved their abnormal systemic glucose metabolism and visceral obesity but also their cardiac abnormalities. We found that imeglimin suppressed the upregulation of iNOS, and restored the expression of Xbp1s and the expression of the E3 ubiquitin ligase STIP1 homology and U-box-containing protein 1 (STUB1), which is responsible for the degradation of Forkhead box protein O1 (FoxO1), a direct transcriptional target of Xbp1s. It also suppressed the excessive transcriptional activity of FoxO1, which is located downstream of Xbp1s and is involved in the form development of HFpEF and cardiac adipogenesis. Imeglimin also restored the expression of Glutathione peroxidase 4 (GPX4), which protects cells against excess lipid peroxidation and governs a novel form of programmed cell death, called ferroptosis.


Assuntos
Insuficiência Cardíaca/prevenção & controle , Volume Sistólico/efeitos dos fármacos , Triazinas/farmacologia , Animais , Insuficiência Cardíaca/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Desdobramento de Proteína
9.
Molecules ; 26(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299654

RESUMO

A tripodal Schiff base ligand, 2,4,6-Tris(4-carboxybenzimino)-1,3,5-triazine (MT) and its trinuclear Dy(III), Er(III), and Gd(III) complexes were synthesized. These were characterized using UV-visible, IR, 1H, and 13C NMR spectroscopies, elemental analysis, and molar conductivity measurements. The spectral studies indicate that the ligand is hexadentate and coordinates to the Ln(III) ions through the oxygen atoms of the carboxylic group. The trinuclear complexes were characterized as being bridged by carboxylate anions to the Dy(III), Er(III), and Gd(III) salen centers and displaying a coordination number of six. Biological studies revealed that MT is more active against the test micro-organisms relative to the trinuclear complexes. Acute toxicity studies revealed that MT is safe and has a wide range of effective doses (ED50). In vivo antimalarial studies indicate that MT could serve as an effective antimalarial agent since it has parasitemia inhibition of 84.02% at 50 mg/kg and 65.81% at 25 mg/kg, close to the value (87.22%) of the standard drug-Artesunate. Molecular docking simulation studies on the compounds against SARS-CoV-2 (6Y84) and E. coli DNA gyrase (5MMN) revealed effective binding interactions through multiple bonding modes. The binding energy calculated for Er(III)MT-6Y84 and Er(III)MT-5MMN complexes showed active molecules with the ability to inhibit SARS-CoV-2 and E. coli DNA gyrase.


Assuntos
Triazinas/química , Triazinas/farmacologia , Ânions/química , Ácidos Carboxílicos/química , Simulação por Computador , Complexos de Coordenação/química , Cristalografia por Raios X/métodos , Disprósio/química , Érbio/química , Gadolínio/química , Elementos da Série dos Lantanídeos/química , Ligantes , Espectroscopia de Ressonância Magnética/métodos , Simulação de Acoplamento Molecular , Estrutura Molecular , Bases de Schiff/química , Triazinas/síntese química
10.
J Biochem Mol Toxicol ; 35(9): e22860, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34313355

RESUMO

The present manuscript deals with the development of novel p-aminobenzoic acid (PABA) associated 1,3,5-triazine derivatives as antimalarial agents. The molecules were developed via microwave-assisted synthesis and structures of compounds were ascertained via numerous analytical and spectroscopic techniques. The synthesized compounds were also subjected to ADMET analysis. In a docking analysis, the title compounds showed high and diverse binding affinities towards wild (-162.45 to -369.38 kcal/mol) and quadruple mutant (-165.36 to -209.47 kcal/mol) Pf-DHFR-TS via interacting with Phe58, Arg59, Ser111, Ile112, Phe116. The in vitro antimalarial activity suggested that compounds 4e, 4b, and 4h showed IC50 ranging from 4.18 to 8.66 µg/ml against the chloroquine-sensitive (3D7) strain of Plasmodium falciparum. Moreover, compounds 4g, 4b, 4e, and 4c showed IC50 ranging from 8.12 to 12.09 µg/ml against chloroquine-resistant (Dd2) strain. In conclusion, our study demonstrated the development of hybrid PABA substituted 1,3,5-triazines as a novel class of Pf-DHFR inhibitor for antimalarial drug discovery.


Assuntos
Antimaláricos , Micro-Ondas , Plasmodium falciparum/crescimento & desenvolvimento , Triazinas , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Humanos , Triazinas/síntese química , Triazinas/química , Triazinas/farmacologia
11.
Eur J Med Chem ; 223: 113537, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34147747

RESUMO

Heterocyclic compounds create an important class of molecules that demonstrates various chemical spaces for the definition of effective medicines. Many N-heterocycles display numerous biological activities. Among condensed heterocycles, pyrazolotriazine derivatives have received the attention of researchers owing to the extensive spectrum of biological activities. The reactivity of identified compounds was similar to the free azoles and triazines. The pyrazolotriazine scaffold exhibited antiasthma, antiinflammatory, anticancer, antithrombogenic activity and showed activity for major depression and pathological anxiety. Pyrazolotriazine derivatives also exhibited antibacterial, anticancer, antimetabolites, antidiabetic, antiamoebic, anticonvulsant, antiproliferative activity, human carbonic anhydrase inhibition, cyclin-dependent kinase 2 inhibition, tyrosinase and urease inhibition, MAO-B inhibition, TTK inhibition, thymidine phosphorylase inhibition, tubulin polymerization inhibition, protoporphyrinogen oxidase inhibition, GABAA agonistic activity, hCRF1 receptor antagonistic activity, and CGRP receptor antagonistic activity. This paper structurally categorized various pyrazolotriazines to isomeric classes into six groups that containing pyrazolo [1,5-d] [1,2,4] triazine, pyrazolo [5,1-c] [1,2,4] triazine, pyrazolo [3,4-e] [1,2,4] triazine, pyrazolo [4,3-e] [1,2,4] triazines, pyrazolo [1,5-a] [1,3,5] triazine, and pyrazolo [3,4-d] [1,2,3] triazine and expressed biological activity, the synthetic procedures for each class of pyrazolotriazines, structure-activity relationship and their mechanism of action. Generally, this review summarily indicated the past and present studies about the discovery of new lead compounds with good biological activity.


Assuntos
Pirazóis/farmacologia , Triazinas/farmacologia , Animais , Humanos , Estrutura Molecular , Pirazóis/síntese química , Relação Estrutura-Atividade , Triazinas/síntese química
12.
Vet Parasitol ; 296: 109477, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34087564

RESUMO

An anticoccidial model of chicken infected with Eimeria tenella was established to investigate the effect of toltrazuril (Tol) combined with the Radix Sophorae Flavescentis (RSF) on coccidiosis. The anticoccidial index (ACI) was evaluated, and the cecal developmental parameters (i.e., villus height, [VH], crypt depth, [CD], and VH/CD) were determined. The distributions of glycoproteins and goblet cells in the cecal tissue were determined through the Periodic Acid-Schiff (PAS) and Alcian blue PAS staining methods, respectively. The mRNA expression levels of interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-10, and IL-17 of the cecal tissue were determined through quantitative real-time PCR. The moderate ACI was obtained using the combination of Tol and RSF. Compared with the normal control (NC) group, the infected control (IC) group showed remarkably lower VH and VH/CD at five and seven days postinfection. Compared with the IC group, the IC + RSF and IC + TolRSF groups showed remarkably higher VH and VH/CD at five and seven days postinfection. Compared with the NC group, the IC group contained fewer glycoproteins and goblet cells, but the Tol and RSF treatment promoted more glycoproteins and goblet cells at five and seven days postinfection. The mRNA expression levels of IL-1ß, IL-2, IL-4, IL-6, IL-10, and IL-17 in the IC group were upregulated (P < 0.01) compared with those in the NC group. The IC + RSF and IC + TolRSF groups had downregulated mRNA expression levels of IL-1ß, IL-6, and IL-17 cytokines (P < 0.01), and upregulated mRNA expression levels of IL-2 and IL-4 cytokines (P < 0.01) compared with the IC group. Results showed that the combination of Tol and RSF exerts anticoccidial effect by reducing inflammation and promoting intestinal mucosal immunity.


Assuntos
Imunidade nas Mucosas , Extratos Vegetais , Ranunculaceae , Triazinas , Animais , Galinhas , Coccidiose/tratamento farmacológico , Coccidiose/veterinária , Coccidiostáticos/farmacologia , Coccidiostáticos/uso terapêutico , Eimeria tenella , Regulação da Expressão Gênica/efeitos dos fármacos , Imunidade nas Mucosas/efeitos dos fármacos , Inflamação/veterinária , Interleucinas/genética , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Doenças das Aves Domésticas/tratamento farmacológico , Ranunculaceae/química , Triazinas/farmacologia , Triazinas/uso terapêutico
13.
Sci Rep ; 11(1): 13235, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34168219

RESUMO

Carotenoid plumage coloration is an important sexually selected trait in many bird species. However, the mechanisms ensuring the honesty of signals based on carotenoid pigments remain unclear. It has recently been suggested that intestinal integrity, which is affected by gut parasites and microbiota and influences nutrient absorption and acquisition, mediates the relationship between carotenoid ornamentation and individual quality. Here, we test whether carotenoid plumage coloration in greenfinches (Chloris chloris) is affected by the treatment of an antibiotic or an antiparasitic drug. We captured wild greenfinches (N = 71) and administered anticoccidial medication toltrazuril (TOLTRA) to one group, antibiotic metronidazole (METRO) to the second group to target trichomonosis, and the third group received no medication. In the METRO group, feathers grown during the experiment had significantly higher chroma of yellow parts, but there was no effect of TOLTRA on feather chroma. The results suggest that METRO increased the efficiency of carotenoid modification or deposition to the feathers rather than nutrient acquisition and/or freed energy resources that could be invested in coloration. Alternatively, though not measured, METRO might have affected microbial community and host physiology as microbial metabolites can modulate mitochondrial and immune function.


Assuntos
Antibacterianos/farmacologia , Coccidiostáticos/farmacologia , Plumas/efeitos dos fármacos , Tentilhões/anatomia & histologia , Metronidazol/farmacologia , Triazinas/farmacologia , Animais , Doenças das Aves/tratamento farmacológico , Doenças das Aves/parasitologia , Índice de Massa Corporal , Carotenoides/metabolismo , Cor , Tentilhões/parasitologia , Isospora/efeitos dos fármacos , Isosporíase/tratamento farmacológico , Isosporíase/veterinária , Masculino , Carga Parasitária/veterinária , Triglicerídeos/sangue
14.
J Environ Sci Health B ; 56(6): 532-539, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33950786

RESUMO

The addition of carbonaceous material such as cow bonechar to the soil can affect the availability of applied pre-emergent herbicides such as indaziflam. However, how cow bonechar affects the bioavailability of indaziflam is not yet known. The aim of this study was to evaluate the effect of cow bonechar on herbicidal activity of indaziflam on weeds in a tropical soil. Cow bonechar was added homogeneously to top soil, at 1, 2, 5, 10, and 20 t ha-1, in addition to treatment with unamended soil. At 21 days after indaziflam (75 g ha-1) application, injury weed levels, weed species that emerged spontaneously were identified and the weeds present in each sampling unit were collected. Only 1.4 t ha-1 cow bonechar added to soil was enough to reduce the weed injury level by 50%. From the addition of 2 t ha-1 cow bonechar the application of indaziflam was not efficient to weed control, being equivalent to treatments without herbicide application. Eight weed species (3 monocots and 5 dicots) were identified in all treatments. Eleusine indica and Digitaria horizontalis accounted for about 99.7% of the entire infestation of the weed community. Cow bonechar decreases indaziflam pre-emergence herbicidal activity in tropical soil for weed control, most likely due to the high sorption and unavailability of the product in the soil solution.


Assuntos
Osso e Ossos , Herbicidas/química , Herbicidas/farmacologia , Indenos/química , Indenos/farmacologia , Plantas Daninhas/efeitos dos fármacos , Triazinas/química , Triazinas/farmacologia , Animais , Bovinos , Solo , Clima Tropical , Controle de Plantas Daninhas
15.
PLoS Pathog ; 17(5): e1009527, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33956888

RESUMO

Baloxavir is approved in several countries for the treatment of uncomplicated influenza in otherwise-healthy and high-risk patients. Treatment-emergent viruses with reduced susceptibility to baloxavir have been detected in clinical trials, but the likelihood of widespread occurrence depends on replication capacity and onward transmission. We evaluated the fitness of A/H3N2 and A/H1N1pdm09 viruses with the polymerase acidic (PA) I38T-variant conferring reduced susceptibility to baloxavir relative to wild-type (WT) viruses, using a competitive mixture ferret model, recombinant viruses and patient-derived virus isolates. The A/H3N2 PA/I38T virus showed a reduction in within-host fitness but comparable between-host fitness to the WT virus, while the A/H1N1pdm09 PA/I38T virus had broadly similar within-host fitness but substantially lower between-host fitness. Although PA/I38T viruses replicate and transmit between ferrets, our data suggest that viruses with this amino acid substitution have lower fitness relative to WT and this relative fitness cost was greater in A/H1N1pdm09 viruses than in A/H3N2 viruses.


Assuntos
Antivirais/farmacologia , Dibenzotiepinas/farmacologia , Modelos Animais de Doenças , Farmacorresistência Viral , Vírus da Influenza A/genética , Morfolinas/farmacologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Piridonas/farmacologia , Triazinas/farmacologia , Replicação Viral , Substituição de Aminoácidos , Animais , Feminino , Furões , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/isolamento & purificação , Masculino , Infecções por Orthomyxoviridae/virologia
16.
Bioorg Med Chem ; 41: 116216, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34023664

RESUMO

Inhibition of soluble epoxide hydrolase (sEH) has recently emerged as a new approach to treat cardiovascular disease and respiratory disease. Inhibitors based on 1,3,5-triazine chemotype were discovered through affinity selection against two triazine-based DNA-encoded libraries. The structure and activity relationship study led to the expansion of the original 1,4-cycloalkyl series to related aniline, piperidine, quinoline, aryl-ether and benzylic series. The 1,3-cycloalkyl chemotype led to the discovery of a clinical candidate (GSK2256294) for COPD.


Assuntos
Cicloexilaminas/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Triazinas/farmacologia , Cicloexilaminas/química , Descoberta de Drogas , Humanos , Estrutura Molecular , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Bibliotecas de Moléculas Pequenas , Triazinas/química
17.
Target Oncol ; 16(3): 339-355, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33939068

RESUMO

BACKGROUND: Preliminary data suggest that combining savolitinib, a potent and highly selective MET-tyrosine kinase inhibitor (TKI), with osimertinib, a third-generation, irreversible, oral epidermal growth factor receptor-TKI (EGFR-TKI), may overcome MET-based resistance to EGFR-TKIs. OBJECTIVE: To investigate the safety and tolerability of savolitinib in Japanese patients with advanced solid malignancies. PATIENTS AND METHODS: In Part C of the phase Ib, multi-arm, open-label, multicenter TATTON study, two cohorts of Japanese adult patients were evaluated across six study centers in Japan. Patients with advanced solid malignancies received oral savolitinib monotherapy 400 mg once daily (qd), escalating to 600 mg; patients with advanced EGFR mutation-positive (EGFRm) non-small-cell lung carcinoma (NSCLC) who progressed on prior EGFR-TKI received oral osimertinib 80 mg+savolitinib 300/400/600 mg qd combination therapy. Primary endpoints: safety/tolerability of savolitinib±osimertinib, and maximum tolerated dose(s) (MTD) definition. RESULTS: Seventeen patients received monotherapy; 12 received combination. Dose-limiting toxicities (DLTs): with monotherapy, 400 mg, none reported; 600 mg, n = 3/9 evaluable patients (33%) reported DLTs (grade 3 and 4 alanine aminotransferase and aspartate transaminase increased, and grade 4 drug-induced liver injury). With combination: 400 mg, 1/6 (17%) reported DLTs (grade 2 fatigue, nausea, and myalgia); 300 mg, none reported; 600 mg, 3/4 (75%) reported DLTs (grade 2 pyrexia, grade 3 skin reaction, and anaphylactic shock). Grade ≥3 adverse events were reported in 41% of patients receiving monotherapy and 33% receiving combination. TATTON is no longer recruiting patients. CONCLUSIONS: The MTD of savolitinib was 400 mg qd in both cohorts. Data demonstrate an acceptable safety profile for savolitinib alone, or with osimertinib. TRIAL REGISTRATION: Clinicaltrials.gov; NCT02143466; 21 May 2014.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pirazinas/uso terapêutico , Triazinas/uso terapêutico , Acrilamidas/farmacologia , Idoso , Compostos de Anilina/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Japão , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Pirazinas/farmacologia , Triazinas/farmacologia
18.
Sci Rep ; 11(1): 10826, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031486

RESUMO

Head and neck cancer is the sixth most common cancer worldwide with a 5-year survival of only 65%. Targeting compensatory signaling pathways may improve therapeutic responses and combat resistance. Utilizing reverse phase protein arrays (RPPA) to assess the proteome and explore mechanisms of synergistic growth inhibition in HNSCC cell lines treated with IGF1R and Src inhibitors, BMS754807 and dasatinib, respectively, we identified focal adhesion signaling as a critical node. Focal Adhesion Kinase (FAK) and Paxillin phosphorylation were decreased as early as 15 min after treatment, and treatment with a FAK inhibitor, PF-562,271, was sufficient to decrease viability in vitro. Treatment of 3D spheroids demonstrated robust cytotoxicity suggesting that the combination of BMS754807 and dasatinib is effective in multiple experimental models. Furthermore, treatment with BMS754807 and dasatinib significantly decreased cell motility, migration, and invasion in multiple HNSCC cell lines. Most strikingly, treatment with BMS754807 and dasatinib, or a FAK inhibitor alone, significantly increased cleaved-PARP in human ex-vivo HNSCC patient tissues demonstrating a potential clinical utility for targeting FAK or the combined targeting of the IGF1R with Src. This ex-vivo result further confirms FAK as a vital signaling node of this combinatorial treatment and demonstrates therapeutic potential for targeting FAK in HNSCC patients.


Assuntos
Dasatinibe/farmacologia , Quinase 1 de Adesão Focal/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Indóis/farmacologia , Pirazóis/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Sulfonamidas/farmacologia , Triazinas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Paxilina/metabolismo , Fosforilação/efeitos dos fármacos , Análise Serial de Proteínas , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico
19.
Sci Rep ; 11(1): 9677, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33958662

RESUMO

Free fatty acid dysregulation in diabetics may elicit the release of inflammatory cytokines from Müller cells (MC), promoting the onset and progression of diabetic retinopathy (DR). Palmitic acid (PA) is elevated in the sera of diabetics and stimulates the production of the DR-relevant cytokines by MC, including IL-1ß, which induces the production of itself and other inflammatory cytokines in the retina as well. In this study we propose that experimental elevation of cytochrome P450 epoxygenase (CYP)-derived epoxygenated fatty acids, epoxyeicosatrienoic acid (EET) and epoxydocosapentaenoic acid (EDP), will reduce PA- and IL-1ß-induced MC inflammation. Broad-spectrum CYP inhibition by SKF-525a increased MC expression of inflammatory cytokines. Exogenous 11,12-EET and 19,20-EDP significantly decreased PA- and IL-1ß-induced MC expression of IL-1ß and IL-6. Both epoxygenated fatty acids significantly decreased IL-8 expression in IL-1ß-induced MC and TNFα in PA-induced MC. Interestingly, 11,12-EET and 19,20-EDP significantly increased TNFα in IL-1ß-treated MC. GSK2256294, a soluble epoxide hydrolase (sEH) inhibitor, significantly reduced PA- and IL-1ß-stimulated MC cytokine expression. 11,12-EET and 19,20-EDP were also found to decrease PA- and IL-1ß-induced NFκB-dependent transcriptional activity. These data suggest that experimental elevation of 11,12-EET and 19,20-EDP decreases MC inflammation in part by blocking NFκB-dependent transcription and may represent a viable therapeutic strategy for inhibition of early retinal inflammation in DR.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Células Ependimogliais/metabolismo , Epóxido Hidrolases/metabolismo , Ácidos Graxos/metabolismo , Neuroglia/patologia , Retinite/prevenção & controle , Células Cultivadas , Cicloexilaminas/farmacologia , Retinopatia Diabética/complicações , Células Ependimogliais/patologia , Epóxido Hidrolases/antagonistas & inibidores , Humanos , Mediadores da Inflamação/metabolismo , NF-kappa B/genética , Regiões Promotoras Genéticas , Retinite/complicações , Retinite/patologia , Triazinas/farmacologia
20.
Bioorg Chem ; 112: 104965, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34020238

RESUMO

Thirty-five new colchicine binding site inhibitors have been designed and synthesized based on the 1,2,4-triazin-3(2H)-one nucleus. Such molecules were synthesized through a cascade reaction between readily accessible α-amino ketones and phenyl carbazate as a masked N-isocyanate precursor. The synthesized derivatives are cisoid restricted combretastatin A4 analogues containing 1,2,4-triazin-3(2H)-one in place of the olefinic bond, and they have the same essential pharmacophoric features of colchicine binding site inhibitors. The synthesized compounds were evaluated in vitro for their antiproliferative activities against a panel of three human cancer cell lines (MCF-7, HepG-2, and HCT-116), using colchicine as a positive control. Among them, two compounds 5i and 6i demonstrated a significant antiproliferative effect against all cell lines with IC50 ranging from 8.2 - 18.2 µM. Further investigation was carried out for the most active cytotoxic agents as tubulin polymerization inhibitors. Compounds 5i and 6i effectively inhibited microtubule assembly with IC50 values ranging from 3.9 to 7.8 µM. Tubulin polymerization assay results were found to be comparable with the cytotoxicity results. The cell cycle analysis revealed significant G2/M cell cycle arrest of the analogue 5i in HepG-2 cells. The most active compounds 4i, 4j, 5 g, 5i and 6i did not induce significant cell death in normal human lung cells Wl-38, suggesting their selectivity against cancer cells. Also, These compounds upregulated the level of active caspase-3 and boosted the levels of the pro-apoptotic protein Bax by five to seven folds in comparison to the control. Moreover, apoptosis analyses were conducted for compound 5i to evaluate its apoptotic potential. Finally, in silico studies were conducted to reveal the probable interaction with the colchicine binding site. ADME prediction study of the designed compounds showed that they are not only with promising tubulin polymerization inhibitory activity but also with favorable pharmacokinetic and drug-likeness properties.


Assuntos
Antineoplásicos/farmacologia , Colchicina/antagonistas & inibidores , Desenho de Fármacos , Triazinas/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
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