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1.
Bioorg Chem ; 130: 106225, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36335650

RESUMO

Enasidenib (AG-221) is the only approved IDH2 inhibitor, clinical study found Enasidenib have some side-effects. In this work, we synthesized series of novel s-triazine derivatives, and the in vitro and in vivo activity of anti-AML has been studied using AM7577 model. The cell activity found Ta and Th showed excellent inhibition to AM7577. We further used the HuKemia Acute Leukemia xenograft model to investigate the in vivo efficacy of compounds Ta and Th, compared with AG-221, although Ta and Th can't reduce the 2-HG level obviously, those two compounds can prolong the survival of rats. The research can expand the structure of novel IDH2 inhibitors and provide useful information for further research of novel AML drugs.


Assuntos
Isocitrato Desidrogenase , Leucemia Mieloide Aguda , Humanos , Ratos , Animais , Mutação , Aminopiridinas/farmacologia , Triazinas/farmacologia , Triazinas/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico
2.
Bioorg Chem ; 130: 106211, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36343598

RESUMO

Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), three series of novel 1,3,5-triazine or pyrimidine derivatives containing semicarbazones have been designed and synthesized to obtain new potent and selective PI3Kα inhibitors. Their inhibitory activities in vitro were evaluated against PI3Kα and three tumor-derived cell lines (U87-MG, MCF-7, and PC-3). We also tested promising compounds (A4, A6, A10, and B1) for other PI3K class I subtype (PI3Kß, PI3Kδ, and PI3Kγ) activity. The representative compound A10 exhibited an IC50 value of 0.32 nM against PI3Kα, and demonstrated extraordinary subtype selectivity. Furthermore, compound A10 obviously inhibited proliferation of MCF-7 cell lines, induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells, and arrested G2 phase in a dose-dependent manner. Additionally, compound A10 induced significant tumor regressions in a xenograft mouse model of U87-MG cell line without an obvious sign of toxicity upon 20 mg/kg oral administration. Compound A10 may serve as a PI3Kα-selective inhibitor and provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family.


Assuntos
Antineoplásicos , Humanos , Camundongos , Animais , Inibidores de Fosfoinositídeo-3 Quinase , Relação Estrutura-Atividade , Proliferação de Células , Antineoplásicos/farmacologia , Triazinas/farmacologia , Linhagem Celular Tumoral , Benzimidazóis/farmacologia , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais
3.
Bioorg Chem ; 130: 106263, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36375350

RESUMO

Bruton's tyrosine kinase (BTK) is a promising drug target for the treatment of B-cell related malignancies. Irreversible inhibition of BTK by a covalent inhibitor has been proved to be a clinically effective therapy. However, most irreversible BTK inhibitors also inhibit other kinases including JAK3 and EGFR, leading to some adverse events. Herein, we reported the structure-based design and optimization of a series of irreversible BTK inhibitors bearing the 6-amino-1,3,5-triazine scaffold. Most of the synthesized compounds demonstrated considerable BTK inhibition and improved anti-proliferative activity against Raji and Ramos cells. Among them, compound C11 exhibited potent BTK inhibition (BTK IC50 = 17.0 nM) and a desirable selectivity profile especially over EGFR. Moreover, C11 effectively blocked activation of BTK and downstream signaling, arrested the cell cycle in G0/G1 phase and induced apoptosis in Raji cells. Its irreversible binding mode was further investigated by both molecular modeling and a washout experiment. Collectively, C11 is a novel selective irreversible BTK inhibitor worthy of further in-depth research.


Assuntos
Inibidores de Proteínas Quinases , Triazinas , Inibidores de Proteínas Quinases/química , Estrutura Molecular , Relação Dose-Resposta a Droga , Tirosina Quinase da Agamaglobulinemia , Relação Estrutura-Atividade , Triazinas/farmacologia , Receptores ErbB/metabolismo
4.
Bioorg Med Chem Lett ; 77: 129042, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36332884

RESUMO

Triazine-linked triazole compounds (4a-j) were designed, synthesized, and then examined for their anticonvulsant abilities. Compounds 4e, 4f, 4g, 4i, and 4j displayed significant anticonvulsant activity in both maximum electroshock seizure (MES) and pentylenetetrazole (PTZ) induced seizure during the preliminary screening. The phase II anticonvulsant activity statistics revealed that compounds 4e, 4f, 4g, 4i, and 4j demonstrated excellent activity as compared to the conventional drugs methaqualone and valproate, supporting the potential of these triazine-linked triazole analogues as novel anticonvulsant agents. To take use of the findings, computational parameters including docking analysis and drug-likeness prediction were carried out. Molecular modelling studies supported the essential pharmacophoric information that the structure activity relationship offered. The triazine-linked triazole analogues that were investigated might be viewed as helpful models for future research and derivatization.


Assuntos
Anticonvulsivantes , Triazinas , Humanos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/química , Simulação de Acoplamento Molecular , Triazinas/farmacologia , Pentilenotetrazol , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Eletrochoque , Triazóis , Relação Estrutura-Atividade , Estrutura Molecular
5.
Int J Mol Sci ; 23(21)2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36362096

RESUMO

Considering the key functions of the 5-HT7 receptor, especially in psychiatry, and the fact that effective and selective 5-HT7 receptor ligands are yet to be available, in this work, we designed and synthesized novel 1,3,5-triazine derivatives particularly based on the evaluation of the effect of substituents at aromatic rings on biological activity. The tested compounds showed high affinity to the 5-HT7 receptor, particularly ligands N2-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N4-phenethyl-1,3,5-triazine-2,4,6-triamine 2 (Ki = 8 nM) and N2-(2-(1H-indol-3-yl)ethyl)-N4-(2-((4-fluorophenyl)amino)ethyl)-1,3,5-triazine-2,4,6-triamine 12 (Ki = 18 nM) which showed moderate metabolic stability, and affinity to the CYP3A4 isoenzyme. As for the hepatotoxicity evaluation, the tested compounds showed moderate cytotoxicity only at concentrations above 50 µM. Compound 12 exhibited less cardiotoxic effect than 2 on Danio rerio in vivo model.


Assuntos
Receptores de Serotonina , Serotonina , Receptores de Serotonina/metabolismo , Ligantes , Serotonina/metabolismo , Triazinas/farmacologia , Relação Estrutura-Atividade
6.
Sci Rep ; 12(1): 16756, 2022 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-36202955

RESUMO

Limited presence of hCA IX in normal physiological tissues and their overexpression only in solid hypoxic tumors made this isoform excellent possible target for developing new anticancer agents. We reported designing and synthesis of two novel series of benzenesulfonamides derivatives as hCA IX inhibitors bearing rigid cyclic linkers (1,3,5-dihydrotriazine in series A and 1,3,5-triazine in series B) in replace of traditional linear linkers. Also, novel cyanoethenyl spacer was assembled next to the 1,3,5-triazine linker in series B. Target compounds of series (A) and (B) were screened against four hCA isoforms. Human CA IX efficiently inhibited in series (A) by compound 5a (KI = 134.8 nM). Meanwhile, in series (B) the most active inhibitor was 12i (KI = 38.8 nM). US-NCI protocol was followed to evaluate the anticancer activity of target compounds against panel of sixty cancer cell lines. Compound 12d, exposed the best activity towards breast cancer (MDA-MB-468) with GI% = 62%. The most active analogues, 12d and 12i were further screened for in vitro cytotoxic activity under hypoxic condition against breast cancer (MDA-MB-468) (IC50 = 3.99 ± 0.21 and 1.48 ± 0.08 µM, respectively) and leukemia (CCRF-CM) cell line (IC50 = 4.51 ± 0.24 and 9.83 ± 0.52 µM, respectively). In addition, 12d arrested breast cancer MDA-MB-468 cell cycle in G0-G1 and S phases and induced its apoptosis which indicated by increasing the level of cleaved caspases 3 and 9. Molecular docking was performed for selected analogues to understand their biological alterations. This study revealed that insertion of 1,3,5-triazines as cyclic linkers enhanced the significant anticancer and hCA IX inhibition activity of benzenesulfonamides.


Assuntos
Antineoplásicos , Neoplasias da Mama , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Caspases/metabolismo , Feminino , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas , Triazinas/farmacologia
8.
Bioorg Chem ; 129: 106157, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36209563

RESUMO

Blocking the PI3K/AKT/mTOR pathway has been widely recognized as an attractive cancer therapeutic strategy because of its crucial role in cell growth and survival. In this study, a novel series of 2-arylurea-1,3,5-triazine derivatives had been synthesized and evaluated as highly potent PI3K and mTOR inhibitors. The new compounds exhibited cytotoxic activities against MCF-7, Hela and A549 cancer cell lines (IC50 = 0.03-36.54 µM). The most promising compound XIN-9 exhibited potent inhibition against PI3K and mTOR kinase (IC50 = 23.8 and 10.9 nM). Mechanistic study using real-time PCR revealed the ability of XIN-9 to inhibit PI3K and mTOR. In addition, compound XIN-9 arrested the cell cycle of MCF-7 cells at the G0/G1 phase. XIN-9 also caused a significant dose-dependent increase of early and late apoptotic events. Molecular docking analysis revealed a high binding affinity for XIN-9 toward PI3K and mTOR. Following in vitro studies, XIN-9 was further evaluated in MCF-7 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 41.67% (po, 75 mg/kg). Overall, this work indicated that compound XIN-9 represents a potential anticancer targeting PI3K/AKT/mTOR pathway.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores MTOR , Proteínas Proto-Oncogênicas c-akt/metabolismo , Simulação de Acoplamento Molecular , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proliferação de Células , Antineoplásicos/química , Triazinas/farmacologia , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Neoplasias/tratamento farmacológico
9.
Parasit Vectors ; 15(1): 319, 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36076292

RESUMO

BACKGROUND: Avian coccidiosis is an important parasitic disease that has serious adverse effects on the global poultry industry. The extensive use of anticoccidial drugs has resulted in an increase in drug resistance. Ethanamizuril (EZL) is a novel triazine with high anticoccidial activity. METHODS: We compared oocyst production and sporulation between EZL-sensitive (S) and EZL-resistant Eimeria tenella strains (R10 and R200) and used label-free quantitative proteomics to identify differentially expressed proteins (DEPs) between these strains. RESULTS: We generated two EZL-resistant E. tenella strains: strain R10, which was induced using a constant dose of 10 mg EZL/kg poultry feed, and strain R200, which was generated by gradually increasing the EZL dosage to 200 mg EZL/kg poultry feed. With an increase in resistance, the total oocyst output decreased, but the percentage of sporulation did not change significantly. We identified a total of 7511 peptides and 1282 proteins, and found 152 DEPs in the R10 strain versus the S strain, 426 DEPs in the R200 strain versus the S strain and 494 DEPs in the R200 strain versus the R10 strain. When compared with the S strain, 86 DEPs were found to have consistent trends in both resistant strains. The DEPs were primarily involved in ATP and GTP binding, invasion, and membrane components. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the DEPs suggested that they are involved in transcription and translation processes. Protein-protein interaction network analysis of the 86 DEPs showed that 10 proteins were hubs in the functional interaction network (≥ 8 edges) and five of them were ribosomal proteins. CONCLUSIONS: The results of the present study indicate that the resistance mechanisms of E. tenella against EZL might be related to the transcriptional and translational processes, especially in the factors that inhibit the growth of parasites. The DEPs found in this study provide new insights into the resistance mechanisms of E. tenella against EZL. Further research on these potential targets holds promise for new chemotherapeutic approaches for controlling E. tenella infections.


Assuntos
Coccidiose , Eimeria tenella , Doenças das Aves Domésticas , Animais , Galinhas/parasitologia , Coccidiose/tratamento farmacológico , Coccidiose/parasitologia , Coccidiose/veterinária , Oocistos , Doenças das Aves Domésticas/tratamento farmacológico , Doenças das Aves Domésticas/parasitologia , Proteômica , Triazinas/farmacologia , Triazinas/uso terapêutico
10.
Eur J Med Chem ; 243: 114761, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36179403

RESUMO

Lymphomas are still difficult to treat even with modern therapies as, among others, multidrug resistance (MDR) is often counteracting a successful cancer therapy. P-gp/ABC-transporters are well-known for their crucial role in the main tumour MDR mechanism, eliminating drugs and cytotoxic substances from the cancer cell by efflux, and their modulators are promising for innovative therapy, but none has been approved in the pharmaceutical market yet. Herein, we have designed, synthesised and analysed 30 novel seleno- and thioether 1,3,5-triazine derivatives conducting comprehensive studies to evaluate their potential application in human JURKAT lymphoma cells. Among the new compounds, four (11, 12, 13 and 23) were much more effective than the reference inhibitor verapamil, being potent ABCB1 inhibitors already at 2 µM, while 5 and 15 showed very potent ABCB1 inhibitory activity only at 20 µM. Results of P-gp ATPase assays, supported with docking studies, indicated the competitive substrate mode of modulating action for 15, while ABCB1, ABCC1 and ABCG2 genes expression induction by 15 with q-PCR was confirmed. All compounds were evaluated for their cytotoxic and antiproliferative properties in both sensitive (PAR) and resistant (MDR) mouse T-lymphoma cell lines, and compound 15, also considering its promising ABCB1 inhibition properties, was revealed to be the best compound in terms of its cytotoxic effect (IC50: 16.73 µM) as well as concerning the antiproliferative effect (IC50: 5.35 µM) in MDR cells. Regarding the mechanistic studies looking at the cell cycle, the thioether 15 and selenium derivatives 26 and 29 were significantly effective in the regulation of cell cycle-related genes alone or in co-treatment with doxorubicin counteracting Cyclin D1 and E1 expression and increasing p53 and p21 levels, shedding first light on their mechanism of action. In summary, we explored the chemical space of seleno- and thioether 1,3,5-triazine derivatives with interesting activity against lymphoma. Especially compound 15 is worthy of being studied deeper to evaluate its precise mode of action further as well it can be improved regarding its potency and drug-likeness.


Assuntos
Antineoplásicos , Linfoma , Camundongos , Animais , Humanos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Sulfetos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Proteínas de Neoplasias , Resistência a Múltiplos Medicamentos , Antineoplásicos/farmacologia , Antineoplásicos/química , Linfoma/tratamento farmacológico , Preparações Farmacêuticas , Triazinas/farmacologia , Linhagem Celular Tumoral
11.
Biomed Pharmacother ; 155: 113537, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36113258

RESUMO

Breast cancer has become the most commonly diagnosed cancer, surpassing lung cancer, with 2.26 million new breast cancers worldwide in 2020. Hence, there is an urgent need to develop effective molecularly targeted therapeutic drugs to treat breast cancer. In this paper, we designed, synthesized and screened a novel thiophene-triazine derivative, XS-2, as a potent dual PI3K/mTOR inhibitor for the treatment of breast cancer. Also, XS-2 was found to be potentially effective against triple-negative breast cancer (TNBC) in vitro during the investigation. We evaluated the in vitro inhibitory effect of XS-2 on 10 cancer cell lines by MTT and 6 kinases to investigated its in vivo antitumor activity in MCF-7 xenograft tumor-bearing BALB/c nude mice. In addition, the in vitro/in vivo toxicity to mice was also assessed by hemolytic toxicity, H&E staining and blood biochemical analysis. In order to investigate the antitumor mechanism of XS-2, a series of experiments were carried out in vitro/in vivo animal model and molecular biological levels such as the cell cycle and the apoptosis assay, real-time PCR, western blot, docking and molecular simulations analysis, etc. What's more, wound healing assay, Transwell and Western Blot were applied to explore the ability of XS-2 to inhibit the cell invasion and migration. The results showed that XS-2 exhibited strong antitumor activity both in vitro and in vivo. The inhibitory activities of XS-2 on ten cancer cell lines were ranging from 1.07 ± 0.11 to 0.002 ± 0.001 µM, which were 1565 times better than that of the lead compound GDC-0941, inhibitory activities against PI3Kα and mTOR kinases were 291.0 and 60.8 nM, respectively. Notably, XS-2 not only showed significant in vivo antitumor activity and low toxicity, with the tumor inhibition rate of 57.0 %, but also exhibited strong inhibitory in the expression of related proteins of PI3K pathway in tumor tissues. In addition, XS-2 significantly inhibited breast cancer MCF-7 and MDA-MB-231 cells in a concentration- and time-dependent manner, and inhibited the migration and invasion ability of MDA-MB-231 and MCF-7 cells. More than that, XS-2 could inhibit the increase of the expression levels of N-cadherin and vimentin upregulated by EGF and reversed the E-cadherin expression down regulated by EGF, resulting in inhibiting EMT in MCF-7 and MDA-MB-231 cells. The results showed that XS-2 was expected to be successfully developed as a high-efficiency and low-toxicity breast cancer therapeutic drug with the potential to inhibit the invasion and migration of TNBC. This provides a new research idea for the treatment of TNBC, which is of great significance.


Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Humanos , Camundongos , Animais , Neoplasias de Mama Triplo Negativas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Vimentina , Camundongos Nus , Fator de Crescimento Epidérmico/farmacologia , Proliferação de Células , Serina-Treonina Quinases TOR/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Caderinas , Tiofenos/farmacologia , Triazinas/farmacologia , Triazinas/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Biochem Biophys Res Commun ; 629: 176-182, 2022 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-36148694

RESUMO

The hydrolytic stability, hemocompatibility, antioxidant properties and in vitro cytotoxic activity of {5-[(4,6-di(aziridin-1-yl)-1,3,5-triazin-2-yl)amino]-2,2-dimethyl-1,3-dioxan-5-yl}methyl 2-(5-phenyl-2H-tetrazol-2-yl)acetate have been studied. 1H NMR spectroscopy showed that this tetrazole-containing derivative of 1,3,5-triazine is stable in neutral (pH 7) and alkaline (pH 10) media; hydrolysis of the dioxane cycle occurs in an acidic environment (pH 3). It has been established that {5-[(4,6-di(aziridin-1-yl)-1,3,5-triazin-2-yl)amino]-2,2-dimethyl-1,3-dioxan-5-yl}methyl-2-(5-phenyl-2H-tetrazol-2-yl)acetate is hemocompatible, exhibits antioxidant properties, but does not show antiradical activity over the entire range of concentrations. In turn, the study of cytotoxic activity in vitro showed that the tetrazole-containing derivative of 1,3,5-triazine has an effect on the cell lines of human alveolar basal epithelium adenocarcinoma A549 (IC50 41.3 µmol l-1), human ovarian teratocarcinoma PA-1 (IC50 10.6 µmol l-1), hepatocarcinoma Huh7 (IC50 19.9 µmol l-1), cervical cancer HeLa (IC50 3.7 µmol l-1), and human embryonic kidney HEK293 (IC50 15.8 µmol l-1). It was suggested one of the possible mechanism of substance 2 cytotoxicity via HIF pathway inhibition.


Assuntos
Antineoplásicos , Triazinas , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Dioxanos , Células HEK293 , Humanos , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacologia , Triazinas/farmacologia
13.
Int J Mol Sci ; 23(18)2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36142768

RESUMO

A (series) range of potential dimorpholinoquinazoline-based inhibitors of the PI3K/Akt/mTOR cascade was synthesized. Several compounds exhibited cytotoxicity towards a panel of cancer cell lines in the low and sub-micromolar range. Compound 7c with the highest activity and moderate selectivity towards MCF7 cells which express the mutant type of PI3K was also tested for the ability to inhibit PI3K-(signaling pathway) downstream effectors and associated proteins. Compound 7c inhibited the phosphorylation of Akt, mTOR, and S6K at 125-250 nM. It also triggered PARP1 cleavage, ROS production, and cell death via several mechanisms. Inhibition of PI3Kα was observed at a concentration of 7b 50 µM and of 7c 500 µM and higher, that can indicate minority PI3Kα as a target among other kinases in the titled cascade for 7c. In vivo studies demonstrated an inhibition of tumor growth in the colorectal tumor model. According to the docking studies, the replacement of the triazine core in gedatolisib (8) by a quinazoline fragment, and incorporation of a (hetero)aromatic unit connected with the carbamide group via a flexible spacer, can result in more selective inhibition of the PI3Kα isoform.


Assuntos
Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Linhagem Celular Tumoral , Proliferação de Células , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinas/farmacologia , Espécies Reativas de Oxigênio , Serina-Treonina Quinases TOR/metabolismo , Triazinas/farmacologia , Ureia
14.
Eur J Med Chem ; 243: 114747, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36103802

RESUMO

Poor proteolytic resistance, toxicity and salt/serum sensitivity of antimicrobial peptides (AMPs) limits their practical clinical application. Here, to overcome these drawbacks of AMPs and develop novel antimicrobial agents, a series of small molecules based on a triazine-piperazine-triazine scaffold that mimic the cationic amphipathic structure of AMPs were synthesized and evaluated their potential as a new class of antimicrobial agents. All designed compounds showed strong antimicrobial activity and negligible hemolytic activity. Particularly, five compounds (9, 11, 12, 15, and 16) presented excellent cell selectivity with proteolytic resistance, salt/serum stability and anti-inflammatory activity against lipopolysaccharide (LPS)-induced inflammation. These five compounds exhibited similar or 2-4 fold higher antimicrobial activity than melittin against six antibiotic-resistant bacteria tested. Similar to the intracellular-targeting AMP, buforin-2, these compounds displayed an intracellular mode of antimicrobial action. These compounds showed potent biofilm inhibitory and eradicating activities against multidrug-resistant Pseudomonas aeruginosa (MDRPA). Additionally, these compounds displayed synergistic or additive effects when combined with selected clinically used antibiotics. Furthermore, these compounds have been proven to inhibit pro-inflammatory cytokine release by directly binding to LPS and blocking the interaction between LPS and CD14/TLR4 receptor in LPS-stimulated RAW264.7 macrophage cells. Overall, our results demonstrate the potential of the designed compounds as a novel class of multifunctional antimicrobial agents to combat bacterial infection.


Assuntos
Anti-Infecciosos , Peptídeos Catiônicos Antimicrobianos , Peptídeos Catiônicos Antimicrobianos/química , Testes de Sensibilidade Microbiana , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/química , Triazinas/farmacologia , Piperazina/farmacologia , Anti-Infecciosos/farmacologia , Biofilmes , Antibacterianos/farmacologia , Antibacterianos/química
15.
J Med Chem ; 65(16): 11270-11290, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-35948061

RESUMO

G-protein-coupled receptor 84 (GPR84) is a proinflammatory orphan G-protein-coupled receptor implicated in several inflammatory and fibrotic diseases. Several agonist and antagonist ligands have been developed that target GPR84; however, a noncompetitive receptor blocker that was progressed to phase II clinical trials failed to demonstrate efficacy. New high-quality antagonists are required to investigate the pathophysiological role of GPR84 and to validate GPR84 as a therapeutic target. We previously reported the discovery of a novel triazine GPR84 competitive antagonist 1. Here, we describe an extensive structure-activity relationship (SAR) of antagonist 1 and also present in silico docking with supporting mutagenesis studies that reveals a potential binding pose for this type of orthosteric antagonist. Lead compound 42 is a potent GPR84 antagonist with a favorable pharmacokinetic (PK) profile suitable for further drug development.


Assuntos
Receptores Acoplados a Proteínas G , Triazinas , Ligantes , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade , Triazinas/farmacologia
16.
mBio ; 13(4): e0105622, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-35938724

RESUMO

Amino acid substitutions I38T and E23K in the influenza polymerase acidic (PA) protein lead to reduced susceptibility to the influenza antiviral drug baloxavir. The in vivo effectiveness of baloxavir and oseltamivir for treatment of these viruses is currently unknown. Using patient-derived influenza isolates, combination therapy was equally effective as monotherapy in reducing viral titers in the upper respiratory tract of ferrets infected with A(H1N1pdm09)-PA/E23K or A(H3N2)-PA/I38T. When treated with baloxavir plus oseltamivir, infection with a mixture of PA/I38T or PA/E23K and corresponding wild-type virus was characterized by a lower selection of viruses with reduced baloxavir susceptibility over the course of infection compared to baloxavir monotherapy. De novo emergence of the oseltamivir resistance mutation NA/H275Y occurred in ferrets treated with oseltamivir alone but not in ferrets treated with baloxavir plus oseltamivir. Our data suggest that combination therapy with influenza drugs with different mechanisms of action decreased the selection pressure for viruses with reduced drug susceptibility. IMPORTANCE Influenza viruses cause significant morbidity and mortality worldwide but can be treated with antiviral drugs. In 2018, a highly effective antiviral drug, baloxavir marboxil, was licensed. However, the selection of viruses with baloxavir resistance was relatively high following treatment, which may compromise the effectiveness of the drug. Here, we took two different influenza viruses that are resistant to baloxavir and tested the effectiveness alone and in combination with oseltamivir (a second influenza antiviral drug) in the ferret model. Our findings suggest that combination treatment may be a more effective method than monotherapy to reduce the selection of resistant viruses. These results may have important clinical implications for the treatment of influenza.


Assuntos
Influenza Humana , Tiepinas , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Dibenzotiepinas , Farmacorresistência Viral/genética , Furões , Humanos , Vírus da Influenza A Subtipo H3N2/genética , Morfolinas , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Oxazinas/farmacologia , Oxazinas/uso terapêutico , Piridinas/farmacologia , Piridonas/farmacologia , Piridonas/uso terapêutico , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Triazinas/farmacologia , Triazinas/uso terapêutico
17.
J Vet Med Sci ; 84(10): 1345-1351, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-35922919

RESUMO

Intestinal coccidiosis caused by Eimeria protozoan species is an economically important disease, especially in poultry and cattle. Anti-coccidial drugs commonly used for controlling coccidiosis are toltrazuril (TTZ) and diclazuril (DCZ). In this study, the efficacies of TTZ and DCZ were compared using a murine model, and the effect of these treatments on the induction of acquired resistance was evaluated. Male C57BL/6J mice were inoculated with 1,000 sporulated E. vermiformis oocytes and treated with TTZ or DCZ. The recommended TTZ dose for cattle (15 mg/kg) completely prevented oocyte excretion. But, mice required 5 mg/kg of DCZ, which is five times the recommended dose for cattle, to reduce oocyte excretion. In E. vermiformis re-infection, TTZ (15 mg/kg) and DCZ (5 mg/kg) treatments did not interfere with the development of acquired resistance. Bodyweight gain was significantly higher in the TTZ-treated group than in the control (untreated/infected) group and the DCZ-treated group, and no significant difference in bodyweight gain was observed between the TTZ-treated group and the healthy (uninfected/untreated) group. Analysis of T lymphocyte subsets in the spleen and mesenteric lymph nodes indicated that the relative populations of CD4+ and CD8+ T cells were reduced in the DCZ-treated and control (untreated/infected) groups, suggesting there was immunosuppression during the infection. However, no reductions in T cell populations were observed in the TTZ-treated group. The results indicated that an optimal anti-coccidial drug is one that can completely break the parasite life cycle in the host animal.


Assuntos
Doenças dos Bovinos , Coccidiose , Coccidiostáticos , Eimeria , Doenças dos Roedores , Animais , Linfócitos T CD8-Positivos , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Coccidiose/tratamento farmacológico , Coccidiose/parasitologia , Coccidiose/veterinária , Coccidiostáticos/uso terapêutico , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitrilas , Triazinas/farmacologia , Triazinas/uso terapêutico
18.
Molecules ; 27(13)2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35807265

RESUMO

Adenosine mediates various physiological activities in the body. Adenosine receptors (ARs) are widely expressed in tumors and the tumor microenvironment (TME), and they induce tumor proliferation and suppress immune cell function. There are four types of human adenosine receptor (hARs): hA1, hA2A, hA2B, and hA3. Both hA1 and hA3 AR play an important role in tumor proliferation. We designed and synthesized novel 1,3,5-triazine derivatives through amination and Suzuki coupling, and evaluated them for binding affinities to each hAR subtype. Compounds 9a and 11b showed good binding affinity to both hA1 and hA3 AR, while 9c showed the highest binding affinity to hA1 AR. In this study, we discovered that 9c inhibits cell viability, leading to cell death in lung cancer cell lines. Flow cytometry analysis revealed that 9c caused an increase in intracellular reactive oxygen species (ROS) and a depolarization of the mitochondrial membrane potential. The binding mode of 1,3,5-triazine derivatives to hA1 and hA3 AR were predicted by a molecular docking study.


Assuntos
Pirimidinas , Receptor A2A de Adenosina , Humanos , Simulação de Acoplamento Molecular , Pirimidinas/química , Receptor A2A de Adenosina/metabolismo , Receptor A3 de Adenosina/química , Relação Estrutura-Atividade , Triazinas/farmacologia
19.
Int J Mol Sci ; 23(13)2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35806186

RESUMO

In the search for new compounds with antitumor activity, new potential anticancer agents were designed as molecular hybrids containing the structures of a triazine ring and a sulfonamide fragment. Applying the synthesis in solution, a base of new sulfonamide derivatives 20-162 was obtained by the reaction of the corresponding esters 11-19 with appropriate biguanide hydrochlorides. The structures of the compounds were confirmed by spectroscopy (IR, NMR), mass spectrometry (HRMS or MALDI-TOF/TOF), elemental analysis (C,H,N) and X-ray crystallography. The cytotoxic activity of the obtained compounds toward three tumor cell lines, HCT-116, MCF-7 and HeLa, was examined. The results showed that some of the most active compounds belonged to the R1 = 4-trifluoromethylbenzyl and R1 = 3,5-bis(trifluoromethyl)benzyl series and exhibited IC50 values ranging from 3.6 µM to 11.0 µM. The SAR relationships were described, indicating the key role of the R2 = 4-phenylpiperazin-1-yl substituent for the cytotoxic activity against the HCT-116 and MCF-7 lines. The studies regarding the mechanism of action of the active compounds included the assessment of the inhibition of MDM2-p53 interactions, cell cycle analysis and apoptosis induction examination. The results indicated that the studied compounds did not inhibit MDM2-p53 interactions but induced G0/G1 and G2/M cell cycle arrest in a p53-independent manner. Furthermore, the active compounds induced apoptosis in cells harboring wild-type and mutant p53. The compound design was conducted step by step and assisted by QSAR models that correlated the activity of the compounds against the HCT-116 cell line with molecular descriptors.


Assuntos
Antineoplásicos , Benzenossulfonatos , Triazinas , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose , Benzenossulfonatos/química , Benzenossulfonatos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Triazinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo
20.
J Virol ; 96(15): e0037222, 2022 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-35867565

RESUMO

Elimination of human immunodeficiency virus (HIV) reservoirs is a critical endpoint to eradicate HIV. One therapeutic intervention against latent HIV is "shock and kill." This strategy is based on the transcriptional activation of latent HIV with a latency-reversing agent (LRA) with the consequent killing of the reactivated cell by either the cytopathic effect of HIV or the immune system. We have previously found that the small molecule 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) acts as an LRA by increasing signal transducer and activator of transcription (STAT) factor activation mediated by interleukin-15 (IL-15) in cells isolated from aviremic participants. The IL-15 superagonist N-803 is currently under clinical investigation to eliminate latent reservoirs. IL-15 and N-803 share similar mechanisms of action by promoting the activation of STATs and have shown some promise in preclinical models directed toward HIV eradication. In this work, we evaluated the ability of HODHBt to enhance IL-15 signaling in natural killer (NK) cells and the biological consequences associated with increased STAT activation in NK cell effector and memory-like functions. We showed that HODHBt increased IL-15-mediated STAT phosphorylation in NK cells, resulting in increases in the secretion of CXCL-10 and interferon gamma (IFN-γ) and the expression of cytotoxic proteins, including granzyme B, granzyme A, perforin, granulysin, FASL, and TRAIL. This increased cytotoxic profile results in increased cytotoxicity against HIV-infected cells and different tumor cell lines. HODHBt also improved the generation of cytokine-induced memory-like NK cells. Overall, our data demonstrate that enhancing the magnitude of IL-15 signaling with HODHBt favors NK cell cytotoxicity and memory-like generation, and thus, targeting this pathway could be further explored for HIV cure interventions. IMPORTANCE Several clinical trials targeting the HIV latent reservoir with LRAs have been completed. In spite of a lack of clinical benefit, they have been crucial to elucidate hurdles that "shock and kill" strategies have to overcome to promote an effective reduction of the latent reservoir to lead to a cure. These hurdles include low reactivation potential mediated by LRAs, the negative influence of some LRAs on the activity of natural killer and effector CD8 T cells, an increased resistance to apoptosis of latently infected cells, and an exhausted immune system due to chronic inflammation. To that end, finding therapeutic strategies that can overcome some of these challenges could improve the outcome of shock and kill strategies aimed at HIV eradication. Here, we show that the LRA HODHBt also improves IL-15-mediated NK cell effector and memory-like functions. As such, pharmacological enhancement of IL-15-mediated STAT activation can open new therapeutic avenues toward an HIV cure.


Assuntos
HIV-1 , Memória Imunológica , Interleucina-15 , Células Matadoras Naturais , Fatores de Transcrição STAT , Triazinas , Latência Viral , Linhagem Celular Tumoral , Quimiocina CXCL10 , Testes Imunológicos de Citotoxicidade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , HIV-1/imunologia , Humanos , Memória Imunológica/efeitos dos fármacos , Interferon gama , Interleucina-15/imunologia , Interleucina-15/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Fatores de Transcrição STAT/metabolismo , Ativação Transcricional/efeitos dos fármacos , Triazinas/farmacologia , Ativação Viral/efeitos dos fármacos , Latência Viral/efeitos dos fármacos
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