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1.
Pharmaceutics ; 13(8)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34452183

RESUMO

MM-129 is a novel inhibitor targeting BTK/PI3K/AKT/mTOR and PD-L1, as it possesses antitumor activity against colon cancer. To evaluate the safety profile of MM-129, we conducted a toxicity study using the zebrafish and rodent model. MM-129 was also assessed for pharmacokinetics features through an in vivo study on Wistar rats. The results revealed that MM-129 exhibited favorable pharmacokinetics with quick absorption and 68.6% of bioavailability after intraperitoneal administration. No serious adverse events were reported for the use of MM-129, confirming a favorable safety profile for this compound. It was not fatal and toxic to mice at an anticancer effective dose of 10 µmol/kg. At the end of 14 days of administering hematological and biochemical parameters, liver and renal functions were all at normal levels. No sublethal effects were either detected in zebrafish embryos treated with a concentration of 10 µM. MM-129 has the potential as a safe and well-tolerated anticancer formulation for future treatment of patients with colon cancer.

2.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443460

RESUMO

Synthetic heterocyclic compounds have incredible potential against different diseases; pyridines, phenolic compounds and the derivatives of azo moiety have shown excellent antimicrobial, antiviral, antidiabetic, anti-melanogenic, anti-ulcer, anticancer, anti-mycobacterial, anti-inflammatory, DNA binding and chemosensing activities. In the present review, the above-mentioned activities of the nitrogen-containing heterocyclic compounds (pyridines), hydroxyl (phenols) and azo derivatives are discussed with reference to the minimum inhibitory concentration and structure-activity relationship, which clearly indicate that the presence of nitrogen in the phenyl ring; in addition, the hydroxyl substituent and the incorporation of a diazo group is crucial for the improved efficacies of the compounds in probing different diseases. The comparison was made with the reported drugs and new synthetic derivatives that showed recent therapeutic perspectives made in the last five years.


Assuntos
Compostos Azo/uso terapêutico , Fenóis/uso terapêutico , Piridinas/uso terapêutico , Compostos Azo/síntese química , Compostos Azo/química , Imageamento Tridimensional , Fenóis/síntese química , Fenóis/química , Piridinas/síntese química , Piridinas/química
3.
J Enzyme Inhib Med Chem ; 36(1): 1509-1520, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34238110

RESUMO

In the present study, a series of azo derivatives (TR-1 to TR-9) have been synthesised via the diazo-coupling approach between substituted aromatic amines with phenol or naphthol derivatives. The compounds were evaluated for their therapeutic applications against alpha-glucosidase (anti-diabetic) and pathogenic bacterial strains E. coli (gram-negative), S. aureus (gram-positive), S. aureus (gram-positive) drug-resistant strain, P. aeruginosa (gram-negative), P. aeruginosa (gram-negative) drug-resistant strain and P. vulgaris (gram-negative). The IC50 (µg/mL) of TR-1 was found to be most effective (15.70 ± 1.3 µg/mL) compared to the reference drug acarbose (21.59 ± 1.5 µg/mL), hence, it was further selected for the kinetic studies in order to illustrate the mechanism of inhibition. The enzyme inhibitory kinetics and mode of binding for the most active inhibitor (TR-1) was performed which showed that the compound is a non-competitive inhibitor and effectively inhibits the target enzyme by binding to its binuclear active site reversibly.


Assuntos
Antibacterianos/farmacologia , Compostos Azo/farmacologia , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Compostos Azo/síntese química , Compostos Azo/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/efeitos dos fármacos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Cinética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologia , Staphylococcus aureus/efeitos dos fármacos
4.
Molecules ; 26(7)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918514

RESUMO

Cancer therapy is one of the most important challenges of modern medical and chemical sciences. Among the many methods of combating cancer, chemotherapy plays a special role. Imperfect modern chemotherapy justifies continuing the search for new, more effective, and safe drugs. Sulfonamides are the classic group of chemotherapeutic drugs with a broad spectrum of pharmacological activity. Recent literature reports show that sulfonamide derivatives have anti-tumor activity in vitro and in vivo. The aim of the study was to synthesize a novel 1,2,4-triazine sulfonamide derivative and check its anticancer potential in DLD-1 and HT-29 colon cancer cells. The biological studies included MTT assay, DNA biosynthesis, cell cycle analysis, Annexin V binding assay, ethidium bromide/acridine orange staining, and caspase-8, -9, and -3/7 activity. The concentrations of important molecules (sICAM-1, mTOR, Beclin-1, cathepsin B) involved in the pathogenesis and poor prognosis of colorectal cancer were also evaluated by ELISA. We demonstrated that the novel compound was able to induce apoptosis through intrinsic and extrinsic pathways and was capable of decreasing sICAM-1, mTOR, cathepsin B concentrations, whereas increased Beclin-1 concentration was detected in both colon cancer cell lines. The novel compound represents promising multi-targeted potential in colorectal cancer, but further in vivo examinations are needed to confirm the claim.


Assuntos
Antineoplásicos/farmacologia , Neoplasias do Colo/patologia , Sulfonamidas/farmacologia , Triazinas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Serina-Treonina Quinases TOR/metabolismo , Triazinas/química
5.
Int J Mol Sci ; 22(4)2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33562512

RESUMO

The molecule CD200, described many years ago as a naturally occurring immunomodulatory agent, capable of regulating inflammation and transplant rejection, has attracted additional interest over the past years with the realization that it may also serve as an important marker for progressive malignancy. A large body of evidence also supports the hypothesis that this molecule can contribute to immunoregulation of, among other diseases, infection, autoimmune disease and allergy. New data have also come to light to characterize the receptors for CD200 (CD200R) and their potential mechanism(s) of action at the biochemical level, as well as the description of a novel natural antagonist of CD200, lacking the NH2-terminal region of the full-length molecule. Significant controversies exist concerning the relative importance of CD200 as a ligand for all reported CD200Rs. Nevertheless, some progress has been made in the identification of the structural constraints determining the interaction between CD200 and CD200R, and this information has in turn proved of use in developing novel small molecule agonists/antagonists of the interaction. The review below highlights many of these newer findings, and attempts to place them in the broad context of our understanding of the role of CD200-CD200R interactions in a variety of human diseases.


Assuntos
Antígenos CD/metabolismo , Imunomodulação , Glicoproteínas de Membrana/metabolismo , Receptores de Orexina/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Doenças Autoimunes/imunologia , Regulação da Expressão Gênica , Sobrevivência de Enxerto , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/metabolismo , Imunomodulação/genética , Infecções/imunologia , Inflamação/imunologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Neoplasias/imunologia , Receptores de Orexina/genética , Receptores de Orexina/imunologia , Domínios e Motivos de Interação entre Proteínas
6.
J Enzyme Inhib Med Chem ; 36(1): 535-548, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33522320

RESUMO

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in men and in women. The impact of the new pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide (MM-129) was evaluated against human colon cancer in vitro and in zebrafish xenografts. Our results show that this new synthesised compound effectively inhibits cell survival in BTK-dependent mechanism. Its effectiveness is much higher at a relatively low concentration as compared with the standard chemotherapy used for CRC, i.e. 5-fluorouracil (5-FU). Flow cytometry analysis after annexin V-FITC and propidium iodide staining revealed that apoptosis was the main response of CRC cells to MM-129 treatment. We also found that MM-129 effectively inhibits tumour development in zebrafish embryo xenograft model, where it showed a markedly synergistic anticancer effect when used in combination with 5-FU. The above results suggest that this novel heterofused 1,2,4-triazine derivative may be a promising candidate for further evaluation as chemotherapeutic agent against CRC.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Triazinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química , Células Tumorais Cultivadas , Peixe-Zebra
7.
Int J Mol Sci ; 21(19)2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33019598

RESUMO

The protective ozone layer is continually depleting due to the release of deteriorating environmental pollutants. The diminished ozone layer contributes to excessive exposure of cells to ultraviolet (UV) radiation. This leads to various cellular responses utilized to restore the homeostasis of exposed cells. DNA is the primary chromophore of the cells that absorbs sunlight energy. Exposure of genomic DNA to UV light leads to the formation of multitude of types of damage (depending on wavelength and exposure time) that are removed by effectively working repair pathways. The aim of this review is to summarize current knowledge considering cellular response to UV radiation with special focus on DNA damage and repair and to give a comprehensive insight for new researchers in this field. We also highlight most important future prospects considering application of the progressing knowledge of UV response for the clinical control of diverse pathologies.


Assuntos
Ciclo Celular/efeitos da radiação , Reparo do DNA/efeitos da radiação , DNA/efeitos da radiação , Regulação da Expressão Gênica/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Ciclo Celular/genética , Quinase 1 do Ponto de Checagem/genética , Quinase 1 do Ponto de Checagem/metabolismo , DNA/química , DNA/genética , DNA/metabolismo , Dano ao DNA , Escherichia coli/genética , Escherichia coli/metabolismo , Escherichia coli/efeitos da radiação , Humanos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Dímeros de Pirimidina/química , Dímeros de Pirimidina/metabolismo , Transdução de Sinais , Ozônio Estratosférico/análise , Luz Solar/efeitos adversos
8.
Molecules ; 25(17)2020 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-32872493

RESUMO

This review focuses on the cytotoxic effect of new synthetic pyrazolo[4,3-e][1,2,4]triazine derivatives against different tumor cell lines. Some annulated pyrazolotriazines i.e., pyrazolo[4,3-e][1,2,4]triazolo[4,3-b][1,2,4]triazines and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine demonstrated significant broad cytotoxic activity in micromolar range concentration, which could have excellent potential to be new candidate therapeutic agents in cancer chemotherapy.


Assuntos
Antineoplásicos , Pirazóis , Sulfonamidas , Triazinas , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/farmacocinética , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Triazinas/síntese química , Triazinas/farmacologia
9.
Int J Mol Sci ; 21(15)2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32717981

RESUMO

The discovery of cytotoxic drugs is focused on designing a compound structure that directly affects cancer cells without an impact on normal cells. The mechanism of anticancer activity is mainly related with activation of apoptosis. However, recent scientific reports show that autophagy also plays a crucial role in cancer cell progression. Thus, the objective of this study was to synthesize 7-methyl-5-phenyl-pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine utilizing nucleophilic substitution reaction at the position N1. The biological activity of tested compounds was assessed in DLD-1 and HT-29 cell lines. The induction of apoptosis was confirmed by Annexin V binding assay and acridine orange/ethidium bromide staining. The loss of mitochondrial membrane potential and caspase-8 activity was estimated using cytometer flow analysis. The concentration of p53, LC3A, LC3B and beclin-1 was measured using the ELISA technique. Our study revealed that anticancer activity of 7-methyl-5-phenyl-pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine derivatives is related with initiation of apoptosis occur on the intrinsic pathway with mitochondrial membrane decrease and extrinsic with increase of activity of caspase-8. Moreover, a decrease in beclin-1, LC3A, and LC3B were observed in two cell lines after treatment with novel compounds. This study showed that novel 7-methyl-5-phenyl-pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine derivatives might be a potential strategy in colon cancer treatment.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias do Colo , Triazinas , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Caspase 8/metabolismo , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Humanos , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/patologia , Proteínas de Neoplasias/metabolismo , Triazinas/síntese química , Triazinas/química , Triazinas/farmacologia
10.
PLoS One ; 15(6): e0229891, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497076

RESUMO

A facile method has been developed for the synthesis of Schiff bases derived from substituted and unsubstituted 3-amino- and 4-amino-1,2,4-triazoles. Condensation of the aminotrizoles with a variety of aromatic aldehydes afforded desired Schiff bases in excellent yields in 3-5 minutes of exposure to ultra-sound. The synthesized compounds were characterized by means of IR, 1HNMR and Mass spectrometry. The synthesized compounds were also screened for their antibacterial potential against Gram-negative (Escherichia coli, Shigella sonnei, Pseudomonas aeruginosa and Salmonella typhi) and two Gram-positive (Staphylococcus aureus and Bacillus subtilis) strains.


Assuntos
Amitrol (Herbicida)/síntese química , Amitrol (Herbicida)/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Ondas Ultrassônicas , Amitrol (Herbicida)/química , Antibacterianos/química , Bactérias/efeitos dos fármacos , Técnicas de Química Sintética , Testes de Sensibilidade Microbiana , Bases de Schiff/química , Triazóis/química
11.
Molecules ; 25(1)2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31948129

RESUMO

A series of new pyrazolo[4,3-e][1,2,4]triazine acyclonucleosides 2-5 and 8 were prepared and evaluated for their anticancer activity against human cancer cell lines (MCF-7, K-562) and CDK2/E, as well as Abl protein kinases inhibitors. Lipophilicity of the compounds was determined using C-18 and immobilized artificial membrane (IAM) chromatography. In order to confirm the molecular structures and synthesis pathway of new acyclonucleosides, X-ray analysis was performed for model compound 3. Theoretical calculations at the DFT/B3LYP/6-311++G(d,p) level were used for the characterization of electronic structures of 1-8. The potential antiviral activity of acyclonucleosides 2-8 was tested in silico using molecular docking method.


Assuntos
Antineoplásicos/química , Nucleosídeos/química , Nucleosídeos/síntese química , Triazinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia/métodos , Humanos , Células MCF-7 , Membranas Artificiais , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
13.
J Enzyme Inhib Med Chem ; 34(1): 1-11, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31456445

RESUMO

The over expression of melanogenic enzymes like tyrosinase caused many hyperpigmentaion disorders. The present work describes the synthesis of hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives 3a-e and 5a-e as antimelanogenic agents. The tyrosinase inhibitory activity of synthesized derivatives 3a-e and 5a-e was determined and it was found that derivative 5c possesses excellent activity with IC50 = 0.0089 µM compared to standard kojic acid (IC50 = 16.69 µM). The presence of hydroxyl groups at the ortho and the para position of cinnamic acid phenyl ring in compound 5c plays a vital role in tyrosinase inhibitory activity. The compound 5d also exhibited good activity (IC50 = 8.26 µM) compared to standard kojic acid. The enzyme inhibitory kinetics results showed that compound 5c is a competitive inhibitor while 5d is a mixed-type inhibitor. The mode of binding for compounds 5c and 5d with tyrosinase enzyme was also assessed and it was found that both derivatives irreversibly bind with target enzyme. The molecular docking and molecular dynamic simulation studies were also performed to find the position of attachment of synthesized compounds at tyrosinase enzyme (PDB ID 2Y9X). The results showed that all of the synthesized compounds bind well with the active binding sites and most potent derivative 5c formed stable complex with target protein. The cytotoxicity results showed that compound 5c is safe at a dose of 12 µg/mL against murine melanoma (B16F10) cells. The same dose of 5c was selected to determine antimelanogenic activity; the results showed that it produced antimelenogenic effects in murine melanoma (B16F10) cells. Based on our investigations, it was proposed that compound 5c may serve as a lead structure to design more potent antimelanogenic agents.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Radical Hidroxila/farmacologia , Melanoma/tratamento farmacológico , Monofenol Mono-Oxigenase/antagonistas & inibidores , Fenóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Radical Hidroxila/síntese química , Radical Hidroxila/química , Cinética , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Fenóis/síntese química , Fenóis/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
14.
Med Chem ; 14(1): 53-59, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29065838

RESUMO

BACKGROUND: Triazoles and their fused derivatives are an important class of compounds that exhibit interesting biological properties, such as antiasthmatic, antimicrobial, antifungal, analgesic, antiallergic, antiinflammatory, herbicidal, plant growth regulative activity, and anti-HIV-1 activities. Moreover, anticancer activity of 1,2,4-triazole containing derivatives has been documented. Due to the fact a convenient approach toward polycyclic frameworks containing fused 1,2,4-triazoles was described. OBJECTIVE: The objective of this article is the synthesis of new pyrazolo[4,3-e]triazolo[4,5- b][1,2,4]triazine derivatives with potential antiproliferative activity. METHODS: Cancer cell proliferation was analysed by means of MTT assay after 96 h treatment. IC50 was calculated using computerized linear regression analysis of quantal log doseprobit functions, according to the method of Litchfield and Wilcoxon. X-ray data were collected on the Bruker SMART APEX II CCD diffractometer; The structure was solved by direct methods using SHELXS-2013 and refined by full-matrix least-squares with SHELXL-2014/7. All calculations were performed using WINGX version 2014.1 package. RESULTS: The series of pyrazolo[4,3-e]triazolo[4,5-b][1,2,4]triazine derivatives were synthesized. MTT assay revealed that the compounds inhibited cancer cells growth at concentrations below 10 µM. The tested compounds showed higher antiproliferative activity than popular cytostatics cisplatin (lung carcinoma) and 5-fluorouracil (colon adenocarcinoma). X-ray examinations showed that final products in the crystalline phase have a linear form. CONCLUSION: In the paper we have reported the synthesis and spectroscopic analysis of new condensed tricyclic derivatives of the pyrazolo[4,3-e]triazolo[4,5-b][1,2,4]triazine. MTT analysis revealed concentration-dependent decrease in lung A549 and colon LS180 cancer cells proliferation. In order to explain the molecular mechanisms involved in anticancer activity of pyrazolo[4,3- e]triazolo[4,5-b][1,2,4]triazine derivatives, our research will be continued.


Assuntos
Antineoplásicos/farmacologia , Triazinas/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química , Triazóis/síntese química , Triazóis/química , Células Tumorais Cultivadas
15.
Comput Biol Chem ; 71: 57-62, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28964980

RESUMO

The QSAR models for a set of pyrazolo[4,3-e][1,2,4]triazines incorporating benzenesulfonamide moiety combined directly with the heterocyclic ring or by NH linkage were generated. The inhibitory potency of compounds against human carbonic anhydrase isoforms IX and XII and antiproliferative activity against human MCF-7 cells were used as the dependent variables. The Codessa pro software was used for the descriptors calculation and the Best Multi-Linear Regression (BMLR) algorithm was employed to build the QSAR models. It was found that quantum descriptors are critical of the compounds activities. The selected models have good predictive accuracy confirmed by a set of the statistical quantities recommended by OECD.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Pirazóis/farmacologia , Relação Quantitativa Estrutura-Atividade , Sulfonamidas/farmacologia , Triazinas/farmacologia , Antígenos de Neoplasias/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/química , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Estrutura Molecular , Pirazóis/química , Relação Estrutura-Atividade , Sulfonamidas/química , Triazinas/química
16.
J Enzyme Inhib Med Chem ; 32(1): 99-105, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27778522

RESUMO

A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their tyrosinase and urease inhibitory activity. Evaluation of prepared derivatives demonstrated that compounds (8b) and (8j) are most potent mushroom tyrosinase inhibitors whereas all of the obtained compounds showed higher urease inhibitory activity than the standard thiourea. The compounds (8a), (8f) and (8i) exhibited excellent enzyme inhibitory activity with IC50 0.037, 0.044 and 0.042 µM, respectively, while IC50 of thiourea is 20.9 µM.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Pirazóis/química , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Triazinas/química , Urease/antagonistas & inibidores , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Concentração Inibidora 50 , Espectroscopia de Prótons por Ressonância Magnética , Estereoisomerismo
17.
J Enzyme Inhib Med Chem ; 31(3): 381-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25798686

RESUMO

A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their relaxant effects in the rat aorta. Evaluation of prepared derivatives demonstrated that compound (8a) is probably a non-selective phosphodiesterase (PDE) inhibitor, as it induced aortic relaxation through endothelium-independent mechanism.


Assuntos
Aorta/efeitos dos fármacos , Aorta/fisiologia , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/análogos & derivados , Vasodilatação/efeitos dos fármacos , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Inibidores da Fosfodiesterase 5/síntese química , Inibidores da Fosfodiesterase 5/química , Ratos , Ratos Wistar , Citrato de Sildenafila/química , Citrato de Sildenafila/farmacologia , Relação Estrutura-Atividade
18.
Bioorg Med Chem ; 23(13): 3674-80, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25921266

RESUMO

New sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine were synthesized and investigated as antitumor agents through carbonic anhydrase (CA, EC 4.2.1.1) inhibition. The newly prepared compounds were tested for their anticancer activity against human breast cancer cell lines (MCF-7, MDA-MB-231) using a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA. Preliminary biological studies with several CA isoforms, revealed that the new derivatives were ineffective as CA I and II inhibitors, but they showed activity against tumor-associated enzymes, such as CA IX. The most effective inhibitor against CA IX was compound 8e that exhibited an inhibition constant KI of 13.8nM, and derivatives 8c-8d with moderate activity (8c: KI=25.4nM; 8d: KI=24.5nM). Compounds 8g-8h exhibited acceptable activity (8g: KI=27.7nM; 8d: KI=26.6nM). The detailed synthesis, spectroscopic and biological data are also reported.


Assuntos
Antígenos de Neoplasias/química , Antineoplásicos/síntese química , Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/química , Sulfonamidas/síntese química , Triazinas/síntese química , Antineoplásicos/farmacologia , Anidrase Carbônica IX , Inibidores da Anidrase Carbônica/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Timidina/metabolismo , Triazinas/farmacologia , Trítio
19.
Bioorg Med Chem ; 23(7): 1421-9, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25757603

RESUMO

In the search for new biologically active chemotypes, several sildenafil analogs were prepared and characterized. The presence of the pyrazolo[4,3-e][1,2,4]triazine core is thought to be of interest for the enzyme inhibitory activity of these compounds. The designed derivatives incorporating the sildenafil scaffold were assayed as carbonic anhydrase inhibitors, and for their cytotoxic activity against MCF-7 and K562 cell lines. The X-ray analysis of one of these model compounds was performed and its crystal structure is described/compared to that of sildenafil.


Assuntos
Inibidores Enzimáticos/síntese química , Citrato de Sildenafila/análogos & derivados , Citrato de Sildenafila/síntese química , Cristalografia por Raios X , Humanos , Células K562 , Células MCF-7 , Inibidores da Fosfodiesterase 5/síntese química
20.
Bioorg Med Chem ; 22(23): 6616-6624, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25456386

RESUMO

Tyrosinase is a multifunctional, glycosylated and copper-containing oxidase which catalyzes the first two steps in mammalian melanogenesis and is responsible for enzymatic browning reactions in damaged fruits during post-harvest handling and processing. Neither hyperpigmentation in human skin nor enzymatic browning in fruits are desirable. These phenomena have encouraged researchers to seek new potent tyrosinase inhibitors for use in foods and cosmetics. This article surveys tyrosinase inhibitors, newly discovered from natural and synthetic sources. The inhibitory strength is comparable to that of the standard inhibitor kojic acid. Also their inhibitory mechanisms are discussed. The new obtained compounds were also tested as PDE5 inhibitors and did not show significant inhibitory effect.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Piperazinas/química , Pirazóis/síntese química , Pirazóis/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Triazinas/síntese química , Triazinas/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Piperazinas/farmacologia , Purinas/química , Purinas/farmacologia , Pirazóis/química , Citrato de Sildenafila , Relação Estrutura-Atividade , Sulfonamidas/química , Triazinas/química
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