RESUMO
It is reported that panaxadiol has neuroprotective effects. Previous studies have found that compound with carbamate structure introduced at the 3-OH position of 20 (R) -panaxadiol showed the most effective neuroprotective activity with an EC50 of 13.17⯵M. Therefore, we designed and synthesized a series of ginseng diol carbamate derivatives with ginseng diol as the lead compound, and tested their anti-AD activity. It was found that the protective effect of compound Q4 on adrenal pheochromocytoma was 80.6⯱â¯10.85â¯% (15⯵M), and the EC50 was 4.32⯵M. According to the ELISA results, Q4 reduced the expression of Aß25-35 by decreasing ß-secretase production. Molecular docking studies revealed that the binding affinity of Q4 to ß-secretase was -49.67â¯kcal/mol, indicating a strong binding affinity of Q4 to ß-secretase. Western blotting showed that compound Q4 decreased IL-1ß levels, which may contribute to its anti-inflammatory effect. Furthermore, compound Q4 exhibits anti-AD activities by reducing abnormal phosphorylation of tau protein and activation of the mitogen activated protein kinase pathway. The learning and memory deficits in mice treated with Q4in vivo were significantly alleviated. Therefore, Q4 may be a promising multifunctional drug for the treatment of AD, providing a new way for anti-AD drugs.
Assuntos
Doença de Alzheimer , Ginsenosídeos , Fármacos Neuroprotetores , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Simulação de Acoplamento Molecular , Carbamatos/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêuticoRESUMO
Pseudolaric Acid B (PAB), a natural product with remarkable anti-tumor activity, is a starting point for new anticancer therapeutics. We designed and synthesized 27 PAB derivatives and evaluated their anti-proliferative activities against four cancer cell lines: MCF-7, HCT-116, HepG2, and A549. Compared with unmodified PAB, the PAB derivatives showed stronger anti-proliferative activity. The ability of compound D3 (IC50 = 0.21 µM) to inhibit HCT-116 cells was approximately 5.3 times that of PAB (IC50 = 1.11 µM) and the antiproliferative action was unrelated to cytotoxicity (SI=20.38), indicating its superior safety profile (PAB; SI=0.95). Compound D3 effectively suppressed the EdU-positive rate and reduced colony formation, arrested HCT-116 cells in the S and G2/M phases and induced apoptosis. In vivo experiments further demonstrated low toxicity of compound D3 while suppressing tumor growth in mice. In summary, given its strong anti-proliferative effect and relative safety, further development of compound D3 is warranted.
RESUMO
Maslinic acid has a variety of biological activities, such as anti-tumor, hypoglycemic, anti-inflammatory, and anti-parasitic. In order to enhance the biological activity of maslinic acid, scholars have carried out a lot of structural modifications, and found some more valuable maslinic acid derivatives. In this paper, the structural modification, biological activity, and structure-activity relationship of maslinic acid were reviewed, providing references for the development of maslinic acid.
Assuntos
Neoplasias , Ácido Oleanólico/análogos & derivados , Triterpenos , Humanos , Relação Estrutura-Atividade , Anti-Inflamatórios/farmacologia , Triterpenos/farmacologia , Triterpenos/químicaRESUMO
Acute lung injury (ALI) are severe forms of diffuse lung disease that impose a substantial health burden all over the world. In the United States, approximately 190,000 cases per year of ALI each year, with an associated 74,500 deaths per year. Anti-inflammatory therapy has become a reasonable approach for the treatment of patients with ALI. In this study, fusidic acid derivatives were used to design new anti-inflammatory compounds with high pharmacological activity and low toxicity. A total of 30 new fusidic acid derivatives were discovered, synthesized, and screened for their anti-inflammatory activity against lipopolysaccharide (LPS)-treated RAW264.7 cells. Of them, b2 was found to be the most active, with a higher efficiency compared with fusidic acid and celecoxib in 10 µM. In vitro, we further measured b2 inhibited inflammatory factor NO (IC50 = 5.382 ± 0.655 µM), IL-6 (IC50 = 7.767 ± 0.871 µM), and TNF-α (IC50 = 7.089 ± 0.775 µM) and b2 inhibited inflammatory cytokines COX-2 and iNOS, ROS production, NF-κB/MAPK and Bax/Bcl-2 signaling pathway pathway. In vivo,b2 attenuated ALI pathological changes and inhibited inflammatory cytokines COX-2 and iNOS in lung tissue and NF-κB/MAPK and Bax/Bcl-2 signaling pathway. In conclusion, b2 may be a promising anti-inflammatory lead compound.
Assuntos
Lesão Pulmonar Aguda , NF-kappa B , Humanos , NF-kappa B/metabolismo , Ácido Fusídico/farmacologia , Ácido Fusídico/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Proteína X Associada a bcl-2 , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Citocinas/metabolismo , Relação Estrutura-Atividade , Lipopolissacarídeos/farmacologiaRESUMO
Alzheimer's disease (AD), a persistent neurological dysfunction, has an increasing prevalence with the aging of the world and seriously threatens the health of the elderly. Although there is currently no effective treatment for AD, researchers have not given up, and are committed to exploring the pathogenesis of AD and possible therapeutic drugs. Natural products have attracted considerable attention owing to their unique advantages. One molecule can interact with multiple AD-related targets, thus having the potential to be developed in a multi-target drug. In addition, they are amenable to structural modifications to increase interaction and decrease toxicity. Therefore, natural products and their derivatives that ameliorate pathological changes in AD should be intensively and extensively studied. This review mainly presents research on natural products and their derivatives for the treatment of AD.
Assuntos
Doença de Alzheimer , Produtos Biológicos , Humanos , Idoso , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Envelhecimento , Sistemas de Liberação de MedicamentosRESUMO
The Mannich reaction is commonly used to introduce N atoms into compound molecules and is thus widely applied in drug synthesis. The Mannich reaction accounts for a certain proportion of structural modifications of natural products. The introduction of Mannich bases can significantly improve the activity, hydrophilicity, and medicinal properties of compounds; therefore, the Mannich reaction is widely used for the structural modification of natural products. In this paper, the application of the Mannich reaction to the structural modification of natural products is reviewed, providing a method for the structural modification of natural products.
Assuntos
Produtos Biológicos , Produtos Biológicos/farmacologia , Bases de Mannich/químicaRESUMO
Natural compounds are rich in pharmacological properties that are a hot topic in pharmaceutical research. The quinoline ring plays important roles in many biological processes in heterocycles. Many pharmacological compounds, including saquinavir and chloroquine, have been marketed as quinoline molecules with good anti-viral and anti-parasitic properties. Therefore, in this review, we summarize the medicinal chemistry of quinoline-modified natural product quinoline derivatives that were developed by several research teams in the past 10 years and find that these compounds have inhibitory effects on bacteria, viruses, parasites, inflammation, cancer, Alzheimer's disease, and others.
RESUMO
Pyrazine is a six-membered heterocyclic ring containing nitrogen, and many of its derivatives are biologically active compounds. References have been downloaded through Web of Science, PubMed, Science Direct, and SciFinder Scholar. The structure, biological activity, and mechanism of natural product derivatives containing pyrazine fragments reported from 2000 to September 2023 were reviewed. Publications reporting only the chemistry of pyrazine derivatives are beyond the scope of this review and have not been included. The results of research work show that pyrazine-modified natural product derivatives have a wide range of biological activities, including anti-inflammatory, anticancer, antibacterial, antiparasitic, and antioxidant activities. Many of these derivatives exhibit stronger pharmacodynamic activity and less toxicity than their parent compounds. This review has a certain reference value for the development of heterocyclic compounds, especially pyrazine natural product derivatives.
Assuntos
Produtos Biológicos , Pirazinas , Pirazinas/farmacologia , Pirazinas/química , Química Farmacêutica , Anti-Inflamatórios/farmacologia , Antibacterianos/farmacologia , Produtos Biológicos/farmacologiaRESUMO
Using dehydroabietic acid as the lead compound for structural modification, 25 dehydroabietic acid derivatives were synthesized. Among them, compound D1 not only showed the strongest relaxation effect on the aortic vascular ring in vitro (Emax = 99.5 ± 2.1%, EC50 = 3.03 ± 0.96 µM), but also significantly reduced systolic and diastolic blood pressure in rats at a dose of 2.0 mg/kg in vivo. Next, the vascular protective effect of the best active D1 and its molecular mechanism were further investigated by HUVECs. The results showed that D1 induced endothelium-dependent diastole in the rat thoracic aorta in a concentration-dependent manner. Endothelium removal or aortic ring pretreatment with NG-nitro-l-arginine methylester (l-NAME), 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), and tetraethylammonium (TEA) significantly inhibited D1-induced relaxation. In addition, wortmannin, KT5823, triciribine, diltiazem, BaCl2, 4-aminopyridine, indomethacin, propranolol, and atropine attenuated D1-induced vasorelaxation. D1 increased the phosphorylation of eNOS in HUVECs Furthermore, D1 attenuated the expression of TNF-α-induced cell adhesion molecules such as ICAM-1 and VCAM-1. However, this effect was attenuated by the eNOS inhibitors l-NAME and asymmetric dimethylarginine (ADMA). The findings suggest that D1-induced vasorelaxation through the PI3K/Akt/eNOS/NO/cGMP/PKG pathway by activating the KCa, Kir and KV channels or muscarinic and ß-adrenergic receptors, and inhibiting the l-type Ca2+ channels, which is closely related to the hypotensive action of the agent. Furthermore, D1 exhibits an inhibitory effect on vascular inflammation, which is associated with the observed vascular protective effects.
Assuntos
Vasodilatação , Vasodilatadores , Animais , Ratos , Aorta Torácica , NG-Nitroarginina Metil Éster/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ratos Sprague-Dawley , Vasodilatadores/química , Tetraetilamônio/químicaRESUMO
Arctium lappa L. is a prevalent medicinal herb and a health supplement that is commonly used in Asia. Over the last few decades, the bioactive component arctigenin has attracted the attention of researchers because of its anti-inflammatory, antioxidant, immunomodulatory, multiple sclerosis fighting, antitumor, and anti-leukemia properties. After summarising the research and literature on arctigenin, this study outlines the current status of research on pharmacological activity, total synthesis, and structural modification of arctigenin. The purpose of this study is to assist academics in obtaining a more comprehensive understanding of the research progress on arctigenin and to provide constructive suggestions for further investigation of this useful molecule.
Assuntos
Arctium , Lignanas , Anti-Inflamatórios , Arctium/química , Furanos/química , Furanos/farmacologia , Lignanas/química , Lignanas/farmacologiaRESUMO
With the aim of finding new anti-inflammatory drugs, a series of new Glycyrrhetinic acid derivatives (1-34) have been designed and synthesized by structural modification, and their anti-inflammatory activities in vitro have been evaluated. The anti-inflammatory activities assay demonstrated that compound 5b suppressed the expression of pro-inflammatory cytokines including IL-6, TNF-α and NO, it also suppressed the expression of iNOS and COX-2 in LPS-induced RAW264.7 cells in a dose-dependent manner. Additionally, western blot results indicated that the suppressing effect of compound 5b on pro-inflammatory cytokines were correlated with the suppression of NF-κB and MAPK signaling pathways. The results attained in this study indicated that compound 5b had the potential to be developed into an anti-inflammation agent and it may be applied to the prevention and treatment of inflammatory diseases.
Assuntos
Anti-Inflamatórios/farmacologia , Ácido Glicirretínico/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Ácido Glicirretínico/síntese química , Ácido Glicirretínico/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-AtividadeRESUMO
Nature products have been extensively used in the discovery and development of new drugs, as the most important source of drugs. The triazole ring is one of main pharmacophore of the nitrogen-containing heterocycles. Thus, a new class of triazole-containing natural product conjugates has been synthesised. These compounds reportedly exert anticancer, anti-inflammatory, antimicrobial, antiparasitic, antiviral, antioxidant, anti-Alzheimer, and enzyme inhibitory effects. This review summarises the research progress of triazole-containing natural product derivatives involved in medicinal chemistry in the past six years. This review provides insights and perspectives that will help scientists in the fields of organic synthesis, medicinal chemistry, phytochemistry, and pharmacology.
Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Triazóis/química , Linhagem Celular Tumoral , Química Farmacêutica , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Toxoplasma gondii infection is widespread worldwide, not only posing a serious threat to human food safety and animal husbandry, but also endangering human health. The selectivity index was employed to measure anti-T. gondii activity. Hederagenin (HE) exhibited potent anti-T. gondii activity and low cytotoxicity. For this reason, HE was selected for in vivo experiments. HE showed 64.8%±13.1% inhibition for peritoneal tachyzoites in mice, higher than spiramycin 56.8%±6.0%. Biochemical parameters such as alanine aminotransferase, aspartate aminotransferase, glutathione, and malondialdehyde, illustrated that HE was a good inhibitor of T. gondii in vivo. This compound was also effective in relieving T. gondii-induced liver damage. Collectively, it was demonstrated that HE had potential as an anti-T. gondii agent.
Assuntos
Ácido Oleanólico , Toxoplasma , Toxoplasmose , Animais , Aspartato Aminotransferases , Camundongos , Ácido Oleanólico/análogos & derivados , Toxoplasmose/tratamento farmacológicoRESUMO
To develop novel anti-inflammatory agents, a series of 5-alkyl-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide derivatives were designed, synthesised, and evaluated for anti-inflammatory effects using RAW264.7 cells. Structures of the synthesised compounds were determined using 1H NMR, 13 C NMR, and HRMS. All the compounds were screened for anti-inflammatory activity based on their inhibitory effects against LPS-induced NO release. Among them, 5-(3,4,5-trimethoxybenzyl)-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide (6p) showed the highest anti-inflammatory activity and inhibited NO release more potently than the lead compound D1. Further studies revealed that compound 6p reduced the levels of NO, TNF-α, and IL-6, and that its anti-inflammatory activity involves the inhibition of COX-2 and iNOS and downregulation of the mitogen-activated protein kinases (MAPK) signal pathway. Notably, compound 6p displayed more prominent anti-inflammatory activity than D1 and the positive control ibuprofen in the in vivo acute inflammatory model. Overall, these findings indicate that compound 6p is a therapeutic candidate for the treatment of inflammation.
Assuntos
Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Descoberta de Drogas , Quinoxalinas/farmacologia , Úlcera Gástrica/tratamento farmacológico , Amidas/síntese química , Amidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Quinoxalinas/síntese química , Quinoxalinas/química , Células RAW 264.7 , Ratos , Úlcera Gástrica/metabolismo , Relação Estrutura-AtividadeRESUMO
To identify anticancer agents with higher potency and lower toxicity, a series of oridonin derivatives with substituted benzene moieties at the C17 position were designed, synthesised, and evaluated for their antiproliferative properties. Most of the derivatives exhibited antiproliferative effects against AGS, MGC803, Bel7402, HCT116, A549, and HeLa cells. Compound 2p (IC50 = 1.05 µM) exhibited the most potent antiproliferative activity against HCT116 cells; it was more potent than oridonin (IC50 = 6.84 µM) and 5-fluorouracil (5-FU) (IC50 = 24.80 µM). The IC50 value of 2p in L02 cells was 6.5-fold higher than that in HCT116 cells. Overall, it exhibited better selective antiproliferative activity and specificity than oridonin and 5-FU. Furthermore, compound 2p arrested HCT116 cells at the G2 phase of the cell cycle and increased the percentage of apoptotic cells to a greater extent than oridonin.
Assuntos
Antineoplásicos/farmacologia , Diterpenos do Tipo Caurano/farmacologia , Desenho de Fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diterpenos do Tipo Caurano/síntese química , Diterpenos do Tipo Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Conformação Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
The aim of the present study was to determine the cytotoxic effects of a series of novel dehydroepiandrosterone derivatives containing triazole at the C16 position on human cancer cells. The cancer cells used in the present study were A549, Hela, HepG-2, BEL7402, MCF-7, and HCT116. Several of the synthesised compounds exhibited potent antiproliferative effects. The most promising compound was (E)-3-hydroxy-16-((1-(4-iodophenyl)-1H-1,2,3-triazole-4-yl)methylene)-10,13-dimet-hyl-1,3,4,7,8,9,10,11,12,13,15,16-dodecahydro-2H-cyclopenta[a]phenanthren-17(14)-one (compound 2n), which showed considerably high antiproliferative activity in the HepG-2 cell line, with an IC50 value of 9.10 µM, and considerably high activity against the MCF-7 cell line, with an IC50 value of 9.18 µM. Flow cytometry assays demonstrated that compound 2n exerted antiproliferative effects by arresting cells in the G2 phase of the cell cycle and inducing apoptosis.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desidroepiandrosterona/análogos & derivados , Triazóis/síntese química , Triazóis/farmacologia , Células A549 , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Estrutura Molecular , Triazóis/químicaRESUMO
Six series of novel isosteviol derivatives; modified in the C-19 position; were synthesized; and their antiproliferative activity was evaluated against three human cancer cell lines (HCT-116; BEL-7402; HepG2) and the human L02 normal cell line in vitro. Most of the derivatives tested here exhibited improved antiproliferative activity with high selectivity when compared with the parent compound isosteviol and the positive control drug 5-fluorouracil. Among these derivatives; compound 5d exhibited the most potent antiproliferative activity and commendable selectivity between cancer and normal cells. In addition; compound 5d inhibited the colony formation of HCT-116 cells in a concentration-dependent manner. Further studies revealed that compound 5d arrested the HCT-116 cell cycle in the S phase; and western blot analysis demonstrated the mechanism may be correlated with a change in the expression of cyclin A; cyclin B1; and cyclin E1. Furthermore; the results of a docking study that involved placing compound 5d into the CDK2/cyclin A binding site revealed that its mode of action was possibly as a CDK2/cyclin A inhibitor.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/farmacologia , Desenho de Fármacos , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Diterpenos do Tipo Caurano/síntese química , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Ensaio Tumoral de Célula-TroncoRESUMO
Two series of xanthotoxin-triazole derivatives were designed, synthesized, and studied for their antiproliferative properties. The in vitro cytotoxicity of the compounds in the AGS cancer cell line and the L02 normal cell line was evaluated via MTT assay. Among the synthesized compounds, 9-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-7H-furo[3,2-g]chromen-7-one (6p) was found to have the greatest antiproliferative activity against AGS cells (IC50=7.5µM) and showed better activity than the lead compound (xanthotoxin, IC50>100µM) and the reference drug (5-fluorouracil, IC50=29.6µM) did. The IC50 value of 6p in L02 cells was 13.3 times higher than that in the AGS cells. Therefore, the compound exhibited better therapeutic activity and specificity compared with the positive control 5-fluorouracil. Cell cycle analysis revealed that compound 6p inhibited cell growth via the induction of S/G2 phase arrest in AGS cells. Compound 6p was identified as a promising lead compound for the further development and identification of 1,2,3-triazole-based anticancer agents.
Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Metoxaleno/química , Triazóis/química , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Metoxaleno/síntese química , Metoxaleno/toxicidade , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Relação Estrutura-AtividadeRESUMO
A new series of novel 7-hydroxy-4-phenylchromen-2-one (1a)-linked 1,2,4-triazoles were synthesised using a click chemistry approach. All derivatives were subjected to 3-(4,5-dimethylthiazol-yl)-diphenyl tetrazolium bromide (MTT) cytotoxicity screening against a panel of six different human cancer cell lines (AGS, MGC-803, HCT-116, A-549, HepG2, and HeLa) to assess their cytotoxic potential. Among the tested molecules, some of the analogues showed better cytotoxic activity than that shown by the 7-hydroxy-4-phenylchromen-2-one (1a). Of the synthesised 1,2,4-triazoles,the 7-((4-(4-Chlorophenyl)-4H-1,2,4-triazol-3-yl)methoxy)-4-phenyl-2H-chromen-2-one (4d) showed the best activity, with an IC50 of 2.63 ± 0.17 µM against AGS cells. Further flow cytometry assays demonstrated that compound 4d exerts its antiproliferative effects by arresting cells in the G2/M phase of the cell cycle and by inducing apoptosis. Collectively, our results indicate that the 1,2,4-triazole derivatives have a significantly stronger antitumour activity than 1,2,3-triazole derivatives. Most of the compounds exhibited better antitumour activity than the positive control drug 5-fluorouracil.
Assuntos
Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Citotoxinas/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Citotoxinas/síntese química , Citotoxinas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
Two novel series of 3,4-dihydroisoquinolin with heterocycle derivatives (4a-t and 9a-e) were synthesized and evaluated for their anticonvulsant activity using maximal electroshock (MES) test and pentylenetetrazole (PTZ)-induced seizure test. All compounds were characterized by IR, ¹H-NMR, 13C-NMR, and mass spectral data. Among them, 9-(exyloxy)-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinolin-3(2H)-one (9a) showed significant anticonvulsant activity in MES tests with an ED50 value of 63.31 mg/kg and it showed wide margins of safety with protective index (PI > 7.9). It showed much higher anticonvulsant activity than that of valproate. It also demonstrated potent activity against PTZ-induced seizures. A docking study of compound 9a in the benzodiazepine (BZD)-binding site of γ-aminobutyric acidA (GABAA) receptor confirmed possible binding of compound 9a with the BZD receptors.