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1.
Molecules ; 24(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370274

RESUMO

Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases. The development of suitable PDE2A tracers for Positron Emission Tomography (PET) would permit the in vivo imaging of the PDE2A and evaluation of disease-mediated alterations of its expression. A series of novel fluorinated PDE2A inhibitors on the basis of a Benzoimidazotriazine (BIT) scaffold was prepared leading to a prospective inhibitor for further development of a PDE2A PET imaging agent. BIT derivatives (BIT1-9) were obtained by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over other PDEs were evaluated. BIT1 demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). BIT1 displayed an IC50 for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. This finding revealed that a derivative bearing both a 2-fluoro-pyridin-4-yl and 2-chloro-5-methoxy-phenyl unit at the 8- and 1-position, respectively, appeared to be the most potent inhibitor. In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as a suitable ligand for 18F-labeling. Nevertheless, future in vivo metabolism studies are required.


Assuntos
Encéfalo/enzimologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Compostos Radiofarmacêuticos/química , Triazinas/síntese química , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/química , Humanos , Ligantes , Camundongos , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacologia , Triazinas/química , Triazinas/farmacologia
2.
Arch Pharm (Weinheim) ; 352(9): e1900053, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31380598

RESUMO

The present research focused on designing a quinazoline skeleton, framed via 1,3,5-triazine derivatives (QBT) through field mapping and alignment studies. The QBT derivatives were synthesized via time- and cost-effective protocol. The 3D-QSAR study, computational physicochemical properties, and ADME calculation of the derivatives were performed to establish the affinity towards the biological system. Molecular docking in the adenosine triphosphate binding site of the RET tyrosine kinase domain (PDB ID: 7IVU) was studied to elucidate vital structural residues necessary for bioactivity. The derivatives were evaluated for anticancer potency against TPC-1 cells (thyroid cancer), MCF-7 cells (breast cancer), and one normal cell line (human foreskin fibroblasts) via 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide assay followed by an in ovo CAM assay. The entire series of derivatives (8a-o) showed mild to significant anticancer potency against the selected cancer cell lines.


Assuntos
Antineoplásicos/síntese química , Desenho de Drogas , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Quinazolinas/química , Triazinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosforilação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Quantitativa Estrutura-Atividade , Triazinas/química , Triazinas/farmacologia
3.
Molecules ; 24(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340573

RESUMO

In this article, we report the synthesis of 2,4,6-substituted s-triazine-based organophosphorus compounds via a two-step process, which enables their production in high yields, and with a high purity as solids. In the first step, a Michaelis-Arbuzov rearrangement of cyanuric chloride with triethyl phosphite afforded 2,4,6-trisdiethoxyphosphinyl-1,3,5-triazine (HEPT). Subsequently, the nucleophilic substitution reaction on the triazine carbon was achieved, owing to the electron-withdrawing ability of the phosphonate groups. This characteristic of HEPT facilitated its derivatization with bi-functional amines, producing novel P-C containing bridged triazine organophosphorus compounds. The molecular structures of all of the compounds were confirmed by NMR spectroscopy, CHN elemental analysis, and single crystal X-ray analysis. In the thermogravimetric analysis in an N2 environment, >33% char formation was observed for the bridged compounds. The chemical composition analysis of the char obtained under the oxidative thermal decomposition of the bridged compounds confirmed the presence of phosphorus- and nitrogen-enriched species, which indicate their function in the condensed phase. Comparatively, the detection of HPO and H-C≡P in the gas phase during the pyrolysis of the bridged compounds can act as a source for PO•, which is known for its gas phase flame inhibition reactions. The synergy of significant char formation and the generation of intermediates leading to PO• during pyrolysis makes these molecules promising flame-retardant additives.


Assuntos
Retardadores de Chama/síntese química , Compostos Organofosforados/síntese química , Triazinas/síntese química , Humanos , Estrutura Molecular , Fosfitos/química , Pirólise , Triazinas/química
4.
ACS Appl Mater Interfaces ; 11(14): 13460-13471, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30864778

RESUMO

The investigation of nondoped exciplex blends of 2,4,6-tris[3-(diphenylphosphinyl)phenyl]-1,3,5-triazine (PO-T2T), working as the one-electron acceptor molecule, with different electron donors is reported. The emissions of these exciplexes span from the blue to orange-red regions, showing clear contribution from thermally activated delayed fluorescence (TADF) and delayed fluorescence originated from nongeminate recombination of charge carriers created by the dissociation of optically generated exciplexes. We focus our studies on the properties of TADF in these systems, covering in particular the physical meaning of the different transient components observed in their luminescence decays. Our results unravel the intricate role of reverse intersystem crossing due to spin-orbit coupling and possibly also due to hyperfine interactions and internal conversion, which affect the efficiency of the TADF mechanism. Remarkable performances are obtained in prototype organic light-emitting diodes fabricated with some of these blends. Green exciplex blends, in particular, exhibited the current efficiency of 60 cd A-1, power efficiency of 71 lm W-1, and external quantum efficiency of 20%. We believe that our results will contribute significantly to highlight the potential advantages of intermolecular exciplexes in the area of organic light-emitting diodes.


Assuntos
Transporte de Elétrons , Oxidantes/química , Triazinas/química , Elétrons , Fluorescência , Temperatura Alta , Luminescência , Oxidantes/síntese química , Triazinas/síntese química
5.
Eur J Med Chem ; 165: 216-224, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30684798

RESUMO

INTRODUCTION: The redox characteristics of 1,2,4-benzotriazine-1,4-dioxides (BTDOs) make them potential radiosensitizing agents for hypoxic cells in solid human cancers. Tirapazamine (TPZ) is the most clinically tested BTDO radiosensitizer, despite its toxicity at effective doses. To date, no BTDOs have been developed as diagnostic markers of tissue hypoxia. HYPOTHESIS: TPZ analogues with appropriate reporting groups can act as potential radiosensitizers and hypoxia selective diagnostics. EXPERIMENTAL AND RESULTS: 3-Chloro-1,2,4-benzotriazine 1-oxide was substituted at the C3 position to afford 3-(2-hydroxyethoxyethyl)-amino-1,2,4-benzotriazine-1-oxide, which was oxidized to 3-(2-hydroxyethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (HO-EOE-TPZ) or converted to 3-(2-tosyloxyethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (Tos-EOE-TPZ). Tos-EOE-TPZ was intended for use as a synthon for preparing 3-(2-azidoethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (N3-EOE-TPZ) and 3-(2-iodoethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (I-EOE-TPZ). The logP values (-0.69 to 0.61) for these molecules bracketed that of TPZ (-0.34). Cell line dependent cytotoxicities (IC50) in air were in the 10-100 µM range, with Hypoxia Cytotoxicity Ratios (HCR; IC50-air/IC50-hypoxia) of 5-10. LUMO calculations indicated that these molecules are in the optimal redox range for radiosensitization, offering cell-line-specific Relative Radiosensitization Ratios (RRSR; SER/OER) of 0.58-0.88, compared to TPZ (0.67-0.76). CONCLUSION: The LUMO, IC50, HCR and RRSR values of 3-(2-substituted ethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxides are similar to the corresponding values for TPZ, supporting the conclusion that these TPZ analogues are potentially useful as hypoxia-activated radiosensitizers. Further studies into their biodistributions in animal models are being pursued to determine the in vivo potential in hypoxia management.


Assuntos
Hipóxia , Radiossensibilizantes/química , Tirapazamina/análogos & derivados , Triazinas/uso terapêutico , Animais , Biomarcadores , Humanos , Oxirredução , Óxidos , Relação Estrutura-Atividade , Tirapazamina/uso terapêutico , Triazinas/síntese química , Triazinas/química
6.
Acta Crystallogr C Struct Chem ; 75(Pt 1): 22-28, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30601127

RESUMO

Synthetic biologists demonstrate their command over natural biology by reproducing the behaviors of natural living systems on synthetic biomolecular platforms. For nucleic acids, this is being done stepwise, first by adding replicable nucleotides to DNA, and then removing its standard nucleotides. This challenge has been met in vitro with `six-letter' DNA and RNA, where the Watson-Crick pairing `concept' is recruited to increase the number of independently replicable nucleotides from four to six. The two nucleobases most successfully added so far are Z and P, which present a donor-donor-acceptor and an acceptor-acceptor-donor pattern, respectively. This pair of nucleobases are part of an `artificially expanded genetic information system' (AEGIS). The Z nucleobase has been already crystallized, characterized, and published in this journal [Matsuura et al. (2016). Acta Cryst. C72, 952-959]. More recently, variants of Taq polymerase have been crystallized with the pair P:Z trapped in the active site. Here we report the crystal structure of the nucleobase 2-aminoimidazo[1,2-a][1,3,5]triazin-4-one (trivially named P) as the monohydrate, C5H5N5O·H2O. The nucleobase P was crystallized from water and characterized by X-ray diffraction. Interestingly, the crystal structure shows two tautomers of P packed in a Watson-Crick fashion that cocrystallized in a 1:1 ratio.


Assuntos
Imidazóis/química , Triazinas/química , Pareamento de Bases , Cristalografia por Raios X , Ligações de Hidrogênio , Imidazóis/síntese química , Isomerismo , Estrutura Molecular , Triazinas/síntese química
7.
Bioorg Chem ; 82: 117-122, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30312866

RESUMO

A series of novel ureido benzenesulfonamides incorporating 1,3,5-triazine moieties were obtained by reacting 4-isocyanato-benzenesulfonamide (2) with 2-amino-4,6-dicholoro-1,3,5-triazine (4). The 4-(3-(4,6-dichloro-1,3,5-triazin-2-yl)ureido) benzenesulfonamide (5) was subsequently derivatized by reaction with various nucleophiles such as, morpholine, ammonia, methyl amine, dimethyl amine, and piperidine. The ureido benzenesulfonamides incorporating triazinyl moieties were investigated as inhibitors of four selected physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, namely, hCA I, II, IX, and XII which are involved in various diseases such as glaucoma, epilepsy, obesity and cancer. The membrane-bound tumor-associated isoform hCA IX was potently inhibited with these compounds with Kis in the range of 0.91-126.2 nM. Specifically, compound 7j showed great potency against hCA IX with sub-nanomolar Ki of 0.91 nM. Since hCA IX is a validated drug target for anticancer agents, these isoform-selective and potent inhibitors may be considered of interest for further medicinal/pharmacologic studies.


Assuntos
Inibidores da Anidrase Carbônica/química , Compostos de Fenilureia/química , Sulfonamidas/química , Triazinas/química , Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/química , Desenho de Drogas , Humanos , Isoenzimas/antagonistas & inibidores , Estrutura Molecular , Compostos de Fenilureia/síntese química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Triazinas/síntese química
8.
Int J Biol Macromol ; 123: 1125-1131, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30462986

RESUMO

In this study, porous magnetic resin grafted chitosan (R-g-Ch) beads were prepared for removal of 4-chlorophenol and phenol from aqueous solutions. The R-g-Ch beads were characterized by vibrating sample magnetometer, Fourier-transform infrared spectroscopy, scanning electron microscopy and thermogravimetry methods. The removal of the phenolic compounds was optimized by varying the experimental conditions. Results herein are well fitted to the pseudo-second order kinetic and Langmuir isotherm. The maximum adsorption capacity of phenol and 4-chlorophenol were found to be 188.6 and 99 mg/g, respectively. The thermodynamic studies suggested that the adsorption process was exothermic, irreversible and feasible within the range of 298-318 K.


Assuntos
Quitosana/química , Magnetismo , Microesferas , Fenóis/isolamento & purificação , Resinas Sintéticas/química , Adsorção , Quitosana/síntese química , Clorofenóis/isolamento & purificação , Análise Diferencial Térmica , Formaldeído/síntese química , Formaldeído/química , Concentração de Íons de Hidrogênio , Cinética , Porosidade , Resorcinóis/síntese química , Resorcinóis/química , Soluções , Temperatura Ambiente , Termogravimetria , Fatores de Tempo , Triazinas/síntese química , Triazinas/química
9.
ChemMedChem ; 14(3): 310-314, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30548443

RESUMO

Glycogen synthase kinase 3ß (GSK-3ß) and casein kinase 1δ (CK-1δ) are emerging targets for the treatment of neuroinflammatory disorders, including Parkinson's disease. An inhibitor able to target these two kinases was developed by docking-based design. Compound 12, 3-(7-amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamide, showed combined inhibitory activity against GSK-3ß and CK-1δ [IC50 (GSK-3ß)=0.17 µm; IC50 (CK-1δ)=0.68 µm]. In particular, classical ATP competition was observed against CK-1δ, and a co-crystal of compound 12 inside GSK-3ß confirmed a covalent interaction between the cyanoacrylamide warhead and Cys199, which could help in the development of more potent covalent inhibitors of GSK-3ß. Preliminary studies on in vitro models of Parkinson's disease revealed that compound 12 is not cytotoxic and shows neuroprotective activity. These results encourage further investigations to validate GSK-3ß/CK-1δ inhibition as a possible new strategy to treat neuroinflammatory/degenerative diseases.


Assuntos
Caseína Quinase Idelta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Triazinas/farmacologia , Animais , Caseína Quinase Idelta/metabolismo , Sobrevivência Celular , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química
10.
Bioorg Med Chem ; 26(22): 5885-5895, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30415894

RESUMO

The expression levels and the subcellular localization of adenosine receptors (ARs) are affected in several pathological conditions as a consequence of changes in adenosine release and metabolism. In this respect, labelled probes able to monitor the AR expression could be a useful tool to investigate different pathological conditions. Herein, novel ligands for ARs, bearing the fluorescent 7-nitrobenzofurazan (NBD) group linked to the N1 (1,2) or N10 (3,4) nitrogen of a triazinobenzimidazole scaffold, were synthesized. The compounds were biologically evaluated as fluorescent probes for labelling A1 and A2B AR subtypes in bone marrow-derived mesenchymal stem cells (BM-MSCs) that express both receptor subtypes. The binding affinity of the synthetized compounds towards the different AR subtypes was determined. The probe 3 revealed a higher affinity to A1 and A2B ARs, showing interesting spectroscopic properties, and it was selected as the most suitable candidate to label both AR subtypes in undifferentiated MSCs. Fluorescence confocal microscopy showed that compound 3 significantly labelled ARs on cell membranes and the fluorescence signal was decreased by the cell pre-incubation with the A1 AR and A2B AR selective agonists, R-PIA and BAY 60-6583, respectively, thus confirming the specificity of the obtained signal. In conclusion, compound 3 could represent a useful tool to investigate the expression pattern of both A1 and A2B ARs in different pathological and physiological processes. Furthermore, these results provide an important basis for the design of new and more selective derivatives able to monitor the expression and localization of each different ARs in several tissues and living cells.


Assuntos
Benzimidazóis/farmacologia , Corantes Fluorescentes/farmacologia , Receptor A1 de Adenosina/metabolismo , Receptor A2B de Adenosina/metabolismo , Triazinas/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/química , Células Cultivadas , Relação Dose-Resposta a Droga , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Microscopia Confocal , Estrutura Molecular , Receptor A1 de Adenosina/química , Receptor A2B de Adenosina/química , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química
11.
J Am Chem Soc ; 140(49): 17120-17126, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30422648

RESUMO

The development of new bio-orthogonal ligation methods for the conjugation of native proteins is of particular importance in the field of chemical biology and biotherapies. In this work, we developed a traceless electrochemical method for protein bioconjugation. The electrochemically promoted tyrosine-click (e-Y-CLICK) allowed the chemoselective Y-modification of peptides and proteins with labeled urazoles. A low potential is applied in an electrochemical cell to activate urazole anchors in situ and on demand, without affecting the electroactive amino acids from the protein. The versatility of the electrosynthetic approach was shown on biologically relevant peptides and proteins such as oxytocin, angiotensin 2, serum bovine albumin, and epratuzumab. The fully conserved enzymatic activity of a glucose oxidase observed after e-Y-CLICK further highlights the softness of the method. The e-Y-CLICK protocols were successfully performed in pure aqueous buffers, without the need for co-solvents, scavenger or oxidizing chemicals, and should therefore significantly broaden the scope of bioconjugation.


Assuntos
Sondas Moleculares/química , Proteínas/química , Triazinas/química , Tirosina/química , Sequência de Aminoácidos , Animais , Aspergillus niger/enzimologia , Bovinos , Química Click/métodos , Técnicas Eletroquímicas/métodos , Glucose Oxidase/química , Humanos , Sondas Moleculares/síntese química , Triazinas/síntese química
12.
Arch Pharm (Weinheim) ; 351(12): e1800154, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30479053

RESUMO

A series of newer benzothiazolotriazine derivatives (4a-k) was designed, synthesized, and characterized as anticonvulsant agents against the two classically used MES and scPTZ animal models. The synthesized derivatives were tested in vivo in both the animal models, followed by a neurotoxicity study by the rotarod method. Compound 4e, 8-chloro-4-(2-chlorocyclohexa-1,5-dien-1-yl)-2-((4-methoxybenzyl)thio)-10aH-benzo[4,5]thiazolo[3,2a][1,3,5]triazine was found most promising among the series in both the animal models, with no neurotoxicity. From this it may be confirmed that the presence of a methoxy (OCH3 ) group at the lipophilic aryl ring was showing high anticonvulsant potency. In the molecular modeling study, compound 4e (docking score = -8.70) showed important hydrogen bond interaction with the amino acids LYS 329, SER 137, GLY 136 and π-π interactions with PHE 189 at the active site of GABA-AT. These derivatives can be further explored for the development of newer/novel anticonvulsant agents.


Assuntos
Anticonvulsivantes/síntese química , Benzotiazóis/síntese química , Desenho de Drogas , Triazinas/síntese química , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Benzotiazóis/química , Benzotiazóis/farmacologia , Sítios de Ligação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Teste de Desempenho do Rota-Rod , Convulsões/tratamento farmacológico , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacologia , Ácido gama-Aminobutírico/metabolismo
13.
J Photochem Photobiol B ; 189: 152-164, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30352369

RESUMO

A new class of triazine ligands (E)-2-(2-(6-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)hydrazono)propanoic acid hydrate (HL1.H2O) and (Z)-2-(((E)-4-amino-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3(2H)ylidene)hydrazono)propanoic acid (H2L2) has been synthesized by the condensation reaction of pyruvic acid with diaminoguanidine and triaminoguanidine respectively. The corresponding Schiff base cobalt complexes [Co(L1)2].2H2O (1) and [Co(HL2)(L2)].H2O (2) have also been synthesized and characterized by analytical, thermal, spectroscopic and diffraction studies. Strong field ligand results low spin Co(III) centre in 2, which was evidenced by the shorter bond length of Co(III) complex. In H2L2 there is a choice of coordination modes based on distinct sets of donor atoms, both of which are seen in complex 2, involving either an -NH2 group on position 4 of the triazine ring, or via a ring nitrogen of the triazine itself. The deprotonation of one version of L2 allows the formation of the ligand field stabilized low spin Co(III) in 2. In complex 1, each ligand binds to the metal via pyruvate oxygen, azomethine nitrogen and triazine nitrogen forming two five-membered stable chelate rings. In complex 2, the coordination sphere assembled by two types of coordinating atoms from the same ligand with different conformation. Their binding ability and mode of binding with CT-DNA and BSA was studied by UV- absorption, fluorescence and CD spectroscopy. Density Functional Theory (DFT) studies provide further insights into the mode of binding, structure and mechanism. The HOMO and LUMO energy gap values indicate that both the complexes are prone to interact with CT-DNA and BSA. We have also performed molecular docking calculations to understand the mode of binding and the corresponding results confirm our experimental findings.


Assuntos
Cobalto/química , Complexos de Coordenação/síntese química , Bases de Schiff/química , Triazinas/síntese química , DNA/metabolismo , Guanidinas/química , Ligantes , Simulação de Acoplamento Molecular , Ácido Pirúvico/química , Soroalbumina Bovina/metabolismo , Solubilidade , Análise Espectral
14.
Molecules ; 23(10)2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30282913

RESUMO

This study focuses on the design, synthesis, biological evaluation, and computer-aided structure-activity relationship (SAR) analysis for a novel group of aromatic triazine-methylpiperazines, with an hydantoin spacer between 1,3,5-traizine and the aromatic fragment. New compounds were synthesized and their affinities for serotonin 5-HT6, 5-HT1A, 5-HT2A, 5-HT7, and dopamine D2 receptors were evaluated. The induced-fit docking (IFD) procedure was performed to explore the 5-HT6 receptor conformation space employing two lead structures. It resulted in a consistent binding mode with the activity data. For the most active compounds found in each modification line, anti-obesity and anti-depressive-like activity in vivo, as well as "druglikeness" in vitro, were examined. Two 2-naphthyl compounds (18 and 26) were identified as the most active 5-HT6R agents within each lead modification line, respectively. The 5-(2-naphthyl)hydantoin derivative 26, the most active one in the series (5-HT6R: Ki = 87 nM), displayed also significant selectivity towards competitive G-protein coupled receptors (6⁻197-fold). Docking studies indicated that the hydantoin ring is stabilized by hydrogen bonding, but due to its different orientation, the hydrogen bonds form with S5.44 and N6.55 or Q6.58 for 18 and 26, respectively. Compound 26 exerted anxiolytic-like and antidepressant-like activities. Importantly, it demonstrated anti-obesity properties in animals fed palatable feed, and did not show toxic effects in vitro.


Assuntos
Hidantoínas/química , Receptores de Serotonina/química , Triazinas/química , Animais , Ansiolíticos/química , Ansiolíticos/uso terapêutico , Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Antidepressivos/química , Antidepressivos/uso terapêutico , Humanos , Ligantes , Estrutura Molecular , Serotonina/química , Serotonina/metabolismo , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/uso terapêutico
15.
Georgian Med News ; (280-281): 173-178, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30204120

RESUMO

Today we know that NO· and ONOO- are clue pathophysiological factors for progression some ischemic diseases of the central nervous system. So investigation of the antioxidants which will be able to decrease NO· and ONOO- toxicity seems to be very of current interest. The six esters and three amides of 2-(3,4-dihydro-3-oxo-2H-[1,2,4]triazino[4,3-c]quinazolin-4-yl)acetic acid were synthesized for this study, and we showed evidence of antioxidant activity of these new original derivatives. We studied the effect of 2-(3,4-dihydro-3-oxo-2H-[1,2,4]triazino[4,3-c]quinazolin-4-yl)acetic acid derivatives on superoxide dismutase activity under the condition of excessive NO· and ONOO- production. NO· induction was performed by the action of light on sodium nitroprusside Na2[Fe(NO)(CN)5]×2H2O in vitro. Also, the investigation of the substances was carried out in the brain supernatant obtained from the white Wistar rats in vivo. For nitrosative stress modeling dinitrozolic complex of Fe2+ and cysteine were utilized. Our data showed that 2-(3,4-dihydro-3-oxo-2H-[1,2,4]triazino[4,3-c]quinazolin-4-yl)acetic acid is not active compound while its esters and amides have antioxidant activity. Compound benzyl ester of this acid revealed the most effective antioxidant activity.


Assuntos
Acetatos/farmacologia , Antioxidantes/farmacologia , Estresse Nitrosativo/efeitos dos fármacos , Quinazolinas/farmacologia , Triazinas/farmacologia , Acetatos/síntese química , Amidas/síntese química , Amidas/farmacologia , Animais , Antioxidantes/síntese química , Encéfalo/metabolismo , Ésteres/síntese química , Ésteres/farmacologia , Masculino , Óxido Nítrico/biossíntese , Ácido Peroxinitroso/biossíntese , Quinazolinas/síntese química , Ratos Wistar , Relação Estrutura-Atividade , Superóxido Dismutase/metabolismo , Triazinas/síntese química , Tirosina/análogos & derivados , Tirosina/metabolismo
16.
ChemMedChem ; 13(22): 2455-2463, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30246417

RESUMO

Herein we describe the design and synthesis of a new series of heteroarylpyrimidine/heteroaryltriazine derivatives on the basis of quinazoline-2,4(1H,3H)-diones as CB2 R-selective ligands using a bioisosterism strategy. An acetamide group was explored to displace the enamine linker of the lead compound for the purpose of stereoisomerism elimination and hydrophilicity increase. As a result, some of the synthesized compounds showed high bioactivity and selectivity for CB2 R in calcium mobilization assays, and four displayed CB2 R agonist activity, with EC50 values below 30 nm. The compound exhibiting the highest agonist activity toward CB2 R (EC50 =7.53±3.15 nm) had a selectivity over CB1 R of more than 1328-fold. Moreover, structure-activity relationship (SAR) studies indicated that the substituents on the nucleus play key roles in the functionality of a ligand, with one such example demonstrating CB2 R antagonist activity. Additionally, molecular docking simulations were conducted with the aim of better understanding of these new derivatives in relation to the structural requirements for agonists/antagonists binding to CB2 R.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Pirimidinas/farmacologia , Receptor CB2 de Canabinoide/agonistas , Triazinas/farmacologia , Animais , Sítios de Ligação , Células CHO , Agonistas de Receptores de Canabinoides/síntese química , Agonistas de Receptores de Canabinoides/química , Cricetulus , Desenho de Drogas , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/química , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química
18.
Eur J Med Chem ; 158: 814-831, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30248654

RESUMO

c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ±â€¯0.1 nM and 5.0 ±â€¯0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ±â€¯0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ±â€¯0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Triazinas/química , Triazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirróis/síntese química , Pirróis/química , Pirróis/farmacologia , Triazinas/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
19.
Molecules ; 23(9)2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30200261

RESUMO

Morpholine- and bis(2-methoxyethyl)amine-substituted 1,3,5-triazine derivatives containing an alkoxy-o-carborane in the 6-position of the triazine ring were successfully synthesized. The molecular structures of the methoxy- and ethoxy-o-carboranyl-1,3,5-triazines were established by X-ray crystallography. In vitro studies showed that the methylene bridged morpholine- and bis(2-methoxyethyl)amine-substituted o-carboranyl-1,3,5-triazines accumulated to high levels in B16 melanoma cells and exhibited higher cytotoxicity than p-boronophenylalanine.


Assuntos
Triazinas/química , Triazinas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Cristalografia por Raios X , Células HeLa , Humanos , Melanoma Experimental , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Triazinas/síntese química
20.
Chem Pharm Bull (Tokyo) ; 66(8): 830-838, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30068804

RESUMO

We report the preparation of new C3- and CS-symmetrical molecules constructed on a triazine (TAZ) template. Anti-herpes simplex virus type 1 (anti-HSV-1) and cytotoxic activities against Vero cells of synthesized TAZ derivatives were evaluated. The results suggested that the presence of an electron-donating group(s) on the benzene ring in benzylamine groups on the TAZ template is an important structural factor for expressing a high level of anti-HSV-1 activity and low cytotoxicity for these C3 types of TAZ derivatives. Among the tested TAZ derivatives, compounds 4f and 7h showed the highest anti HSV-1 activities (EC50=0.98 and 1.23 µM, respectively) and low cytotoxic activities to Vero cells (50% cytotoxic concentration (CC50)=292.2 and >200 µM, respectively).


Assuntos
Antivirais/síntese química , Benzilaminas/síntese química , Herpesvirus Humano 1/efeitos dos fármacos , Triazinas/síntese química , Animais , Antivirais/farmacologia , Benzilaminas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Desenho de Drogas , Humanos , Relação Estrutura-Atividade , Triazinas/farmacologia , Células Vero
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