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1.
J Agric Food Chem ; 67(42): 11598-11606, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31560195

RESUMO

A total of 22 quinazoline thioether derivatives incorporating a 1,2,4-triazolo[4,3-a]pyridine moiety were designed, synthesized, and evaluated as antimicrobial agents in agriculture. Among these compounds, the chemical structure of compound 6l was further confirmed via single-crystal X-ray diffraction analysis. The bioassay results revealed that some of the compounds possessed noticeable in vitro antibacterial activities against the tested phytopathogenic bacteria. For example, compounds 6b and 6g had EC50 values as low as 10.0 and 24.7 µg/mL against Xanthomonas axonopodis pv. citri (Xac), respectively, which were significantly better than that of the commercial agrobactericide bismerthiazol (56.9 µg/mL). Particularly, compound 6b was also found to be capable of suppressing the pathogenic bacterium Xanthomonas oryzae pv. oryzae (Xoo) approximately 12-fold more potent than control bismerthiazol, in terms of their EC50 values (7.2 versus 89.8 µg/mL). Importantly, the most active compound 6b turned out to be one with the highest hydrophilicity and the lowest molecular weight within the series. In vivo bioassays further showed the application prospect of 6b as a promising plant bactericide for controlling Xoo. Additionally, in vitro antifungal activities of these compounds were also evaluated at the concentration of 50 µg/mL. Overall, the present study demonstrated the potential of 1,2,4-triazolo[4,3-a]pyridine-bearing quinazoline thioether derivatives as efficient agricultural antibacterial agents for crop protection.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Sulfetos/química , Sulfetos/farmacologia , Agroquímicos/química , Agroquímicos/farmacologia , Antibacterianos/síntese química , Desenho de Drogas , Piridinas/química , Relação Estrutura-Atividade , Xanthomonas/efeitos dos fármacos
2.
J Agric Food Chem ; 67(40): 11005-11017, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31532657

RESUMO

The limited number of agrochemicals targeting plant bacterial diseases has driven us to develop highly efficient, low-cost, and versatile antibacterial alternatives. Herein, a novel type of simple furan-functionalized quinazolin-4-amines was systematically fabricated and screened for their antibacterial activity. Bioassay results revealed that compounds C1 and E4 could substantially block the growth of two frequently mentioned pathogens Xanthomonas oryzae pv oryzae and X. axonopodis pv citri in vitro, displaying appreciable EC50 values of 7.13 and 10.3 mg/L, respectively. This effect was prominently improved by comparing those of mainly used agrochemicals. An in vivo experiment against bacterial blight further illustrated their viable applications as antimicrobial ingredients. Quantitative proteomics demonstrated that C1 possessed a remarkable ability to manipulate the upregulation and downregulation of expressed proteins, which probably involved d-glucose and biotin metabolic pathways. This finding was substantially verified by parallel reaction monitoring analysis. Scanning electron microscopy images and fluorescence spectra also indicated that the designed compounds had versatile capacities for destroying the integrity of bacteria. Given these remarkable characteristics, furan-functionalized quinazoline hybrids can serve as a viable platform for developing innovative antibiotic alternatives against bacterial infections.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Furanos/farmacologia , Quinazolinas/farmacologia , Xanthomonas/efeitos dos fármacos , Antibacterianos/síntese química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Furanos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Doenças das Plantas/microbiologia , Proteômica , Quinazolinas/química , Relação Estrutura-Atividade , Xanthomonas/genética , Xanthomonas/crescimento & desenvolvimento , Xanthomonas/metabolismo
3.
J Agric Food Chem ; 67(33): 9254-9264, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31356740

RESUMO

In continuation of our search for potent protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) inhibitors, we designed and synthesized a series of novel herbicidal cycloalka[d]quinazoline-2,4-dione-benzoxazinones. The bioassay results of these synthesized compounds indicated that most of the compounds exhibited very strong Nicotiana tabacum PPO (NtPPO) inhibition activity. More than half of the 37 synthesized compounds displayed over 80% control of all three tested broadleaf weeds at 37.5-150 g ai/ha by postemergent application, and a majority of them showed no phytotoxicity toward at least one kind of crop at 150 g ai/ha. Promisingly, 17i (Ki = 6.7 nM) was 6 and 4 times more potent than flumioxazin (Ki = 46 nM) and trifludimoxazin (Ki = 31 nM), respectively. Moreover, 17i displayed excellent, broad-spectrum herbicidal activity, even at levels as low as 37.5 g ai/ha, and it was determined to be safe for wheat at 150 g ai/ha in postemergent application, indicating the great potential for 17i development as a herbicide for weed control in wheat fields.


Assuntos
Benzoxazinas/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Herbicidas/química , Herbicidas/farmacologia , Proteínas de Plantas/antagonistas & inibidores , Protoporfirinogênio Oxidase/antagonistas & inibidores , Quinazolinas/química , Benzoxazinas/farmacologia , Desenho de Drogas , Cinética , Proteínas de Plantas/química , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/enzimologia , Protoporfirinogênio Oxidase/química , Relação Quantitativa Estrutura-Atividade , Quinazolinas/farmacologia , Tabaco/efeitos dos fármacos , Tabaco/enzimologia , Controle de Plantas Daninhas
4.
Eur J Med Chem ; 179: 109-122, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247373

RESUMO

Toll-like receptors (TLRs) are promising targets for treatment of viral infections, autoimmune diseases, and cancers. Here, two new series of selective small-molecule TLR7 agonists with novel scaffolds and good selectivity over TLR8 are described, some with potencies in the low micromolar range. 8-Hydroxy-1-isobutylchromeno[3,4-d]imidazol-4(1H)-one (26) from the first series was designed and synthesized on the basis of previously described TLR7 antagonist 2, and is shown to be a selective TLR7 agonist (EC50, 1.8 µM). The second series was based on 2-(trifluoromethyl)quinolin-4-amine and 2-(trifluoromethyl)quinazolin-4-amine scaffolds, which were defined according to our in-house ligand-based virtual screening protocol. Further synthesis of a focused library of analogs, biological evaluation, and docking studies provided systematic exploration of the structure-activity relationships, which indicate that a secondary or tertiary amine with smaller flexible alkyl substituents up to three carbon atoms in length, or bulkier rigid aliphatic rings is required at position 4 on 2-(trifluoromethyl)quinoline/quinazoline scaffold for potent TLR7 agonist activity. The influence of selected TLR7 agonists on cytokine production is also reported showing that N-cyclopropyl-2-(trifluoromethyl)quinazolin-4-amine (46) is able to induce increased levels of IL-6 and IL-8. These data demonstrate successful in-silico definition of novel TLR7 versus TLR8-selective compounds as promising chemical probes for further development of potent small-molecule immunomodulators.


Assuntos
Imidazóis/farmacologia , Quinazolinas/farmacologia , Quinolinas/farmacologia , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Citocinas/análise , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Receptor 7 Toll-Like/metabolismo
5.
Biol Pharm Bull ; 42(6): 873-876, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155586

RESUMO

To establish a synthetic route to d3-poziotinib hydrochloride. Treatment of 4-chloro-7-hydroxyquinazolin-6-yl pivalate (1) with d3-methyliodide afforded the etherization product, which reacted with 3,4-dichloro-2-fluoroaniline to generate the key intermediate d3-4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl pivalate (3). Followed the de-protection reaction, the nucleophilic substitution (SN2) reaction with tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (TSP), and the de-protection reaction of t-butoxycarbonyl (Boc) group, and the amide formation reaction with acrylyl chloride, d3-poziotinib was obtained, which was converted to hydrochloride salt by treatment with concentrated hydrochloric acid (HCl). Starting from a known compound 4-chloro-7-hydroxyquinazolin-6-yl pivalate (1), after 7 steps transformation, d3-poziotinib hydrochloride was obtained with a total yield of 9.02%. The structure of d3-poziotinib hydrochloride was confirmed by 1H-NMR, 13C-NMR, and high resolution (HR)-MS. Meanwhile, the in vitro microsomal stability experiment showed that d3-poziotinib had a longer half time (t1/2 = 4.6 h) than poziotinib (t1/2 = 3.5 h).


Assuntos
Antineoplásicos , Deutério , Quinazolinas , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Deutério/química , Deutério/farmacocinética , Desenho de Drogas , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Quinazolinas/química , Quinazolinas/farmacocinética , Ratos
6.
Phys Chem Chem Phys ; 21(25): 13826-13834, 2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31211310

RESUMO

Free energy perturbation (FEP) approaches with stratification have seen widespread and increasing use in computational studies of biologically relevant molecules. However, when the molecular systems are characterized by a complex conformational free energy landscape, the assessment of convergence remains a concern for many practitioners. The sampling problem in FEP has been authoritatively addressed in a recent perspective paper [D. Mobley, J. Comput.-Aided Mol. Des., 2012, 26, 93], incisively entitled "Let's get honest about sampling". Here, I return to the issue of sampling in the determination of the octanol-water partition coefficient for a synthetic precursor of kinase inhibitors that has been included in the recent extension of the SAMPL6 blind challenge of log P coefficients. I will show that even for this simple compound, whose conformational space is essentially dictated by two sp3 rotable bonds connecting rigid planar units, canonical sampling using standard techniques can be surprisingly hard to achieve. I will also show how the conformational sampling problem can be effectively bypassed using unidirectional and bidirectional nonequilibrium work methods, reliably recovering the solvation energy with minimal methodological uncertainty.


Assuntos
Modelos Moleculares , Inibidores de Proteínas Quinases/química , Quinazolinas/química , Solventes/química , Conformação Molecular , Octanóis/química , Termodinâmica , Incerteza , Água/química
7.
Eur J Med Chem ; 178: 417-432, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202990

RESUMO

In novel synthetic 28 4-arylamino-6-fluoro quinazoline derivatives, compound 3a displayed the most remarkable inhibitory activities against tumor cells (IC50 values ranging between 0.71 and 2.30 µM) in vitro. Importantly, 3a obviously inhibited the proliferation and metastasis of A549 cells in a zebrafish xenograft model, while also mediated cell apoptosis and G0/G1-phase cell cycle arrest in A549 cells. Interestingly, 3a had excellent fluorescence at 439 nm (λex = 375 nm) in DMSO and at 428 nm (λex = 372 nm) in 0.5% DMSO-phosphate buffer, and the self-fluorescent characteristic revealed 3a itself accumulates in the mitochondria of A549 cells, which suggested the antitumor process of 3a may involve the mitochondrial apoptotic pathway. The hypothesis was verified by the increase of the intracellular reactive oxygen species, the decrease of mitochondrial membrane potential, the release of cytochrome C from the mitochondria into the cytoplasm, and the cascade activation of caspase-9 and caspase-3 when A549 cells were treated with 3a. This work has great implications for further development of anticancer agents that can be enriched in mitochondria and can be tracked in real-time in biological systems due to the ideal fluorescence.


Assuntos
Antineoplásicos/farmacologia , Fluorescência , Mitocôndrias/efeitos dos fármacos , Quinazolinas/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Peixe-Zebra
8.
J Chromatogr A ; 1602: 474-480, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31202495

RESUMO

Evodiae Fructus is used as a traditional Chinese medicine for the treatment of several kinds of diseases with its bioactive constituents. In this study, a capillary electrochromatography-mass spectrometry (CEC-MS) method was developed to determine three bioactive compounds including evodiamine, rutaecarpine and limonin in Evodiae Fructus fruit. Home-developed monolithic columns with methyl-vinylimidazole functionalized organic polymer monolilth as stationary phases were used in CEC-MS with excellent separation selectivity and high efficiency. The CEC-MS methods provided 4-16 folds improvement of LODs when compared with CEC-UV method. The conditions, which could affect separation efficiency and detection sensitivity, were optimized. Under optimum conditions, baseline separation with high detection sensitivity was obtained. The method showed good linearity (R2 >0.99) of 0.8-160 µg mL-1 with low limits of detection of 0.15-0.31 µg mL-1. Relative standard deviations of migration time and relative peak areas were <13.89%. Recoveries of evodiamine, rutaecarpine and limonin in Evodiae Fructus fruit were tested and calculated, which ranged from 102% to 113%. Finally, the three bioactive compounds in Evodiae Fructus herb samples from different regions were analyzed and studied. It has been demonstrated that the developed method has great potential for quality control of Evodiae Fructus herb.


Assuntos
Eletrocromatografia Capilar/métodos , Evodia/química , Imidazóis/química , Espectrometria de Massas/métodos , Polímeros/química , Acetonitrilos/química , Amônia/química , Calibragem , Medicamentos de Ervas Chinesas/química , Eletrólitos/química , Frutas/química , Concentração de Íons de Hidrogênio , Alcaloides Indólicos/química , Limite de Detecção , Limoninas/química , Quinazolinas/química , Padrões de Referência , Reprodutibilidade dos Testes
9.
Eur J Med Chem ; 175: 349-356, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096155

RESUMO

Twelve 2,3-dihydro-[1,4]-dioxino[2,3-f]quinazoline derivatives were designed and evaluated as vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors. The most half-maximal inhibitory concentration (IC50) values of them were less than 10 nM. Among these compounds, 13d displayed highly effective inhibitory activity against VEGFR-2 (IC50 = 2.4 nM) and excellent antiproliferative activities against human umbilical vein endothelial cells (HUVECs) (IC50 = 1.2 nM). When anti-tumor animal experiments were carried out in mice, the tumor almost disappeared (TGI = 133.0%) after six days of administration of 13d. Therefore, 13d was a potential and effective anticancer agent. The binding conformations were respectively compared between VEGFR-2 with 13d and leading compound lenvatinib, and shows that they have similar binding modes.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Quinazolinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/química , Animais , Antineoplásicos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Quinazolinas/química , Quinolinas/química , Quinolinas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Ureia/química , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Eur J Med Chem ; 172: 36-47, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30939352

RESUMO

A series of novel 2,4-disubstituted quinazolines were synthesized and evaluated for their anti-tumor activity against five human cancer cells (MDA-MB-231, MCF-7, PC-3, HGC-27 and MGC-803) using MTT assay. Among them, compound 9n showed the most potent cytotoxicity against breast cancer cells. Compound 9n also significantly inhibited the colony formation and migration of MDA-MB-231 and MCF-7 cells. Meanwhile, compound 9n induced cell cycle arrest at G1 phase and cell apoptosis, as well as increased accumulation of intracellular ROS. Furthermore, compound 9n exerted anti-tumor effects in vitro via decreasing the expression of anti-apoptotic protein Bcl-2 and increasing the pro-apoptotic protein Bax and p53. Mechanistically, compound 9n markedly decreased p-EGFR and p-PI3K expression, which revealed that compound 9n targeted breast cancer cells via interfering with EGFR-PI3K signaling pathway. Molecular docking suggested that compound 9n could indeed bind into the active pocket of EGFR. All the findings suggest that compound 9n might be a valuable lead compound for anti-tumor agents targeting breast cancer cells.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/deficiência , Receptores ErbB/metabolismo , Feminino , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosfatidilinositol 3-Quinases/deficiência , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
11.
Eur J Pharm Sci ; 133: 145-159, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30946965

RESUMO

Non-small cell lung cancer is a major sub-type of lung cancer that is associated with a poor diagnosis resulting in poor therapy for the disorder. In order to achieve a better prognosis, innovative multi-functional systems need to be developed which will aide in diagnosis as well as therapy for the disorder. One such multi-functional delivery system fabricated is Quantum Dots (QDs). QDs are photo-luminescent inorganic nanoparticles utilized for tumor detection, preclinically. Erlotinib hydrochloride, a tyrosine kinase inhibitor, is a first-generation drug developed to treat NSCLC. Its active metabolite, Desmethyl Erlotinib (OSI-420), exhibits similar anticancer activity as erlotinib. OSI-420 was conjugated to QDs to fabricate a delivery system and was then characterized by FT-IR, H NMR, UV-VIS, particle size, zeta potential, fluorescence spectroscopy and TEM. Drug loading was estimated using UV-VIS spectroscopy (52.2 ±â€¯7.5%). A concentration-dependent release of OSI-420 was achieved using esterase enzymes, which was further confirmed using LC-MS. A cellular uptake study revealed the internalization potential of QDs and QD-OSI 420. A cellular recovery study was performed to confirm the internalization potential. Cell viability studies revealed that QD-OSI 420 conjugates had significantly better efficacy than pure drugs in all tested cell lines. QD conjugated OSI-420 demonstrated an IC60 of 2.5 µM in erlotinib-resistant A549 cell lines, where erlotinib or OSI-420 alone could not exhibit 60% inhibition when evaluated up to 20 µM. Similar cytotoxic enhancement of erlotinib was seen with QD-OSI 420 in other NSCLC cell lines as well. These results were strengthened by 3D-SCC model of A549 which revealed that QD-OSI 420 was significantly better in reducing in-vitro 3D tumor volume, as compared to pure drugs. This study, being one of its kind, explores the feasibility of conjugating OSI-420 with QDs as an alternative to traditional anti-cancer therapy, by improving intracellular drug delivery.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pontos Quânticos/administração & dosagem , Quinazolinas/administração & dosagem , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Esterases/química , Humanos , Lisossomos/metabolismo , Inibidores de Proteínas Quinases/química , Pontos Quânticos/química , Quinazolinas/química
12.
Molecules ; 24(8)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010230

RESUMO

Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR competent tumors to cytotoxic chemotherapies or radiotherapy, normal cell toxicity has remained an obstacle to their use in this context. Hypoxia-activated prodrugs (HAPs) provide a means to limit exposure of normal cells to active drug, thus adding a layer of tumor selectivity. We have investigated potential HAPs of model PARPi in which we attach a bioreducible "trigger" to the amide nitrogen, thereby blocking key binding interactions. A representative example showed promise in abrogating PARPi enzymatic activity in a biochemical assay, with a ca. 160-fold higher potency of benzyl phthalazinone 4 than the corresponding model HAP 5, but these N-alkylated compounds did not release the PARPi upon one-electron reduction by radiolysis. Therefore, we extended our investigation to include NU1025, a PARPi that contains a phenol distal to the core binding motif. The resulting 2-nitroimidazolyl ether provided modest abrogation of PARPi activity with a ca. seven-fold decrease in potency, but released the PARPi efficiently upon reduction. This investigation of potential prodrug approaches for PARPi has identified a useful prodrug strategy for future exploration.


Assuntos
Inibidores de Poli(ADP-Ribose) Polimerases/química , Antineoplásicos/química , Cromatografia Líquida , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Pró-Fármacos/química , Quinazolinas/química
13.
Exp Oncol ; 41(1): 3-6, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30932417

RESUMO

Quinazolines are among the most useful heterocyclic compounds due to their diverse chemical reactivity and a wide range of biological activity. Despite a large number of publications devoted to quinazolines and their derivatives, information is presented predominantly regarding the features of the synthesis of these compounds and their structure. The studies of specific pharmacological activity and antitumor activity of these compounds are mainly limited to primary screening using enzyme systems and cell lines. In this mini review information concerning the potential targets for antitumor action of quinazoline compounds is summarized and discussed.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias/metabolismo , Quinazolinas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Estudos Clínicos como Assunto , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/química , Quinazolinas/uso terapêutico , Resultado do Tratamento
14.
Eur J Med Chem ; 170: 55-72, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878832

RESUMO

The 4-aminoquinazoline core is an interesting pharmacophore and its applications in medicinal chemistry are wide spread. The core has been used for making many kinase inhibitors in past few years. Many researcher demonstrated 4-aminoquinazoline derivatives as specific kinase inhibitors, including tyrosine kinase and serine/theronine kinases. A number of anticancer drugs with 4-aminoquinazoline core are in the market, e.g. gefitinib, erlotinib, afatinib, lapatinib, decomitinib etc. 4-aminoquinazoline derivatives are applied for target specific treatment of lung, breast, colon, prostate cancers. In this review, we discussed the current development of 4-aminoquinazoline derivatives as kinase inhibitors and their uses as anticancer agents in recent years.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/química , Quinazolinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Técnicas de Química Sintética/métodos , Humanos , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/síntese química , Quinazolinas/farmacologia
15.
Nanoscale ; 11(11): 5005-5013, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30839969

RESUMO

It is acknowledged that the targeting ability of multivalent ligand-modified nanoparticles (MLNs) strongly depends on the ligand spatial presentation determined by ligand valency. However, the receptor overexpression level varies between different types or stages of tumors. Thus, it is essential to explore the influence of ligand valency on the targeting ability of MLNs to tumors with different levels of receptor overexpression. In this study, a dual-acting agent raltitrexed was used as a ligand to target the folate receptor (FR). Different copies of the raltitrexed-modified multivalent dendritic polyethyleneimine ligand cluster PRn (n = 2, 4, and 8) were conjugated onto magnetic nanoparticles to form multivalent magnetic NPs (MMNs) with different valences. The in vitro studies demonstrated that Fe-PR4 was the most effective valency in the treatment of high FR overexpressing KB cells with a decentralized receptor distribution, owing to the fact that Fe-PR2 was negative in statistical rebinding and Fe-PR8 could induce steric hindrance in the limited binding area. Instead, in moderate FR overexpressing HeLa cells with clustered receptor display, the extra ligands on Fe-PR8 would facilitate statistical rebinding more beneficially. Furthermore, in in vivo tumor inhibition and targeted magnetic resonance imaging (MRI) of KB tumors and another moderate FR expressing H22 tumor, similar results were obtained with the cell experiments. Overall, the optimizable treatment effect of Fe-PRn by modulating the ligand valency based on the overexpressing tumor receptor distribution behavior supports the potential of Fe-PRn as a nanomedicine for personalized theranostics.


Assuntos
Meios de Contraste/química , Portadores de Fármacos/química , Receptores de Folato com Âncoras de GPI/metabolismo , Nanopartículas de Magnetita/química , Nanomedicina Teranóstica/métodos , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Endocitose , Receptores de Folato com Âncoras de GPI/genética , Expressão Gênica , Humanos , Imagem por Ressonância Magnética , Camundongos , Neoplasias/tratamento farmacológico , Polietilenoimina/química , Quinazolinas/administração & dosagem , Quinazolinas/química , Quinazolinas/farmacocinética , Tiofenos/administração & dosagem , Tiofenos/química , Tiofenos/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Curr Top Med Chem ; 19(8): 609-619, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30834838

RESUMO

BACKGROUND: High numbers of infection with resistant forms of Micobacterium tuberculosis (Mtb) contribute to a constant growing demand in new highly active and effective therapeutics. Current drug discovery efforts directed towards new antituberculosis agents include the development of new inhibitors of enoyl-acyl carrier protein reductase (InhA) that do not require activation by the specific enzymes. Tryptanthrin is a known inhibitor of Mtb InhA and its analogues are investigated as potential agents with antimycobacterial efficiency. OBJECTIVE: The main objective of the presented research was to develop a new group of tryptanthrin analogues with good inhibition properties against Mtb. METHODS: Synthesis of new derivatives of 5H-[1,3,4]thiadiazolo[2,3- b]quinazolin-5-one and evaluation of their activity against Mtb, as well as acute and chronic toxicity studies were carried out. Molecular modeling studies were performed to investigate the binding mechanisms of the synthesized ligands with InhA. Binding energies and non-covalent interactions stabilizing the ligand-receptor complexes were obtained from the results of molecular docking. RESULTS: The most active compound in the obtained series, 2-(propylthio)-5H-[1,3,4]thiadiazolo[2,3- b]quinazolin-5-one, exhibited the superior inhibition activity (up to 100%) against mycobacterial growth at MIC 6.5 µg/mL, showed good affinity to the InhA enzyme in docking studies and demonstrated a very low per oral toxicity in animals falling under the category 5 according to GHS classification. CONCLUSION: 2-(propylthio)-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-one can be further explored for the development of a new series of compounds active against Mtb.


Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Proteínas de Bactérias/química , Sítios de Ligação , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Simulação de Acoplamento Molecular , Quinazolinas/química , Relação Estrutura-Atividade , Testes de Toxicidade
17.
J Enzyme Inhib Med Chem ; 34(1): 203-217, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30835140

RESUMO

A series of quinazoline derivatives with benzylidene hydrazine carboxamide were designed and synthesised as EGFR inhibitors. Most compounds exhibited exceptional anti-proliferative activity against A549, HepG2, MCF-7 and H1975 cells. Furthermore, six compounds demonstrated excellent inhibition activity against EGFRWT with the IC50 value both less than 2 nM. Among the six compounds, 44 exhibited the strongest activity (0.4 nM) and potently inhibited EGFRL858R/T790M (0.1 µM). Excitingly, the most potent compound 14 showed excellent enzyme inhibitory activity with 6.3 nM and 8.4 nM for both EGFRWT and EGFRT790M/L858R. The result of AO single staining and Annexin V/PI staining showed that the compound 14 and 44 could induce remarkable apoptosis of A549 cells. The compound 14 arrested the cell cycle at the S phase and compound 44 arrested the cell cycle at the G0 phase in A549 cells. These preliminary results demonstrate that compound 14 and 44 may be promising lead compound-targeting EGFR.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desenho de Drogas , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Gefitinibe/química , Gefitinibe/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
18.
Int J Mol Sci ; 20(6)2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901916

RESUMO

We previously published a series of 8-methoxypirazolo[1,5-a]quinazolines (PQs) and their 4,5-dihydro derivatives (4,5(H)PQ) bearing the (hetero)arylalkylester group at position 3 as ligands at the γ-aminobutyric type A (GABAA) subtype receptor. Continuing the study in this field, we report here the design and synthesis of 3-(hetero)arylpyrazolo[1,5-a]quinazoline and 3-(hetero)aroylpyrazolo[1,5-a]quinazoline 8-methoxy substituted as interesting analogs of the above (hetero)arylalkylester, in which the shortening or the removal of the linker between the 3-(hetero)aryl ring and the PQ was performed. Only compounds that are able to inhibit radioligand binding by more than 80% at 10 µM have been selected for electrophysiological studies on recombinant α1ß2γ2L GABAA receptors. Some compounds show a promising profile. For example, compounds 6a and 6b are able to modulate the GABAAR in an opposite manner, since 6b enhances and 6a reduces the variation of the chlorine current, suggesting that they act as a partial agonist and an inverse partial agonist, respectively. The most potent derivative was 3-(4-methoxyphenylcarbonyl)-8-methoxy-4,5-dihydropyrazolo[1,5-a] quinazoline 11d, which reaches a maximal activity at 1 µM (+54%), and it enhances the chlorine current at ≥0.01 µM. Finally, compound 6g, acting as a null modulator at α1ß2γ2L, shows the ability to antagonize the full agonist diazepam and the potentiation of CGS 9895 on the new α+/ß- 'non-traditional' benzodiazepine site.


Assuntos
Agonistas de Receptores de GABA-A/síntese química , Antagonistas de Receptores de GABA-A/síntese química , Pirazóis/química , Quinazolinas/química , Receptores de GABA-A/química , Animais , Sítios de Ligação , Células Cultivadas , Técnicas de Química Sintética , Agonistas de Receptores de GABA-A/química , Agonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-A/química , Antagonistas de Receptores de GABA-A/farmacologia , Ligantes , Estrutura Molecular , Ligação Proteica , Pirazóis/farmacologia , Quinazolinas/farmacologia
19.
Appl Microbiol Biotechnol ; 103(9): 3773-3781, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30863875

RESUMO

In nature, cyclic dipeptide prenyltransferases catalyze regioselective Friedel-Crafts alkylations of tryptophan-containing cyclic dipeptides. This enzyme class, belonging to the dimethylallyl tryptophan synthase superfamily, is known to be flexible toward aromatic prenyl acceptors, while mostly retaining its typical regioselectivity. Ardeemin fumiquinazoline (FQ) (1), a tryptophan-containing cyclic tripeptide derivative, is assembled in Aspergillus fischeri by the non-ribosomal peptide synthetase ArdA and modified by the prenyltransferase ArdB, leading to the pharmaceutically active hexacyclic ardeemin. Therefore, 1 and its enantiomer ent-ardeemin FQ (2) constitute potential substrates for aromatic prenyltransferases. In this study, we investigated the acceptance of both enantiomers by two cyclic dipeptide C2-prenyltransferases BrePT and FtmPT1 and three C3-prenyltransferases CdpNPT, CdpC3PT, and AnaPT. LC-MS analysis of the incubation mixtures and NMR analysis of the isolated products revealed that the stereochemistry at C11 and C14 in 1 and 2 has a strong influence on their acceptance by these enzymes and the regioselectivity of the prenylation reactions. 1 was very well accepted by BrePT, FtmPT1, and CdpNPT, with C2- or C3-prenylated derivatives as predominant products, which fills the prenylation gaps by tryptophan prenyltransferases reported in a previous study. 2 was a poor substrate for all the enzymes and converted with low regioselectivity and mainly prenylated at C6 and C7 of the indole moiety.


Assuntos
Aspergillus/enzimologia , Dimetilaliltranstransferase/química , Proteínas Fúngicas/química , Alcaloides Indólicos/metabolismo , Quinazolinas/metabolismo , Aspergillus/genética , Aspergillus/metabolismo , Dimetilaliltranstransferase/metabolismo , Dipeptídeos/metabolismo , Proteínas Fúngicas/metabolismo , Alcaloides Indólicos/química , Espectroscopia de Ressonância Magnética , Prenilação , Quinazolinas/química , Estereoisomerismo , Especificidade por Substrato
20.
Eur J Med Chem ; 168: 146-153, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30818175

RESUMO

CGRP, known as the most potent vasodilator substance, plays an important role in hypertension initiation and development. TRPV1 and TRPA1 are critical in promoting the synthesis and release of CGRP, thereby regulating the cardiovascular tone. Rutaecarpine exhibits potent vasodilator and hypertensive effects by stimulating CGRP synthesis and release via activation of TRPV1. And NO has been shown to react with H2S in vivo to form HNO, thereby activating HNO-TRPA1-CGRP pathway. Inspired by combination therapy, 11 rutaecarpine-furoxan hybrids were designed, synthesized and evaluated. The results demonstrated that most hybrids exerted comparable or improved vasodilator activities. Among which, 13a is the most potent both ex vivo (EC50 = 13.1 nM) and in vivo. Mechanistic studies revealed that the vasodilator and anti-hypertensive effects of the hybrids might involve the promotion of CGRP release via dual activation of TRPV1 and TRPA1. This work suggests that dual-targeted hybrids might be an effective and promising approach to discover and develop novel anti-hypertensive drugs.


Assuntos
Anti-Hipertensivos/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Hipertensão/tratamento farmacológico , Alcaloides Indólicos/farmacologia , Oxidiazóis/farmacologia , Quinazolinas/farmacologia , Vasodilatadores/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Pressão Sanguínea/efeitos dos fármacos , Determinação da Pressão Arterial , Relação Dose-Resposta a Droga , Desenho de Drogas , Alcaloides Indólicos/química , Masculino , Estrutura Molecular , Oxidiazóis/química , Quinazolinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Vasodilatadores/síntese química , Vasodilatadores/química
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