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1.
J Agric Food Chem ; 67(37): 10498-10504, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31452369

RESUMO

Owing to the changing needs of agriculture, the exploration of new pest control agents remains as critical as ever. The analogues 3a-3v of the natural product cerbinal were synthesized from genipin by an efficient and practical method under additive-free conditions. The antiviral and insecticidal effects of cerbinal and these cyclopenta[c]pyridines (3a-3v) were evaluated systematically. Most of the synthesized compounds exhibited higher anti-TMV activities than the lead compound cerbinal. Compound 3s (2-(4-methoxyphenyl)) had the most promising inhibitory activities against TMV (inactivation effect 49.0 ± 0.8%, curative effect 41.2 ± 4.3%, and protection effect 51.5 ± 2.7% at 500 µg/mL). Among the synthesized compounds, only 3v (2-(2-chloro-4-(trifluoromethoxy)phenyl)) reached the activity level of cerbinal against Plutella xylostella. This suggested that the cyclopenta[c]pyridines obtained by modifications of cerbinal at position 2 are very significant for the anti-TMV activity, and yet were exceptionally less active for the insecticidal activities.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Indenos/química , Indenos/farmacologia , Inseticidas/química , Inseticidas/farmacologia , Animais , Antivirais/química , Produtos Biológicos/química , Descoberta de Drogas , Indenos/síntese química , Inseticidas/síntese química , Iridoides/química , Estrutura Molecular , Mariposas/efeitos dos fármacos , Mariposas/crescimento & desenvolvimento , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Vírus do Mosaico do Tabaco/crescimento & desenvolvimento
2.
Eur J Med Chem ; 178: 141-153, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31177074

RESUMO

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for development of various tumor types. In this study, we synthesized a series of novel 2,4-diarylaminopyrimidine derivatives possessing a unique N-(3-pyridinylmethyl)urea moiety as ALK inhibitors. The most promising analog 5m bearing a 3-methoxy-4-morpholinophenyl substituent significantly inhibited proliferation of ALK positive H3122 and Karpas-299 cells with IC50 values about 10 nM, which were comparable with positive control LDK378. Compound 5m suppressed phosphorylation of ALK and its downstream proteins, and showed low cytotoxicity on normal human primary fibroblast cells (BJ cells). The binding mode of 5m was proposed by docking simulation, which explains the important role of N-(3-pyridinylmethyl)urea moiety. Furthermore, compound 5m exhibited favorable liver microsomal stability and significant efficacy in H3122 xenograft mice model. Interestingly, compound 5m also showed broader anti-proliferative activity on other human tumor cell lines, which was different from other ALK inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Quinase do Linfoma Anaplásico/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estabilidade de Medicamentos , Feminino , Fibroblastos/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/toxicidade , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/toxicidade , Piridinas/síntese química , Piridinas/farmacologia , Piridinas/toxicidade , Pirimidinas/síntese química , Pirimidinas/farmacologia , Pirimidinas/toxicidade , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Eur J Med Chem ; 178: 168-176, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31181481

RESUMO

The androgen receptor (AR) is a steroid hormone receptor and its high expression and disruption of its regulation are strongly implicated in prostate cancer (PCa) development. One of the current therapies includes application of steroidal antiandrogens leading to blockade of the AR action by the abrogation of AR-mediated signaling. We introduced here novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused steroidal compounds, described their synthesis based on [8π+2π] cycloaddition reactions of diazafulvenium methides with different steroidal scaffolds and showed their biological evaluation in different prostate cancer cell lines in vitro. Our results showed the ability of novel compounds to suppress the expression of known androgen receptor targets, Nkx3.1 and PSA in two prostate cell lines, 22Rv1 and VCaP. Candidate compound diminished the transcription of AR-regulated genes in the reporter cell line in a concentration-dependent manner. Antiproliferative activity of the most promising steroid was studied by clonogenic assay and induction of apoptosis in treated cells was documented by immunoblot detection of cleaved PARP.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Pirazóis/farmacologia , Piridinas/farmacologia , Esteroides/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Simulação de Acoplamento Molecular , Pirazóis/síntese química , Pirazóis/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , Receptores Androgênicos/metabolismo , Esteroides/síntese química , Esteroides/metabolismo , Fatores de Transcrição/metabolismo
4.
Eur J Med Chem ; 177: 316-337, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158747

RESUMO

Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki = 0.004 and 0.007 µM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggests that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells.


Assuntos
Inibidores Enzimáticos/farmacologia , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Piridinas/farmacologia , Pirimidinonas/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Histona Desmetilases com o Domínio Jumonji/química , Histona Desmetilases com o Domínio Jumonji/metabolismo , Estrutura Molecular , Ligação Proteica , Piridinas/síntese química , Piridinas/química , Piridinas/metabolismo , Pirimidinonas/síntese química , Pirimidinonas/química , Pirimidinonas/metabolismo , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 178: 177-194, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185410

RESUMO

Microtubule is one of the important targets for cancer treatment. A novel class of diaryl substituted imidazo[4,5-c]pyridin-2-ones and imidazo[4,5-c]pyridines were designed based on combination principles by merging the structures of ß-lactams and purine-type compounds known as tubulin polymerization inhibitor and katanin activity up-regulator, respectively. Their antitumor activities were evaluated in vitro and the mechanism was elucidated, leading to the identification of 1,6-diaryl-1H-imidazo[4,5-c]pyridin-2(3H)-one 20b as the first bifunctional agent that can target both tubulin and katanin simultaneously. The in vivo assays verified that compound 20b significantly inhibited xenograft tumor growth with good pharmacokinetic characteristics, demonstrating a promising potential for further development into anti-tumor drug candidates with a unique mechanism of dual-targeting microtubule.


Assuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Katanina/antagonistas & inibidores , Piridinas/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Carcinoma Endometrioide/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacocinética , Katanina/metabolismo , Ligantes , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Estrutura Molecular , Neoplasias Ovarianas/tratamento farmacológico , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Molecules ; 24(9)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075948

RESUMO

The preparation of 24-functionalized 12,22:26,32-terpyridines (4'-functionalized 3,2:6',3''-terpyridines) by the reaction of three 4-alkoxybenzaldehydes with 3-acetylpyridine and ammonia was investigated; under identical reaction conditions, two (R = nC4H9, C2H5) gave the expected products whereas a third (R = nC3H7) gave only a cyclohexanol derivative derived from the condensation of three molecules of 3-acetylpyridine with two of 4-(n-propoxy)benzaldehyde. A comprehensive survey of ''unexpected'' products from reactions of ArCOCH3 derivatives with aromatic aldehydes is presented. Three different types of alternative product are identified.


Assuntos
Química Orgânica/métodos , Piridinas/síntese química , Ciclização , Isomerismo , Ligantes , Espectroscopia de Prótons por Ressonância Magnética , Piridinas/química
7.
Eur J Med Chem ; 176: 410-418, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31125895

RESUMO

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), has a high diagnostic potential in neurodegenerative disorders and cancer. However, TSPO is considered a challenge for molecular imaging due to the poor availability of suitable radiotracers with adequate pharmacokinetic properties. Here, we describe the development of a radiofluorinated pyridinyl isoquinoline analogue of the established TSPO PET tracer (R)-[11C]PK11195 with improved binding properties in all known human TSPO phenotypes. We conducted a complete preclinical evaluation using in vitro, in vivo and ex vivo methods to assess the performance of this novel radiotracer and observed high specific binding of the radiotracer to TSPO, as well as high metabolic stability. Therefore, we propose this radiolabeled compound for further evaluation in animal models as well as in clinical trials.


Assuntos
Isoquinolinas/metabolismo , Piridinas/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Receptores de GABA/metabolismo , Animais , Feminino , Radioisótopos de Flúor/química , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Isoquinolinas/farmacocinética , Marcação por Isótopo , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
8.
Eur J Med Chem ; 175: 2-19, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31055149

RESUMO

2-(piperazin-1-yl)N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides are described as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and amyloid ß aggregation inhibitors. Formation of synthesized compounds (P1P9) was justified via H1 NMR, C13 NMR, mass spectra and single crystal X-Ray diffraction study. All compounds were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activity, inhibition of self-mediated Aß aggregation and Cu(II)-mediated Aß aggregation. Also, docking study carried out was in concordance with in vitro results. The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity (IC50 = 4.8 nM). Kinetic study of P3 suggested it to be a mixed type inhibitor. In vitro study revealed that all the compounds are capable of inhibiting self-induced ß-amyloid (Aß) aggregation with the highest inhibition percentage to be 81.65%. Potency of P1 and P3 to inhibit self-induced Aß1-42 aggregation was ascertained by TEM analysis. Compounds were also evaluated for their Aß disaggregation, antioxidation, metal-chelation activity.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Pirazóis/química , Pirazóis/uso terapêutico , Piridinas/química , Piridinas/uso terapêutico , Acetilcolinesterase/efeitos dos fármacos , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/ultraestrutura , Antioxidantes/farmacologia , Hidrolases de Éster Carboxílico/efeitos dos fármacos , Quelantes/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Cobre/química , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Microscopia Eletrônica de Transmissão , Simulação de Acoplamento Molecular , Pirazóis/síntese química , Piridinas/síntese química , Espectrometria de Fluorescência
9.
Chem Biodivers ; 16(6): e1900097, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942951

RESUMO

New N-substituted-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivatives were synthesized employing a convenient one-pot three-component method and their structures were characterized by 1 H-NMR and single crystal X-ray diffraction analysis. All the synthesized compounds were in vitro screened for antimicrobial activity against Gram-positive (Sarcina lutea) and Gram-negative bacteria (Escherichia coli). In this work, we introduced a chiral residue on the tetrahydropyridine nitrogen, the hitherto the less investigated position on this pharmacophore in order to explore the effect. The antibacterial results showed that the synthesized compounds were active only against Gram-positive bacteria and the (R)-enantiomers displayed a greater antimicrobial potency than their (S)-counterparts. The structure-activity relationship here investigated may provide some interesting clues for future development of tetrahydrothienopyridine derivatives with higher antimicrobial activity.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Cristalografia por Raios X , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
10.
Eur J Med Chem ; 173: 1-14, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981112

RESUMO

Further optimization of the trimethoxyphenyl scaffold of parent chalcone compound (2a) by introducing a pyridine ring afforded a series of novel pyridine-chalcone derivatives as potential anti-tubulin agents. All the target compounds were evaluated for their antiproliferative activities. Among them, representative compound 16f exhibited the most potent activity with the IC50 values ranging from 0.023 to 0.045 µM against a panel of cancer cell lines. Further mechanism study results demonstrated that compound 16f effectively inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Moreover, cellular mechanism studies disclosed that 16f caused G2/M phase arrest, induced cell apoptosis and disrupted the intracellular microtubule network. Also, 16f reduced the cell migration and disrupted the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, 16f significantly inhibited tumor growth in H22 xenograft models without apparent toxicity, which was stronger than the reference compound CA-4, indicating that it is worthy to investigate 16f as a potent microtubule-destabilizing agent for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Chalcona/farmacologia , Desenho de Drogas , Microtúbulos/efeitos dos fármacos , Piridinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microtúbulos/metabolismo , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacos
11.
Eur J Med Chem ; 173: 107-116, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30995566

RESUMO

A series of new pyrazolo[3,4-b]pyridin-3-yl pyrimidine derivatives were synthesized and evaluated for the activation of sGC. Compared with riociguat, compound 13a exhibited equivalent in vitro activity on preconstricted rat thoracic aorta rings and in Rat heart Langendorff preparation. Compound 13a also showed acceptable PK profiles, which might become a promising candidate for the treatment of pulmonary hypertension.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Pirazóis/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Guanilil Ciclase Solúvel/metabolismo , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Relação Dose-Resposta a Droga , Hipertensão Pulmonar/metabolismo , Masculino , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
12.
Arch Pharm (Weinheim) ; 352(5): e1800338, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30888688

RESUMO

A series of novel 4-phenoxypyridine derivatives containing the 4-oxo-1,4-dihydropyridazine-3-carboxamide moiety were synthesized and evaluated for their in vitro cytotoxic activity against the A549 cancer cell line, and some compounds were further examined for their cytotoxic activity against the H460, BGC823, MKN45, and HT-29 cancer cell lines. Most of the compounds exhibited moderate to significant cytotoxicity. The most promising compound 15b (with VEGFR2 inhibitory concentration [IC50 ] value of 0.23 µM) showed remarkable cytotoxicity against A549, BGC-823, MKN45, H460, and HT-29 cells, with IC50 values of 0.75, 1.68, 2.63, 5.08 and 7.22 µM, respectively. Their preliminary structure-activity relationship studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity. Moreover, treatment of A549 cells with compound 15b resulted in cell cycle arrest in the G0 /G1 phase in a dose-dependent manner. Further apoptotic studies and acridine orange/ethidium bromide staining were also performed on A549 cells, which showed that compound 15b could induce apoptosis. Wound-healing assay results indicated that compound 15b strongly inhibited A549 cell motility.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Piridinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , 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 , Humanos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade
13.
Analyst ; 144(9): 3094-3102, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30920566

RESUMO

Two new pyridine-type rhodamine B chemosensors (RBPO and RBPF) used to detect Fe3+ have been designed and synthesized, and the sensing behavior towards various metal ions was evaluated via UV-vis and fluorescence spectroscopic techniques. Both RBPO and RBPF not only have good spectral responses to Fe3+ in an EtOH/H2O solution (3 : 1, v/v, HEPES, 0.5 mM, pH = 7.33) with low detection limits and high binding constants, but also suffer from less interference from common metal cations. The two chemosensors are further proven to be practical in sensitively monitoring trace Fe3+ in real water specimens. Intracellular imaging applications demonstrated that RBPO and RBPF can be used as two fluorescent chemosensors for the detection of Fe3+ in living human breast adenocarcinoma (MCF-7) cells.


Assuntos
Corantes Fluorescentes/química , Ferro/análise , Piridinas/química , Rodaminas/química , Água Potável/análise , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Água Doce/análise , Humanos , Concentração de Íons de Hidrogênio , Limite de Detecção , Células MCF-7 , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Piridinas/síntese química , Piridinas/toxicidade , Rodaminas/síntese química , Rodaminas/toxicidade , Espectrometria de Fluorescência/métodos
14.
Comput Biol Chem ; 80: 54-65, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30901601

RESUMO

Development of novel, safe and effective drug candidates combating the emerging drug resistance has remained a major focus in the mainstream of anti-tuberculosis research. Here, we inspired to design and synthesize series of new pyridin-4-yl-1,3,4-oxadiazol-2-yl-thio-ethylidene-hydrazinecarbothioamide derivatives as potential anti-tubercular agents. The anti-tubercular bioactive assay demonstrated that the synthesized compounds exhibit potent anti-tubercular activity (MIC = 3.9-7.81 µg/mL) in comparison with reference drugs Rifampicin and Isoniazid.We employed pharmacophore probing approach for the identification of CYP51 as a possible drug target for the synthesized compounds. To understand the preferable binding mode, the synthesized molecules were docked onto the active site of Sterol 14 α-demethylases (CYP51) target. From the binding free energy of the docking results it was revealed that the compounds were effective CYP51 inhibitors and acts as antitubercular agent.


Assuntos
Antituberculosos/farmacologia , Oxidiazóis/farmacologia , Piridinas/farmacologia , Tiossemicarbazonas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/metabolismo , Domínio Catalítico , Família 51 do Citocromo P450/química , Família 51 do Citocromo P450/metabolismo , Desenho de Drogas , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/metabolismo , Depuradores de Radicais Livres/farmacologia , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/metabolismo , Ligação Proteica , Piridinas/síntese química , Piridinas/química , Piridinas/metabolismo , Rifampina/farmacologia , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Tiossemicarbazonas/metabolismo
15.
Eur J Med Chem ; 168: 330-339, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30826509

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder with no radical therapy. Aggregation of amyloid ß-peptide (Aß) induced by various factors is associated with pathogenesis of AD. A pyridine amine derivative, 3-bis(pyridin-2-ylmethyl)aminomethyl-5-hydroxybenzyltriphenylphosphonium bromide (PAT), is synthesized. The inhibition of self- and metal-induced Aß aggregation by PAT is confirmed by thioflavine T fluorescence, circular dichroism spectroscopy, and TEM. Western blot, RT-PCR and fluorescence imaging indicate that PAT can alleviate the Aß-induced paralysis, reduce the production of ROS, and protect the mitochondrial function in transgenic C. elegans. Genetic analyses indicate that heat shock protein is involved in the alleviation of Aß toxicity. PAT also inhibits the activity of acetylcholinesterase in C. elegans. Morris water maze test shows that the memory and cognitive ability of APP/PS1 AD model mice are significantly improved by PAT. Both in vitro and in vivo studies demonstrate that PAT is effective in counteracting Aß toxicity and ameliorating cognitive functions in AD mice, and therefore a potential lead compound of anti-AD drugs.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminas/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Piridinas/farmacologia , Doença de Alzheimer/metabolismo , Aminas/síntese química , Aminas/química , Peptídeos beta-Amiloides/metabolismo , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Agregados Proteicos/efeitos dos fármacos , Piridinas/síntese química , Piridinas/química , Ratos , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 168: 426-435, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30831410

RESUMO

A series of novel 3,5-diaryl-1H-pyrazolo[3,4-b]pyridines as tubulin polymerization inhibitors targeting the colchicine site were designed via ring tethering strategy, which was supported by conformational analysis. The general, chemically unstable and rotational linker, carbanyl group, was locked by 1H-pyrazolo[3,4-b]pyridine to avoid carbonyl reduction and restrict the instability of molecular conformation caused by the rotation of the carbon-carbon single bond beside carbonyl group. All of target compounds were synthesized and evaluated for their antiproliferative activities against three human cancer lines (SGC-7901, A549 and HeLa) by MTT assay. Most of these compounds showed prominent in vitro potency and the most potent compound in this scaffold 13d (SGC-7901: IC50 = 13 nM) could significantly inhibit tubulin polymerization and strongly disrupt cytoskeleton. The results of molecular modeling study revealed that 13d interacts with tubulin by binding to the colchicine site.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Pirazóis/farmacologia , Piridinas/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Polimerização/efeitos dos fármacos , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade
17.
Anal Chim Acta ; 1058: 155-165, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-30851849

RESUMO

Cysteine (Cys), homocysteine (Hcy) and glutathione (GSH) play many crucial physiological roles in organisms. Their abnormal levels can cause and indicate various diseases. In the present study, a small-molecule fluorescent probe 2-(imidazo[1,2-a]pyridin-2-yl)phenyl acrylate (IPPA) was designed, synthesized and characterized by NMR, FT-IR and HRMS. IPPA can selectively detect Cys over other analytes because of an approximately 76 times enhancement in fluorescence intensity. The limit of detection of IPPA for Cys was 0.33 µM. The pseudo-first-order rate constant of the reaction between IPPA and Cys was approximately 10 times that of the reaction between IPPA and Hcy (KCys 3.18 × 10-3 S-1vs KHcy 4.92 × 10-4 S-1), indicating that Cys can be distinguished from Hcy. In addition, IPPA exhibits strong anti-interference ability, small molecular weight, high efficiency, low toxicity and good cell permeability. It was successfully used in imaging HepG2 cells and zebrafish. The fluorescence response of IPPA for calf serum are powerful proofs for practical application. Therefore, IPPA has high potential for bioassay applications.


Assuntos
Acrilatos/química , Cisteína/sangue , Corantes Fluorescentes/química , Imidazóis/química , Piridinas/química , Acrilatos/síntese química , Acrilatos/toxicidade , Animais , Bovinos , Teoria da Densidade Funcional , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células Hep G2 , Humanos , Imidazóis/síntese química , Imidazóis/toxicidade , Limite de Detecção , Microscopia de Fluorescência/métodos , Modelos Químicos , Piridinas/síntese química , Piridinas/toxicidade , Peixe-Zebra
18.
Molecules ; 24(6)2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30871137

RESUMO

The quaternization reactions of nicotinamide, with different electrophiles: methyl iodide and substituted 2-bromoacetophenones (4-Cl, 4-Br, 4-H, 4-CH3, 4-F, 4-OCH3, 4-Ph, 2-OCH3, 4-NO2) are reported. The preparations were carried out by conventional synthesis and under microwave irradiation in absolute ethanol and acetone. The synthesis performed by microwave dielectric heating significantly improved yield, up to 8 times, and shortened down the reaction time from ca. one day in conventional, to 10⁻20 min. The structures of the synthesized compounds were confirmed by IR, ¹H- and 13C-NMR spectroscopy, mass spectrometry and elemental analysis. The compounds have been screened for antifungal activities against Fusarium oxysporum, Fusarium culmorum, Macrophomina phaseolina and Sclerotinia sclerotiorum at concentrations of 10 µg/mL and 100 µg/mL. Six compounds showed the strong inhibition of mycelium growth at a concentration of 10 µg/mL. All tested compounds revealed the great inhibitory activities against S. sclerotiorum at a concentration of 100 µg/mL.


Assuntos
Antifúngicos/síntese química , Ascomicetos/efeitos dos fármacos , Fusarium/efeitos dos fármacos , Niacinamida/análogos & derivados , Piridinas/síntese química , Acetofenonas/química , Antifúngicos/química , Antifúngicos/farmacologia , Hidrocarbonetos Iodados/química , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Micro-Ondas , Estrutura Molecular , Niacinamida/química , Piridinas/química , Piridinas/farmacologia
19.
Chem Asian J ; 14(8): 1249-1261, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30714356

RESUMO

Using a scaffold-hopping approach, imidazo[1,2-a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3-kinase (PI3K) inhibitors have been synthesized for biological evaluation. Compounds were prepared using a heteroaryl Heck reaction procedure, involving the palladium-catalysed coupling of 2-(difluoromethyl)imidazo[1,2-a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5-triazines or pyrimidines, with the iodo intermediates being preferred in terms of higher yields and milder reaction conditions. The new compounds maintain the PI3K isoform selectivity of their benzimidazole analogues, but in general show less potency.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Piridinas/química , Relação Estrutura-Atividade
20.
Org Biomol Chem ; 17(7): 2020-2027, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30706071

RESUMO

Bromodomain and PHD finger containing protein transcription factor (BPTF) is an epigenetic protein involved in chromatin remodelling and is a potential anticancer target. The BPTF bromodomain has one reported small molecule inhibitor (AU1, rac-1). Here, advances made on the structure-activity relationship of a BPTF bromodomain ligand are reported using a combination of experimental and molecular dynamics simulations leading to the active enatiomer (S)-1. Additionally, a ligand deconstruction analysis was conducted to characterize important pharmacophores for engaging the BPTF bromodomain. These studies have been enabled by a protein-based fluorine NMR approach, highlighting the versatility of the method for selectivity, ligand deconstruction, and ligand binding. To enable future analysis of biological activity, cell growth analyses in a panel of cancer cell lines were carried out using CRISPR-Cas9 and (S)-1 to identify cell-based model systems that are sensitive to BPTF inhibition.


Assuntos
Proteínas do Tecido Nervoso/antagonistas & inibidores , Pirazóis/farmacologia , Piridinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Antígenos Nucleares , Proliferação de Células , Cristalografia por Raios X , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
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