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1.
Mol Pharmacol ; 98(2): 168-180, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32474444

RESUMO

The two major nicotinic acetylcholine receptors (nAChRs) in the brain are the α4ß2 and α7 subtypes. A "methyl scan" of the pyrrolidinium ring was used to detect differences in nicotine's interactions with these two receptors. Each methylnicotine was investigated using voltage-clamp and radioligand binding techniques. Methylation at each ring carbon elicited unique changes in nicotine's receptor interactions. Replacing the 1'-N-methyl with an ethyl group or adding a second 1'-N-methyl group significantly reduced interaction with α4ß2 but not α7 receptors. The 2'-methylation uniquely enhanced binding and agonist potency at α7 receptors. Although 3'- and 5'-trans-methylations were much better tolerated by α7 receptors than α4ß2 receptors, 4'-methylation decreased potency and efficacy at α7 receptors much more than at α4ß2 receptors. Whereas cis-5'-methylnicotine lacked agonist activity and displayed a low affinity at both receptors, trans-5'-methylnicotine retained considerable α7 receptor activity. Differences between the two 5'-methylated analogs of the potent pyridyl oxymethylene-bridged nicotine analog A84543 were consistent with what was found for the 5'-methylnicotines. Computer docking of the methylnicotines to the Lymnaea acetylcholine binding protein crystal structure containing two persistent waters predicted most of the changes in receptor affinity that were observed with methylation, particularly the lower affinities of the cis-methylnicotines. The much smaller effects of 1'-, 3'-, and 5'-methylations and the greater effects of 2'- and 4'-methylations on nicotine α7 nAChR interaction might be exploited for the design of new drugs based on the nicotine scaffold. SIGNIFICANCE STATEMENT: Using a comprehensive "methyl scan" approach, we show that the orthosteric binding sites for acetylcholine and nicotine in the two major brain nicotinic acetylcholine receptors interact differently with the pyrrolidinium ring of nicotine, and we suggest reasons for the higher affinity of nicotine for the heteromeric receptor. Potential sites for nicotine structure modification were identified that may be useful in the design of new drugs targeting these receptors.


Assuntos
Nicotina/análogos & derivados , Piridinas/síntese química , Receptores Nicotínicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Sítios de Ligação , Masculino , Metilação , Simulação de Acoplamento Molecular , Estrutura Molecular , Nicotina/química , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , Xenopus laevis
2.
J Med Chem ; 63(8): 4370-4387, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32227948

RESUMO

Chlamydia trachomatis is the most common sexually transmitted bacterial disease globally and the leading cause of infertility and preventable infectious blindness (trachoma) in the world. Unfortunately, there is no FDA-approved treatment specific for chlamydial infections. We recently reported two sulfonylpyridines that halt the growth of the pathogen. Herein, we present a SAR of the sulfonylpyridine molecule by introducing substituents on the aromatic regions. Biological evaluation studies showed that several analogues can impair the growth of C. trachomatis without affecting host cell viability. The compounds did not kill other bacteria, indicating selectivity for Chlamydia. The compounds presented mild toxicity toward mammalian cell lines. The compounds were found to be nonmutagenic in a Drosophila melanogaster assay and exhibited a promising stability in both plasma and gastric fluid. The presented results indicate this scaffold is a promising starting point for the development of selective antichlamydial drugs.


Assuntos
Chlamydia trachomatis/efeitos dos fármacos , Peptídeo Hidrolases/metabolismo , Inibidores de Proteases/síntese química , Piridinas/síntese química , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Chlamydia trachomatis/fisiologia , Clorobenzenos/síntese química , Clorobenzenos/farmacologia , Relação Dose-Resposta a Droga , Drosophila melanogaster , Células HeLa , Humanos , Camundongos , Inibidores de Proteases/farmacologia , Piridinas/farmacologia
3.
J Med Chem ; 63(6): 3298-3316, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32125159

RESUMO

Cruzain, an essential cysteine protease of the parasitic protozoan, Trypanosoma cruzi, is an important drug target for Chagas disease. We describe here a new series of reversible but time-dependent inhibitors of cruzain, composed of a dipeptide scaffold appended to vinyl heterocycles meant to provide replacements for the irreversible reactive "warheads" of vinyl sulfone inactivators of cruzain. Peptidomimetic vinyl heterocyclic inhibitors (PVHIs) containing Cbz-Phe-Phe/homoPhe scaffolds with vinyl-2-pyrimidine, vinyl-2-pyridine, and vinyl-2-(N-methyl)-pyridine groups conferred reversible, time-dependent inhibition of cruzain (Ki* = 0.1-0.4 µM). These cruzain inhibitors exhibited moderate to excellent selectivity versus human cathepsins B, L, and S and showed no apparent toxicity to human cells but were effective in cell cultures of Trypanosoma brucei brucei (EC50 = 1-15 µM) and eliminated T. cruzi in infected murine cardiomyoblasts (EC50 = 5-8 µM). PVHIs represent a new class of cruzain inhibitors that could progress to viable candidate compounds to treat Chagas disease and human sleeping sickness.


Assuntos
Inibidores de Cisteína Proteinase/farmacologia , Peptidomiméticos/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Tripanossomicidas/farmacologia , Compostos de Vinila/farmacologia , Animais , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/metabolismo , Desenho de Fármacos , Ensaios Enzimáticos , Humanos , Cinética , Camundongos , Simulação de Acoplamento Molecular , Mioblastos Cardíacos/efeitos dos fármacos , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Ligação Proteica , Proteínas de Protozoários/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/metabolismo , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Compostos de Vinila/síntese química , Compostos de Vinila/metabolismo
4.
J Med Chem ; 63(6): 3327-3347, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32129996

RESUMO

Cyclin-dependent kinases (CDKs) are promising therapeutic targets for cancer therapy. Herein, we describe our efforts toward the discovery of a series of 5-chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4-diamine derivatives as dual CDK6 and 9 inhibitors. Intensive structural modifications lead to the identification of compound 66 as the most active dual CDK6/9 inhibitor with balancing potency against these two targets and good selectivity over CDK2. Further biological studies revealed that compound 66 was directly bound to CDK6/9, resulting in suppression of their downstream signaling pathway and inhibition of cell proliferation by blocking cell cycle progression and inducing cellular apoptosis. More importantly, compound 66 significantly inhibited tumor growth in a xenograft mouse model with no obvious toxicity, indicating the promising therapeutic potential of CDK6/9 dual inhibitors for cancer treatment. Therefore, the above results are of great importance in the development of dual CDK6/9 inhibitors for cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/química , Quinase 6 Dependente de Ciclina/metabolismo , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/química , Quinase 9 Dependente de Ciclina/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Piridinas/administração & dosagem , Piridinas/síntese química , Piridinas/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/síntese química , Pirimidinas/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade
5.
J Med Chem ; 63(6): 3274-3289, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32011145

RESUMO

Trypsin and thrombin, structurally similar serine proteases, recognize different substrates; thrombin cleaves after Arg, whereas trypsin cleaves after Lys/Arg. Both recognize basic substrate headgroups via Asp189 at the bottom of the S1 pocket. By crystallography and isothermal titration calorimetry (ITC), we studied a series of d-Phe/d-DiPhe-Pro-(amino)pyridines. Identical ligand pairs show the same binding poses. Surprisingly, one ligand binds to trypsin in protonated state and to thrombin in unprotonated state at P1 along with differences in the residual solvation pattern. While trypsin binding is mediated by an ordered water molecule, in thrombin, water is scattered over three hydration sites. Although having highly similar S1 pockets, our results suggest different electrostatic properties of Asp189 possibly contributing to the selectivity determinant. Thrombin binds a specific Na+ ion next to Asp189, which is absent in trypsin. The electrostatic properties across the S1 pocket are further attenuated by charged Glu192 at the rim of S1 in thrombin, which is replaced by uncharged Gln192 in trypsin.


Assuntos
Antitrombinas/metabolismo , Dipeptídeos/metabolismo , Piridinas/metabolismo , Trombina/metabolismo , Inibidores da Tripsina/metabolismo , Tripsina/metabolismo , Animais , Antitrombinas/síntese química , Sítios de Ligação , Calorimetria , Bovinos , Cristalografia por Raios X , Dipeptídeos/síntese química , Humanos , Ligantes , Ligação Proteica , Prótons , Piridinas/síntese química , Termodinâmica , Trombina/química , Tripsina/química , Inibidores da Tripsina/síntese química , Água/metabolismo
6.
J Med Chem ; 63(4): 1724-1749, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32031803

RESUMO

We previously reported a milestone in the optimization of NBD-11021, an HIV-1 gp120 antagonist, by developing a new and novel analogue, NBD-14189 (Ref1), which showed antiviral activity against HIV-1HXB2, with a half maximal inhibitory concentration of 89 nM. However, cytotoxicity remained high, and the absorption, distribution, metabolism, and excretion (ADME) data showed relatively poor aqueous solubility. To optimize these properties, we replaced the phenyl ring in the compound with a pyridine ring and synthesized a set of 48 novel compounds. One of the new analogues, NBD-14270 (8), showed a marked improvement in cytotoxicity, with 3-fold and 58-fold improvements in selectivity index value compared with that of Ref1 and NBD-11021, respectively. Furthermore, the in vitro ADME data clearly showed improvements in aqueous solubility and other properties compared with those for Ref1. The data for 8 indicated that the pyridine scaffold is a good bioisostere for phenyl, allowing the further optimization of this molecule.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Piridinas/farmacologia , Pirróis/farmacologia , Tiazóis/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Células CACO-2 , Células HEK293 , Proteína gp120 do Envelope de HIV/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/síntese química , Piridinas/farmacocinética , Pirróis/síntese química , Pirróis/farmacocinética , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinética
7.
J Med Chem ; 63(6): 3028-3046, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32069401

RESUMO

PI3K-Akt-mTOR signaling pathway has been validated as an effective targeting pathway for cancer therapy. However, no PI3K/mTOR dual inhibitor has been approved by the FDA yet. Therefore, it is still essential to discover a candidate with good efficacy and low toxicity. In our design, a series of imidazo[1,2-a]pyridine derivatives had been synthesized and subjected to activity assessment in vitro and in vivo. 15a was proved to be a potent PI3K/mTOR dual inhibitor with excellent kinase selectivity, modest plasma clearance, and acceptable oral bioavailability. Besides, 15a displayed significant inhibition of tumor growth in HCT116 and HT-29 xenografts without obvious effect on body weight.


Assuntos
Imidazóis/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Desenho de Fármacos , Feminino , Células HCT116 , Células HT29 , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacocinética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/metabolismo
8.
Eur J Med Chem ; 189: 112061, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31951960

RESUMO

Epidermal growth factor receptor (EGFR), a member of the HER family, is closely related to the development of multiple cancers. Herein, we report the discovery of small molecule EGFR degraders based on the proteolysis targeting chimera (PROTAC) strategy. In the present study, 13 EGFR degraders containing pyrido[3,4-d] pyrimidine moiety were designed and synthesized. Promising PROTACs 2 and 10 induced degradation of EGFR in HCC827 cells with the DC50 values of 45.2 and 34.8 nM, respectively. Cellular protein-controlling machinery ubiquitin proteasome system (UPS) was involved in the degradation process. Furthermore, the degraders 2 and 10 could significantly induce the apoptosis of HCC827 cells and arrest the cells in G1 phase. These findings demonstrated that compounds 2 and 10 could serve as effective EGFRdel19-targeting degraders in HCC827 cells. v.


Assuntos
Antineoplásicos/farmacologia , Proteólise/efeitos dos fármacos , Piridinas/farmacologia , Pirimidinas/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Piridinas/síntese química , Pirimidinas/síntese química
9.
Eur J Med Chem ; 189: 112039, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31962262

RESUMO

Terpyridine complexes are known for their broad biological activities, of which their anticancer potency is the most extensively studied. Strikingly, free ligand activity has rarely been described in the literature. In this study, a lipophilic derivative of terpyridine 4'-(1-decyl-2,3-triazol-4-yl)phenyl-2,2':6',2″-terpyridine (L) and its complexes were investigated to determine their mechanism of anticancer activity. Our results show that a free ligand expresses the same level of activity on a panel of cancer cells with a low toxicity towards normal fibroblasts as complexes with Cd, Zn or Cu. Breast cancer (MCF-7 cell line) was the most vulnerable for the tested compounds with the IC50 values in the nanomolar range (IC50 = 40 nM for L.) The addition of Cu(II) ions increased its activity even further, thus suggesting that ligand exchange and ROS production are the main components of its activity. A cell cycle analysis indicated its inhibition at the G0/G1 phase and the subsequent apoptosis as the cell death mode. A detailed analysis of the protein level that was involved in the aforementioned processes confirmed previous results. Furthermore, the reactive oxygen species generation and DNA intercalation confirmed its cleaving activity.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Piridinas/farmacologia , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Cádmio/química , Bovinos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Cobre/química , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/farmacologia , Mitocôndrias/metabolismo , Piridinas/síntese química , Espécies Reativas de Oxigênio/metabolismo , Zinco/química
10.
J Med Chem ; 63(4): 1511-1525, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31951127

RESUMO

We recently reported the discovery of a potent, selective, and brain-penetrant V1a receptor antagonist, which was not suitable for full development. Nevertheless, this compound was found to improve surrogates of social behavior in adults with autism spectrum disorder in an exploratory proof-of-mechanism study. Here we describe scaffold hopping that gave rise to triazolobenzodiazepines with improved pharmacokinetic properties. The key to balancing potency and selectivity while minimizing P-gp mediated efflux was fine-tuning of hydrogen bond acceptor basicity. Ascertaining a V1a antagonist specific brain activity pattern by pharmacological magnetic resonance imaging in the rat played a seminal role in guiding optimization efforts, culminating in the discovery of balovaptan (RG7314, RO5285119) 1. In a 12-week clinical phase 2 study in adults with autism spectrum disorder balovaptan demonstrated improvements in Vineland-II Adaptive Behavior Scales, a secondary end point comprising communication, socialization, and daily living skills. Balovaptan entered phase 3 clinical development in August 2018.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Transtorno do Espectro Autista/tratamento farmacológico , Benzodiazepinas/uso terapêutico , Piridinas/uso terapêutico , Receptores de Vasopressinas/metabolismo , Triazóis/uso terapêutico , Adolescente , Adulto , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/síntese química , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacocinética , Transtorno do Espectro Autista/metabolismo , Benzodiazepinas/síntese química , Benzodiazepinas/farmacocinética , Encéfalo/metabolismo , Criança , Ensaios Clínicos como Assunto , Descoberta de Drogas , Feminino , Humanos , Masculino , Mamíferos , Piridinas/síntese química , Piridinas/farmacocinética , Triazóis/síntese química , Triazóis/farmacocinética
11.
Dalton Trans ; 49(6): 1897-1906, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-31970351

RESUMO

A ligand comprised of a macrocyclic pyridinophane core having a pendant arm containing a secondary amine group linked through a methylene spacer to a pyridyl-oxadiazole-phenyl (PyPD) fluorescent system has been prepared (L). The crystal structures of [ZnL](ClO4)2 and [CuL](ClO4)2 show that M2+ is coordinated to all the nitrogen atoms of the macrocyclic core, the secondary amine of the pendant arm and the nitrogen atom of the pyridine group of the fluorescent moiety, the latter bond being clearly weaker than the one with the pyridine of the macrocycle. Solution studies showed the formation of a highly stable Cu2+ complex with 1 : 1 stoichiometry, whereas with Zn2+ least stable complexes were formed and, given the right conditions, a [Zn3L2]6+ species was also detected, but it was not possible to isolate this species in the solid state. Following Zn2+ coordination, a strong chelation-induced enhancement of fluorescence was observed, a behaviour that was not observed with any of the other metal cations tested.


Assuntos
Cobre/química , Corantes Fluorescentes/química , Compostos Macrocíclicos/química , Oxidiazóis/química , Piridinas/química , Zinco/química , Compostos Aza/síntese química , Compostos Aza/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Fluorescência , Corantes Fluorescentes/síntese química , Compostos Macrocíclicos/síntese química , Modelos Moleculares , Oxidiazóis/síntese química , Piridinas/síntese química
12.
Molecules ; 25(2)2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31963275

RESUMO

It has been found that both eugenol and isoeugenol derivatives reacted with 2-pyridinesulfenyl and 2-pyridineselenenyl halides in a regioselective mode affording products with opposite regiochemistry. Synthesis of new families of 2H,3H-[1,3]thia- and -selenazolo[3,2-a]pyridin-4-ium heterocycles has been developed by annulation reactions of 2-pyridinechalcogenyl halides with natural compounds (eugenol, isoeugenol, methyl eugenol, methyl isoeugenol, acetyl eugenol, trans-anethole) and their structural analogs. The influence of the substrate structure and the nature of halogen on the product yields are studied. The 2-pyridinesulfenyl and 2-pyridineselenenyl chlorides are more efficient reagents compared to corresponding bromides. The obtained condensed heterocycles are novel water-soluble functionalized compounds with promising biological activity.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Piridinas/química , Piridinas/farmacologia , Produtos Biológicos/síntese química , Técnicas de Química Sintética , Estrutura Molecular , Piridinas/síntese química , Solubilidade , Análise Espectral , Relação Estrutura-Atividade
13.
J Med Chem ; 63(3): 1397-1414, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31934767

RESUMO

Colony-stimulating factor 1 receptor (CSF-1R) is involved in inflammatory disorders as well as in many types of cancer. Based on high-throughput screening and docking results, we performed a detailed structure-activity-relationship study, leading to the discovery of a new series of compounds with nanomolar IC50 values against CSF-1R without the inhibition of fibroblast growth factor receptors. One of the most promising hits, compound 29, potently inhibited CSF-1R kinase with an IC50 value of 0.7 nM, while it showed no inhibition to the same family member FMS-like tyrosine kinase 3. Compound 29 displayed excellent anti-inflammatory effects against RAW264.7 macrophages indicated by significant inhibition against the activation of the CSF-1R pathway with low cytotoxicity. In addition, compound 29 exhibited strong in vivo anti-inflammatory efficacy alongside favorable drug characteristics. This novel compound 29 may serve as a new drug candidate with promising applications in inflammatory disorders.


Assuntos
Alquinos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Alquinos/síntese química , Alquinos/farmacocinética , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Feminino , Inflamação/induzido quimicamente , Lipopolissacarídeos , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Células RAW 264.7 , Ratos Sprague-Dawley , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade
14.
J Fluoresc ; 30(1): 157-174, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31970584

RESUMO

Enzymatic polymerization of 2,6-diaminopyridine (DAP) compound in the presence of HRP (Horse radish peroxidase) and H2O2 (hydrogen peroxide) with Poly(DAP-en) with the structures of two different types of polymers obtained by the oxidative polymerization of Poly(DAP-ox) using H2O2 in an aqueous basic environment was illuminated by 1H-NMR, 13C-NMR, FT-IR, UV-Vis spectral methods. GPC (gel permeation chromatography), TGA (thermal gravimetric analysis), DSC (differential scanning calorimetry), CV (cyclic voltammetry), fluorescence analysis and conductivity measurements to characterize the compounds and their electronic structure were examined. SEM analyzes were performed for the morphological properties of the compounds. As a result of the analysis, it was observed that the polymer obtained by enzymatic polymerization was better than the polymer obtained by oxidative method. It was observed that the results of the fluorescence measurements were better than Poly(DAP-en) in Poly(DAP-ox) emitting blue and green light. According to TGA analysis, the first decay temperatures for Poly (DAP-en) and Poly (DAP-ox) were calculated as 342 °C and 181 °C, respectively. The higher value of glass transition temperature for poly (DAP-en) confirms that the average molar mass is higher than 8650 Da for Poly (DAP-en) according to GPC analysis.


Assuntos
Peroxidase do Rábano Silvestre/metabolismo , Piridinas , Condutividade Elétrica , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Estrutura Molecular , Oxirredução , Polimerização , Polímeros/química , Polímeros/metabolismo , Piridinas/análise , Piridinas/síntese química , Piridinas/metabolismo , Solubilidade , Espectrometria de Fluorescência , Temperatura
15.
Eur J Med Chem ; 187: 111904, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31806537

RESUMO

Aiming to develop potent autotaxin (ATX) inhibitors for fibrosis diseases, a novel series of tetrahydropyrido[4,3-d]pyrimidine derivatives was designed and synthesized based on our previous study. The enzymatic assay combined with anti-proliferative activities against cardiac fibroblasts (CFs) and hepatic stellate cell (HSC) in vitro were applied for preliminary evaluation of anti-fibrosis potency of target compounds, resulting in two outstanding ATX inhibitors 8b and 10g with the IC50 values in a nanomolar range (24.6 and 15.3 nM). Differently, 8b was the most prominent compound against CFs with inhibition ratio of 81.5%, while 10g exhibited the maximum inhibition ratio of 83.7% against t-HSC/Cl-6 cells. In the further pharmacological evaluations in vivo, collagen deposition assay demonstrated the conspicuous capacity of 8b to suppress TGF-ß-mediated cardiac fibrosis. Simultaneously, H&E and Masson stains assays of mice liver validated 10g as an excellent anti-hepatofibrosis candidate, which reduced CCl4-induced hepatic fibrosis level prominently. Besides, the molecular binding models identified the essential interactions between 8b and ATX which was coincided with the SARs.


Assuntos
Inibidores Enzimáticos/farmacologia , Fibrose/tratamento farmacológico , Diester Fosfórico Hidrolases/metabolismo , Piridinas/farmacologia , Pirimidinas/farmacologia , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose/metabolismo , Fibrose/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 186: 111855, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31740051

RESUMO

There is an increasing interest in the field of cancer therapy for small compounds targeting pyrimidine biosynthesis, and in particular dihydroorotate dehydrogenase (DHODH), the fourth enzyme of this metabolic pathway. Three available DHODH structures, featuring three different known inhibitors, were used as templates to screen in silico an original chemical library from Erevan University. This process led to the identification of P1788, a compound chemically related to the alkaloid cerpegin, as a new class of pyrimidine biosynthesis inhibitors. In line with previous reports, we investigated the effect of P1788 on the cellular innate immune response. Here we show that pyrimidine depletion by P1788 amplifies cellular response to both type-I and type II interferons, but also induces DNA damage as assessed by γH2AX staining. Moreover, the addition of inhibitors of the DNA damage response led to the suppression of the P1788 stimulatory effects on the interferon pathway. This demonstrates that components of the DNA damage response are bridging the inhibition of pyrimidine biosynthesis by P1788 to the interferon signaling pathway. Altogether, these results provide new insights on the mode of action of novel pyrimidine biosynthesis inhibitors and their development for cancer therapies.


Assuntos
Furanos/farmacologia , Piridinas/farmacologia , Piridonas/farmacologia , Pirimidinas/antagonistas & inibidores , Células Cultivadas , Dano ao DNA , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Piridonas/química , Pirimidinas/biossíntese , Relação Estrutura-Atividade
17.
J Enzyme Inhib Med Chem ; 35(1): 1-20, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31619080

RESUMO

Inflammatory bowel disease (IBD) is a chronic immuno-inflammation in gastrointestinal tract. We have evaluated the activity of the compounds to inhibit the adhesion of monocytes to colon epithelial cells is triggered by a pro-inflammatory cytokine, tumour necrosis factor (TNF)-α. The in vitro activity of the compounds, 13b (an ureido-derivative), 14c, 14j, 14k, 14n (thioureido-), 18c and 18d (sulfonamido-), was in correlation with in vivo anti-colitis activity revealed as significant recovery in body- and colon-weights and colon myeloperoxidase level, a biochemical marker of inflammation reflecting neutrophil infiltration. In vivo, TNBS-induced changes in the expression of inflammatory cytokines (TNF-α, IL-6, IL-1ß, IL-10, and TGF-ß), NLRP3 inflammasome components (NLRP-3, Caspase-1, and IL-18), and epithelial junction molecules (E-cadherin, claudin2/3, and ZO-1) were blocked and recovered by oral administration of the compounds (1 mg/kg). Compound 14n which showed the best efficacy can be a promising lead for orally available therapeutics for pathology of IBD.


Assuntos
Anti-Inflamatórios/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Piridinas/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Células Cultivadas , Colite/induzido quimicamente , Colite/tratamento farmacológico , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Células HT29 , Humanos , Doenças Inflamatórias Intestinais/patologia , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ácido Trinitrobenzenossulfônico , Células U937
18.
Eur J Med Chem ; 187: 111966, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31869655

RESUMO

A new class of 2-amino-4-(1,2,4-triazol)pyridine derivatives were designed and synthesized as potent epidermal growth factor receptor inhibitors. In particular, compound 10c exhibited significant inhibitory against EGFRL858R/T790M, and also displayed potent anti-proliferative activity against non-small cell lung cancer cell line H1975. Besides, compound 10j showed potent inhibitory activity against glioblastoma cell line U87-EGFRvⅢ, which was at least 3-fold more potent than Osimertinib and 25-fold superior to Lazertinib. Moreover, molecular modeling and molecular dynamics simulations disclosed the binding model of the most active compound to the domain of EGFR. This contribution provides 2-amino-4-(1,2,4-triazol)pyridines as a new scaffold for EGFRT790M and/or EGFRvⅢ inhibitor.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química
19.
J Med Chem ; 63(2): 827-846, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31860298

RESUMO

We recently reported the crystal structure of tubulin in complex with a colchicine binding site inhibitor (CBSI), ABI-231, having 2-aryl-4-benzoyl-imidazole (ABI). Based on this and additional crystal structures, here we report the structure-activity relationship study of a novel series of pyridine analogues of ABI-231, with compound 4v being the most potent one (average IC50 ∼ 1.8 nM) against a panel of cancer cell lines. We determined the crystal structures of another potent CBSI ABI-274 and 4v in complex with tubulin and confirmed their direct binding at the colchicine site. 4v inhibited tubulin polymerization, strongly suppressed A375 melanoma tumor growth, induced tumor necrosis, disrupted tumor angiogenesis, and led to tumor cell apoptosis in vivo. Collectively, these studies suggest that 4v represents a promising new generation of tubulin inhibitors.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Piridinas/síntese química , Piridinas/farmacologia , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Colchicina/química , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Modelos Moleculares , Relação Estrutura-Atividade
20.
J Med Chem ; 63(2): 847-879, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31860309

RESUMO

Trypanosoma protists are pathogens leading to a spectrum of devastating infectious diseases. The range of available chemotherapeutics against Trypanosoma is limited, and the existing therapies are partially ineffective and cause serious adverse effects. Formation of the PEX14-PEX5 complex is essential for protein import into the parasites' glycosomes. This transport is critical for parasite metabolism and failure leads to mislocalization of glycosomal enzymes, with fatal consequences for the parasite. Hence, inhibiting the PEX14-PEX5 protein-protein interaction (PPI) is an attractive way to affect multiple metabolic pathways. Herein, we have used structure-guided computational screening and optimization to develop the first line of compounds that inhibit PEX14-PEX5 PPI. The optimization was driven by several X-ray structures, NMR binding data, and molecular dynamics simulations. Importantly, the developed compounds show significant cellular activity against Trypanosoma, including the human pathogen Trypanosoma brucei gambiense and Trypanosoma cruzi parasites.


Assuntos
Proteínas de Membrana/antagonistas & inibidores , Proteínas de Protozoários/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Animais , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Espectroscopia de Ressonância Magnética , Proteínas de Membrana/biossíntese , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mioblastos/efeitos dos fármacos , Mioblastos/parasitologia , Proteínas de Protozoários/biossíntese , Ratos , Relação Estrutura-Atividade , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei gambiense/metabolismo , Trypanosoma brucei rhodesiense/efeitos dos fármacos
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