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1.
PLoS One ; 15(6): e0229891, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497076

RESUMO

A facile method has been developed for the synthesis of Schiff bases derived from substituted and unsubstituted 3-amino- and 4-amino-1,2,4-triazoles. Condensation of the aminotrizoles with a variety of aromatic aldehydes afforded desired Schiff bases in excellent yields in 3-5 minutes of exposure to ultra-sound. The synthesized compounds were characterized by means of IR, 1HNMR and Mass spectrometry. The synthesized compounds were also screened for their antibacterial potential against Gram-negative (Escherichia coli, Shigella sonnei, Pseudomonas aeruginosa and Salmonella typhi) and two Gram-positive (Staphylococcus aureus and Bacillus subtilis) strains.


Assuntos
Amitrol (Herbicida)/síntese química , Amitrol (Herbicida)/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Ondas Ultrassônicas , Amitrol (Herbicida)/química , Antibacterianos/química , Bactérias/efeitos dos fármacos , Técnicas de Química Sintética , Testes de Sensibilidade Microbiana , Bases de Schiff/química , Triazóis/química
2.
J Med Chem ; 63(9): 4496-4505, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302130

RESUMO

The insertion of single 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres of trans-amide bonds (triazole scan) was recently applied to the 177Lu-labeled tumor-targeting analog of minigastrin, [Nle15]MG11. The reported novel mono-triazolo-peptidomimetics of [Nle15]MG11 showed either improved resistance against enzymatic degradation or a significantly increased affinity toward the target receptor but never both. To enhance further the tumor-targeting properties of the minigastrin analogs, we studied conjugates with multiple amide-to-triazole substitutions for additive or synergistic effects. Promising candidates were identified by modification of two or three amide bonds, which yielded both improved stability and increased receptor affinity of the peptidomimetics in vitro. Biodistribution studies of radiolabeled multi-triazolo-peptidomimetics in mice bearing receptor-positive tumor xenografts revealed up to 4-fold increased tumor uptake in comparison to the all-amide reference compound [Nle15]MG11. In addition, we report here for the first time a linear peptidomimetic with three triazole insertions in its backbone and maintained biological activity.


Assuntos
Antineoplásicos/farmacologia , Gastrinas/farmacologia , Peptidomiméticos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Desenho de Fármacos , Gastrinas/síntese química , Gastrinas/metabolismo , Gastrinas/farmacocinética , Humanos , Lutécio/química , Camundongos , Neoplasias/metabolismo , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacocinética , Ligação Proteica , Radioisótopos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Receptor de Colecistocinina B/metabolismo , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética
3.
J Med Chem ; 63(9): 4824-4836, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302132

RESUMO

Mammary-tissue-restricted cytochrome P450 4Z1 (CYP4Z1) has garnered interest for its potential role in breast cancer progression. CYP4Z1-dependent metabolism of arachidonic acid preferentially generates 14,15-epoxyeicosatrienoic acid (14,15-EET), a metabolite known to influence cellular proliferation, migration, and angiogenesis. In this study, we developed time-dependent inhibitors of CYP4Z1 designed as fatty acid mimetics linked to the bioactivatable pharmacophore, 1-aminobenzotriazole (ABT). The most potent analogue, 8-[(1H-benzotriazol-1-yl)amino]octanoic acid (7), showed a 60-fold lower shifted-half-maximal inhibitory concentration (IC50) for CYP4Z1 compared to ABT, efficient mechanism-based inactivation of the enzyme evidenced by a KI = 2.2 µM and a kinact = 0.15 min-1, and a partition ratio of 14. Furthermore, 7 exhibited low off-target inhibition of other CYP isozymes. Finally, low micromolar concentrations of 7 inhibited 14,15-EET production in T47D breast cancer cells transfected with CYP4Z1. This first-generation, selective mechanism-based inhibitor (MBI) will be a useful molecular tool to probe the biochemical role of CYP4Z1 and its association with breast cancer.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Família 4 do Citocromo P450/antagonistas & inibidores , Ácidos Graxos/farmacologia , Triazóis/farmacologia , Ácido Araquidônico/metabolismo , Linhagem Celular Tumoral , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/metabolismo , Desenho de Fármacos , Ácidos Graxos/síntese química , Ácidos Graxos/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Oxirredução , Triazóis/síntese química , Triazóis/metabolismo
4.
J Med Chem ; 63(9): 4484-4495, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302139

RESUMO

MG11 is a truncated analog of minigastrin, a peptide with high affinity and specificity toward the cholecystokinin-2 receptor (CCK2R), which is overexpressed by different tumors. Thus, radiolabeled MG11 derivatives have great potential for use in cancer diagnosis and therapy. A drawback of MG11 is its fast degradation by proteases, leading to moderate tumor uptake in vivo. We introduced 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres to replace labile amide bonds of the peptide. The "triazole scan" yielded peptidomimetics with improved resistance to enzymatic degradation and/or enhanced affinity toward the CCK2R. Remarkably, our lead compound achieved a 10-fold increase in receptor affinity, resulting in a 2.6-fold improved tumor uptake in vivo. Modeling of the ligand-CCK2R complex suggests that an additional cation-π interaction of the aromatic triazole moiety with the Arg356 residue of the receptor is accountable for these observations. We show for the first time that the amide-to-triazole substitution strategy offers new opportunities in drug development that go beyond the metabolic stabilization of bioactive peptides.


Assuntos
Antineoplásicos/farmacologia , Gastrinas/farmacologia , Peptidomiméticos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Feminino , Gastrinas/síntese química , Gastrinas/metabolismo , Gastrinas/farmacocinética , Humanos , Lutécio/química , Camundongos , Neoplasias/metabolismo , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacocinética , Ligação Proteica , Conformação Proteica , Radioisótopos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Receptor de Colecistocinina B/metabolismo , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética
5.
Nature ; 579(7799): 379-384, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32188949

RESUMO

Automated synthesis platforms accelerate and simplify the preparation of molecules by removing the physical barriers to organic synthesis. This provides unrestricted access to biopolymers and small molecules via reproducible and directly comparable chemical processes. Current automated multistep syntheses rely on either iterative1-4 or linear processes5-9, and require compromises in terms of versatility and the use of equipment. Here we report an approach towards the automated synthesis of small molecules, based on a series of continuous flow modules that are radially arranged around a central switching station. Using this approach, concise volumes can be exposed to any reaction conditions required for a desired transformation. Sequential, non-simultaneous reactions can be combined to perform multistep processes, enabling the use of variable flow rates, reuse of reactors under different conditions, and the storage of intermediates. This fully automated instrument is capable of both linear and convergent syntheses and does not require manual reconfiguration between different processes. The capabilities of this approach are demonstrated by performing optimizations and multistep syntheses of targets, varying concentrations via inline dilutions, exploring several strategies for the multistep synthesis of the anticonvulsant drug rufinamide10, synthesizing eighteen compounds of two derivative libraries that are prepared using different reaction pathways and chemistries, and using the same reagents to perform metallaphotoredox carbon-nitrogen cross-couplings11 in a photochemical module-all without instrument reconfiguration.


Assuntos
Técnicas de Química Sintética/instrumentação , Técnicas de Química Sintética/métodos , Triazóis/síntese química , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Automação/instrumentação , Automação/métodos , Carbono/química , Indicadores e Reagentes/química , Nitrogênio/química , Oxirredução , Processos Fotoquímicos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Software , Soluções/química , Triazóis/química
7.
Eur J Med Chem ; 191: 112152, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088495

RESUMO

Protein kinase inhibitors and epigenetic regulatory molecules are two main kinds of anticancer drugs developed in recent years. Both kinds of drugs harbor their own advantages and disadvantages in the treatment of cancer, and the development of small molecules which could target at kinases and epigenetic targets simultaneously can avoid the defects of drugs which only targets at kinases or epigenetic proteins. In this study, a series of 4,5-dihydro-[1,2,4]triazolo [4,3-f]pteridine derivatives were designed and synthesized based on the structure of PLK1 inhibitor BI-2536. Subsequent targets affinity screen and antiproliferative activity test led to the discovery of the most potent dual PLK1/BRD4 inhibitor 9b with good potency for both PLK1 (IC50 = 22 nM) and BRD4 (IC50 = 109 nM) as well as favorable antiproliferative activity against a panel of cancer cell lines. 9b could induce cell cycle arrest and apoptosis in acute myeloid leukemia cell line MV 4-11 in a concentration dependent manner. It could also downregulate the transcription of several proliferation-related oncogenes, including c-MYC, MYCN and BCL-2. Finally, in a MV4-11 mouse xenograft model, 9b exhibited favorable in vivo antitumor activity with 66% tumor growth inhibition (TGI) at a dose of 60 mg/kg while without obvious toxicity. This study thus provided us a start point for the development of new dual PLK1/BRD4 inhibitors as anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pteridinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Pteridinas/síntese química , Pteridinas/química , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo , Triazóis/síntese química , Triazóis/química , Células Tumorais Cultivadas
8.
Eur J Med Chem ; 191: 112133, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105979

RESUMO

Tariquidar derivatives have been described as potent and selective ABCG2 inhibitors. However, their susceptibility to hydrolysis limits their applicability. The current study comprises the synthesis and characterization of novel tariquidar-related inhibitors, obtained by bioisosteric replacement of the labile moieties in our previous tariquidar analog UR-ME22-1 (9). CuAAC ("click" reaction) gave convenient access to a triazole core as a substitute for the labile amide group and the labile ester moiety was replaced by different acyl groups in a Sugasawa reaction. A stability assay proved the enhancement of the stability in blood plasma. Compounds UR-MB108 (57) and UR-MB136 (59) inhibited ABCG2 in a Hoechst 33342 transport assay with an IC50 value of about 80 nM and belong to the most potent ABCG2 inhibitors described so far. Compound 57 was highly selective, whereas its PEGylated analog 59 showed some potency at ABCB1. Both 57 and 59 produced an ABCG2 ATPase-depressing effect which is in agreement with our precedent cryo-EM study identifying 59 as an ATPase inhibitor that exerts its effect via locking the inward-facing conformation. Thermostabilization of ABCG2 by 57 and 59 can be taken as a hint to comparable binding to ABCG2. As reference substances, compounds 57 and 59 allow additional mechanistic studies on ABCG2 inhibition. Due to their stability in blood plasma, they are also applicable in vivo. The highly specific inhibitor 57 is suited for PET labeling, helping to further elucidate the (patho)physiological role of ABCG2, e.g. at the BBB.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Quinolinas/farmacologia , Triazóis/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Relação Dose-Resposta a Droga , Humanos , Células KB , Células MCF-7 , Estrutura Molecular , Proteínas de Neoplasias/metabolismo , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Células Tumorais Cultivadas
9.
Molecules ; 25(4)2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32059480

RESUMO

Bacterial resistance remains a significant threat and a leading cause of death worldwide, despite massive attempts to control infections. In an effort to develop biologically active antibacterial and antifungal agents, six novel aryl-substituted-1,2,3-triazoles linked to carbohydrate units were synthesized through the Cu(I)-catalyzed azide-alkyne cycloaddition CuAAC of substituted-arylazides with a selection of alkyne-functionalized sugars. The chemical structures of the new derivatives were verified using different spectroscopic techniques. The novel clicked 1,2,3-triazoles were evaluated for in vitro antibacterial activity against Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa, and the obtained results were compared with the activity of the reference antibiotic "Ampicillin". Likewise, in vitro antifungal activity of the new 1,2,3-triazoles was investigated against Candida albicans and Aspergillus niger using "Nystatin" as a reference drug. The results of the biological evaluation pointed out that Staphylococcus aureus was more susceptible to all of the tested compounds than other examined microbes. In addition, some tested compounds exhibited promising antifungal activity.


Assuntos
Anti-Infecciosos/farmacologia , Química Click , Glicosídeos/farmacologia , Triazóis/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Aspergillus niger/efeitos dos fármacos , Aspergillus niger/patogenicidade , Candida albicans/efeitos dos fármacos , Candida albicans/patogenicidade , Glicosídeos/síntese química , Glicosídeos/química , Humanos , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
10.
Molecules ; 25(4)2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32075253

RESUMO

In this study cytotoxicity of organotin(IV) compounds with 1,2,4-triazolo[1,5-a]pyrimidines, Me3Sn(5tpO) (1), n-Bu3Sn(5tpO) (2), Me3Sn(mtpO) (3), n-Bu3Sn(mtpO) (4), n-Bu3Sn(HtpO2) (5), Ph3Sn(HtpO2) (6) where 5HtpO = 4,5-dihydro-5-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, HmtpO = 4,7-dihydro-5-methyl-7-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, and H2tpO2 = 4,5,6,7-tetrahydro-5,7- dioxo-[1,2,4]triazolo-[1,5-a]-pyrimidine, was assessed on three different human tumor cell lines: HCT-116 (colorectal carcinoma), HepG2 (hepatocarcinoma) and MCF-7 (breast cancer). While 1 and 3 were inactive, compounds 2, 4, 5 and 6 inhibited the growth of the three tumor cell lines with IC50 values in the submicromolar range and showed high selectivity indexes towards the tumor cells (SI > 90). The mechanism of cell death triggered by the organotin(IV) derivatives, investigated on HCT-116 cells, was apoptotic, as evident from the externalization of phosphatidylserine to the cell surface, and occurred via the intrinsic pathway with fall of mitochondrial inner membrane potential and production of reactive oxygen species. While compound 6 arrested the cell progression in the G2/M cell cycle phase and increased p53 and p21 levels, compounds 2, 4 and 5 blocked cell duplication in the G1 phase without affecting the expression of either of the two tumor suppressor proteins. Compounds 1 and 2 were also investigated using single crystal X-ray diffraction and found to be, in both cases, coordination polymers forming 1 D chains based on metal-ligand interactions. Interestingly, for n-Bu3Sn(5tpO)(2) H-bonding interactions between 5tpO- ligands belonging to adjacent chains were also detected that resemble the "base-pairing" assembly and could be responsible for the higher biological activity compared to compound 1. In addition, they are the first example of bidentate N(3), O coordination for the 5HtpO ligand on two adjacent metal atoms.


Assuntos
Apoptose/efeitos dos fármacos , Citotoxinas/farmacologia , Regulação Neoplásica da Expressão Gênica , Compostos Orgânicos de Estanho/farmacologia , Pirimidinas/farmacologia , Triazóis/farmacologia , Apoptose/genética , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Citotoxinas/síntese química , Desenho de Fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Células HCT116 , Células Hep G2 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Compostos Orgânicos de Estanho/síntese química , Pirimidinas/síntese química , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
11.
Org Lett ; 22(4): 1396-1401, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32013455

RESUMO

Alkyl N-aryl 1,2,3-triazole-carboxylates are important molecules or intermediates in medicinal chemistry, but the synthesis of N2-aryl counterparts remains elusive. Herein, we describe a Cu-mediated annulation reaction of alkyl 3-aminoacrylates with aryldiazonium salts, both of which are readily available substrates. Furthermore, alkyl 2-aminoacrylates are also viable substrates. Diverse alkyl N2-aryl 1,2,3-triazole-carboxylates and their analogues can be rapidly prepared under mild conditions. Especially, this protocol allows one to access several druglike variants of carbonic anhydrase inhibitors and celecoxib.


Assuntos
Acrilatos/química , Inibidores da Anidrase Carbônica/síntese química , Ácidos Carboxílicos/síntese química , Cobre/química , Compostos de Diazônio/química , Triazóis/síntese química , Inibidores da Anidrase Carbônica/química , Ácidos Carboxílicos/química , Estrutura Molecular , Sais/química , Triazóis/química
12.
Org Biomol Chem ; 18(10): 1957-1967, 2020 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-32101244

RESUMO

1,4- and 1,5-Disubstituted triazole amino acid monomers have gained increasing interest among peptidic foldamers, as they are easily prepared via Cu- and Ru-catalyzed click reactions, with the potential for side chain variation. While the latter is key to their applicability, the synthesis and structural properties of the chiral mono- or disubstituted triazole amino acids have only been partially addressed. We here present the synthesis of all eight possible chiral derivatives of a triazole monomer prepared via a ruthenium-catalyzed azide alkyne cycloaddition (RuAAC). To evaluate the conformational properties of the individual building units, a systematic quantum chemical study was performed on all monomers, indicating their capacity to form several low energy conformers. This feature may be used to effect structural diversity when the monomers are inserted into various peptide sequences. We envisage that these results will facilitate new applications for these artificial oligomeric compounds in diverse areas, ranging from pharmaceutics to biotechnology.


Assuntos
Peptidomiméticos/síntese química , Triazóis/síntese química , Alquinos/química , Azidas/química , Química Click , Reação de Cicloadição , Modelos Moleculares , Polimerização , Polímeros/síntese química , Teoria Quântica , Estereoisomerismo , Termodinâmica
13.
Molecules ; 25(3)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973234

RESUMO

A new series of nitrogen and sulfur heterocyclic systems were efficiently synthesized by linking the following four rings: indole; 1,2,4-triazole; pyridazine; and quinoxaline hybrids. The strength of the acid that catalyzes the condensation of 4-amino-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1 with aromatic aldehydes controlled the final product. Reflux in glacial acetic acid yielded Schiff bases 2-6, whereas concentrated HCl in ethanol resulted in a cyclization product at C-3 of the indole ring to create indolo-triazolo-pyridazinethiones 7-16. This fascinating cyclization approach was applicable with a wide range of aromatic aldehydes to create the target cyclized compounds in excellent yield. Additionally, the coupling of the new indolo-triazolo-pyridazinethiones 7-13 with 2,3-bis(bromomethyl)quinoxaline, as a linker in acetone and K2CO3, yielded 2,3-bis((5,6-dihydro-14H-indolo[2,3-d]-6-aryl-[1,2,4-triazolo][4,3-b]pyridazin-3 ylsulfanyl)methyl)quinoxalines 19-25 in a high yield. The formation of this new class of heterocyclic compounds in high yields warrants their use for further research. The new compounds were characterized using nuclear magnetic resonance (NMR) and mass spectral analysis. Compound 6 was further confirmed by the single crystal X-ray diffraction technique.


Assuntos
Compostos Heterocíclicos/síntese química , Indóis/síntese química , Nitrogênio/química , Piridazinas/síntese química , Quinoxalinas/síntese química , Enxofre/química , Triazóis/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Compostos Heterocíclicos/química , Ligação de Hidrogênio , Indóis/química , Conformação Molecular , Espectroscopia de Prótons por Ressonância Magnética , Piridazinas/química , Quinoxalinas/química , Triazóis/química , Difração de Raios X
14.
Molecules ; 25(3)2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31979299

RESUMO

Efficient synthesis of 2,5-diaryl substituted 4-azido-1,2,3-triazoles by the reaction of sodium azide with dichlorosubstituted diazadienes was demonstrated. The optical properties of the prepared azidotriazoles were studied to reveal a luminescence maximum in the 360-420 nm region. To improve the luminescence quantum yields a family of 4-azido-1,2,3-triazoles bearing ortho-propargyloxy substituents in the 5 position was prepared. Subsequent intramolecular thermal cyclization permits to construct additional triazole fragment and obtain unique benzoxazocine derivatives condensed with two triazole rings. This new family of condensed heterocycles has a flattened heterocyclic system structure to provide more conjugation of the 5-aryl fragment with the triazole core. As a result, a new type of UV/"blue light-emitting" materials with better photophysical properties was obtained.


Assuntos
Triazóis/química , Ciclização , Fluorescência , Luz , Cloreto de Metileno/química , Estrutura Molecular , Rotação , Azida Sódica/química , Espectrometria de Fluorescência , Triazóis/síntese química , Triazóis/farmacologia , Triazóis/efeitos da radiação , Raios Ultravioleta
15.
Molecules ; 25(3)2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31979319

RESUMO

The coagulation cascade is the process of the conversion of soluble fibrinogen to insoluble fibrin that terminates in production of a clot. Factor Xa (FXa) is a serine protease involved in the blood coagulation cascade. Moreover, FXa plays a vital role in the enzymatic sequence which ends with the thrombus production. Thrombosis is a common causal pathology for three widespread cardiovascular syndromes: acute coronary syndrome (ACS), venous thromboembolism (VTE), and strokes. In this research a series of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives as a potential factor Xa (FXa) inhibitor were designed, synthesized, and evaluated for their FXa inhibitor activity, cytotoxicity activity and coagulation parameters. Rational design for the desired novel molecules was performed through protein-ligand complexes selection and ligand clustering. The microwave-assisted synthetic strategy of selected compounds was carried out by using Ullmann-Goldberg, N-propargylation, Mannich addition, Friedel-Crafts, and 1,3-dipolar cycloaddition type reactions under microwave irradiation. The microwave methodology proved to be an efficient way to obtain all novel compounds in high yields (73-93%). Furthermore, a thermochemical analysis, optimization and reactivity indexes such as electronic chemical potential (µ), chemical hardness (η), and electrophilicity (ω) were performed to understand the relationship between the structure and the energetic behavior of all the series. Then, in vitro analysis showed that compounds 27, 29-31, and 34 exhibited inhibitory activity against FXa and the corresponding half maximal inhibitory concentration (IC50) values were calculated. Next, a cell viability assay in HEK293 and HepG2 cell lines, and coagulation parameters (anti FXa, Prothrombin time (PT), activated Partial Thromboplastin Time (aPTT)) of the most active novel molecules were performed to determine the corresponding cytotoxicity and possible action on clotting pathways. The obtained results suggest that compounds 27 and 29 inhibited FXa targeting through coagulation factors in the intrinsic and extrinsic pathways. However, compound 34 may target coagulation FXa mainly by the extrinsic and common pathway. Interestingly, the most active compounds in relation to the inhibition activity against FXa and coagulation parameters did not show toxicity at the performed coagulation assay concentrations. Finally, docking studies confirmed the preferential binding mode of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives inside the active site of FXa.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/síntese química , Inibidores do Fator Xa/farmacologia , Fator Xa/química , Quinolinas/química , Triazóis/química , Compostos de Anilina/síntese química , Compostos de Anilina/química , Azidas/síntese química , Azidas/química , Testes de Coagulação Sanguínea , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Fator Xa/metabolismo , Inibidores do Fator Xa/química , Humanos , Concentração Inibidora 50 , Ligantes , Micro-Ondas , Simulação de Acoplamento Molecular , Quinolinas/síntese química , Triazóis/síntese química
16.
Acta Pharm ; 70(2): 145-159, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31955138

RESUMO

Middle East respiratory syndrome coronavirus (MERS-CoV) had emerged and spread because of the worldwide travel and inefficient healthcare provided for the infected patients in several countries. Herein we investigated the anti-MERS-CoV activity of newly synthesized sixteen halogenated triazole compounds through the inhibition of helicase activity using the FRET assay. All new compounds underwent justification for their target structures via microanalytical and spectral data. SAR studies were performed. Biological results revealed that the most potent compounds were 4-(cyclopent-1-en-3-ylamino)-5-(2-(4-iodophenyl)hydrazinyl)-4H-1,2,4-triazole-3-thiol (16) and 4-(cyclopent-1-en-3-ylamino)-5-[2-(4-chlorophenyl)hydrazinyl]-4H-1,2,4-triazole-3-thiol (12). In silico molecular docking of the most potent compounds was performed to the active binding site of MERS-CoV helicase nsp13. Molecular docking results are in agreement with experimental findings.


Assuntos
Antivirais/farmacologia , Desenho Assistido por Computador , Infecções por Coronavirus/tratamento farmacológico , DNA Helicases/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Simulação de Acoplamento Molecular , Triazóis/farmacologia , Proteínas Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/metabolismo , Infecções por Coronavirus/virologia , DNA Helicases/química , DNA Helicases/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/enzimologia , Coronavírus da Síndrome Respiratória do Oriente Médio/crescimento & desenvolvimento , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/metabolismo , Proteínas Virais/química , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacos
17.
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
18.
Eur J Med Chem ; 186: 111908, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31791643

RESUMO

Artemisinin and its analogs have shown potent anticancer activity in primary cancer cultures and cell lines by inhibiting cancer proliferation, metastasis, and angiogenesis. Despite its apparent compatibility to normal cells and low IC50 values in comparison to the commonly used anticancer drugs, the underlying mechanisms behind their cytotoxic effects are not yet fully understood. Surprisingly, the efficacy of synthetic 1,2,4-trioxanes against cancer has not been explored yet. Given the high antitumor activity of artemisinin dimers in comparison to their monomers, we report here the synthesis of simple 1,2,3-triazole conjugated 1,2,4-trioxanes and their potential antitumor activity by studying their inhibitory effect on osteopontin (OPN) expression in MDA-MB-435 breast cancer cells. It may be noted that despite being a strong marker to identify human tumor metastasis, no study on effect of artemisinin and its synthetic and semisynthetic derivatives on OPN expression has ever been studied. Although our initial studies did not notice any straight-line relationship between the number of trioxane units in a molecule to the extent of inhibition of OPN protein expression, we could observe better results in some cases in comparison to artemisinin. We have observed that artemisinin did not show appreciable OPN downregulation in MDA-MB-435 cancer cells, but dihydroartemisinin (DHA) and some synthetic 1,2,4-trioxane monomers and dimers showed downregulation of OPN expression. Therefore, these compounds may act as an anti-metastatic agent in controlling breast cancer cells metastasis.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Compostos Heterocíclicos/farmacologia , Osteopontina/antagonistas & inibidores , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Estrutura Molecular , Osteopontina/biossíntese , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
19.
Chem Pharm Bull (Tokyo) ; 68(1): 64-69, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31708557

RESUMO

Invasive fungal disease constitutes a growing health problem and development of novel antifungal drugs with high potency and selectivity are in an urgent need. In this study, a novel series of triazole derivatives containing different ester skeleton were designed and synthesized. Microdilution broth method was used to investigate antifungal activity. Significant inhibitory activity of compounds 5c, 5d, 5e, 5f, 5m and 5n was evaluated against the Candida albicans (I), Candida albicans clinical isolate (II), Candida glabrata clinical isolate (I), and Candida glabrata (II) with minimum inhibitory concentrations (MIC80) values ranging from 2 to 16 µg/mL. Notably, compounds 5e and 5n showed the best inhibition against Candida albicans (II), Candida glabrata (I), and Candida glabrata (II) at the concentrations of 2 and 8 µg/mL, respectively. Molecular docking study revealed that the target compounds interacted with CYP51 mainly through hydrophobic and van der Waals interactions. The results indicated that these novel triazole derivatives could serve as promising leads for development of antifungal agents.


Assuntos
Antifúngicos/síntese química , Desenho de Fármacos , Simulação de Acoplamento Molecular , Triazóis/química , Antifúngicos/química , Antifúngicos/farmacologia , Sítios de Ligação , Candida/efeitos dos fármacos , Domínio Catalítico , Ésteres/química , Testes de Sensibilidade Microbiana , Eletricidade Estática , Esterol 14-Desmetilase/química , Esterol 14-Desmetilase/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacologia
20.
Chemistry ; 26(19): 4289-4296, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31834653

RESUMO

Cystobactamids belong to the group of arene-based oligoamides that effectively inhibit bacterial type IIa topoisomerases. Cystobactamid 861-2 is the most active member of these antibiotics. Most amide bonds present in the cystobactamids link benzoic acids with anilines and it was found that some of these amide bonds undergo chemical and enzymatic hydrolysis, especially the one linking ring C with ring D. This work reports on the chemical synthesis and biological evaluation of thirteen new cystobactamids that still contain the methoxyaspartate hinge. However, we exchanged selected amide bonds either by the urea or the triazole groups and modified ring A in the latter case. While hydrolytic stability could be improved with these structural substitutes, the high antibacterial potency of cystobactamid 861-2 could only be preserved in selected cases. This includes derivatives, in which the urea group is positioned between rings A and B and where the triazole is found between rings C and D.


Assuntos
Amidas/química , Compostos de Anilina/química , Antibacterianos/química , Bactérias/efeitos dos fármacos , Benzoatos/química , Triazóis/síntese química , Ureia/síntese química , Hidrólise , Estrutura Molecular , Triazóis/química , Ureia/química
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