Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 627
Filtrar
1.
Eur J Med Chem ; 186: 111867, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31757525

RESUMO

Using the principle of bioisosteric replacement, we present a structure-based design approach to obtain new Axl kinase inhibitors with significant activity at the kinase and cellular levels. Through a stepwise structure-activity relationships exploration, a series of 6,7-disubstituted quinoline derivatives, which contain 1,3,4-oxadiazol acetamide moiety as novel Linker, were ultimately synthesized with Axl as the primary target. Most of them exhibited moderate to excellent activity, with IC50 values ranging from 0.032 to 1.54 µM against the tested cell lines. Among them, the most promising compound 47e, as an Axl kinase inhibitor (IC50 = 10 nM), shows remarkable cytotoxicity against A549, HT-29, PC-3, MCF-7, H1975 and MDA-MB-231 cell lines. More importantly, 47e also shows a significant inhibitory effect on EGFR-TKI resistant NSCLC cell lines H1975/gefitinib. Meanwhile, this study provides a novel type of linker for Axl kinase inhibitors, namely 1,3,4-oxadiazol acetamide moiety, which is out of the scope of the "5- atoms role ".


Assuntos
Acetamidas/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Oxidiazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 185: 111866, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734023

RESUMO

Introducing pyrimidine bases, the basic components of nucleic acid, to P2 ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitors because of the carbonyl and amino groups promoting the formation of extensive hydrogen bonding interactions. In this work, we provide evidence that inhibitor 10e, with N-2-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide as the P2 ligand and a 4-methoxylphenylsulfonamide as the P2' ligand, displayed remarkable enzyme inhibitory and antiviral activity, with the IC50 2.53 nM in vitro and a promising inhibition ratio with 68% against wild-type HIV-1 in vivo, with low cytotoxicity. This inhibitor also exhibited appreciable antiviral activity against DRV-resistant HIV-1 variants, which was of great value for further study.


Assuntos
Acetamidas/farmacologia , Aminas/farmacologia , Fármacos Anti-HIV/farmacologia , Protease de HIV/metabolismo , HIV-1/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Aminas/síntese química , Aminas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , HIV-1/enzimologia , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
3.
Eur J Med Chem ; 186: 111861, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31734025

RESUMO

Respiratory syncytial virus (RSV) and influenza A virus (IAV) are two of the most common viruses that cause substantial morbidity and mortality in infants, young children, elderly persons, and immunocompromised individuals worldwide. Currently, there are no licensed vaccines or selective antiviral drugs against RSV infections and most IAV strains become resistant to clinical anti-influenza drug. Here, we described the discovery of a series of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamide as novel and potent RSV and IAV dual inhibitors. Thirty-five derivatives were designed, prepared, and evaluated for their anti-RSV and anti-IAV activities. Among the tested compounds, 14'c, 14'e, 14'f, 14'h, and 14'i exhibited excellent activity against both RSV and IAV, which showed low micromolar to sub-micromolar EC50 values. Further, compounds 14'c and 14'e were identified as the most promising dual inhibitors with lesser cytotoxicity than the clinical drug, ribavirin. These findings may contribute to the development of a lead compound for the treatment of RSV and/or IAV infections.


Assuntos
Acetamidas/farmacologia , Antivirais/farmacologia , Desenho de Fármacos , Influenzavirus A/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Acetamidas/síntese química , Acetamidas/química , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
4.
Eur J Med Chem ; 185: 111874, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31735575

RESUMO

The fragment hopping approach is widely applied in drug development. A series of diarylpyrimidines (DAPYs) were obtained by hopping the thioacetamide scaffold to novel human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitors (NNRTIs) to address the cytotoxicity issue of Etravirine and Rilpivirine. Although the new compounds (11a-l) in the first-round optimization possessed less potent anti-viral activity, they showed much lower cytotoxicity. Further optimization on the sulfur led to the sulfinylacetamide-DAPYs exhibiting improved anti-viral activity and a higher selectivity index especially toward the K103N mutant strain. The most potent compound 12a displayed EC50 values of 0.0249 µM against WT and 0.0104 µM against the K103N mutant strain, low cytotoxicity (CC50 > 221 µM) and a high selectivity index (SI WT > 8873, SI K103N > 21186). In addition, this compound showed a favorable in vitro microsomal stability across species. Computational study predicted the binding models of these potent compounds with HIV-1 reverse transcriptase thus providing further insights for new developments.


Assuntos
Acetamidas/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Acetamidas/síntese química , Acetamidas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
5.
Med Chem ; 16(3): 340-349, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31032753

RESUMO

OBJECTIVE: Several anti-tubulin agents were introduced for the cancer treatment so far. Despite successes in the treatment of cancer, these agents cause toxic side effects, including peripheral neuropathy. Comparing anti-tubulin agents, indibulin seemed to cause minimal peripheral neuropathy, but its poor aqueous solubility and other potential clinical problems have led to its remaining in a preclinical stage. METHODS: Herein, indibulin analogues were synthesized and evaluated for their in vitro anti-cancer activity using MTT assay (on the MCF-7, T47-D, MDA-MB231 and NIH-3T3 cell lines), annexin V/PI staining assay, cell cycle analysis, anti-tubulin assay and caspase 3/7 activation assay. RESULTS: One of the compounds, 4a, showed good anti-proliferative activity against MCF-7 cells (IC50: 7.5 µM) and low toxicity on a normal cell line (IC50 > 100 µM). All of the tested compounds showed lower cytotoxicity on normal cell line in comparison to reference compound, indibulin. In the annexin V/PI staining assay, induction of apoptosis in the MCF-7 cell line was observed. Cell cycle analysis illustrated an increasing proportion of cells in the sub-G-1 phase, consistent with an increasing proportion of apoptotic cells. No increase in G2/M cells was observed, consistent with the absence of anti-tubulin activity. A caspase 3/7 assay protocol showed that apoptosis induction by more potent compounds was due to activation of caspase 3. CONCLUSION: Newly synthesized compounds exerted acceptable anticancer activity and further investigation of current scaffold would be beneficial.


Assuntos
Acetamidas/farmacologia , Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Pirróis/farmacologia , Moduladores de Tubulina/farmacologia , Acetamidas/síntese química , Aminopiridinas/síntese química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Pirróis/síntese química , Moduladores de Tubulina/síntese química
6.
Eur J Med Chem ; 185: 111827, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732256

RESUMO

Human African trypanosomiasis (HAT), caused by the parasitic protozoa Trypanosoma brucei, is one of the fatal diseases in tropical areas and current medicines are insufficient. Thus, development of new drugs for HAT is urgently needed. Leucyl-tRNA synthetase (LeuRS), a recently clinically validated antimicrobial target, is an attractive target for development of antitrypanosomal drugs. In this work, we report a series of α-phenoxy-N-sulfonylphenyl acetamides as T. brucei LeuRS inhibitors. The most potent compound 28g showed an IC50 of 0.70 µM which was 250-fold more potent than the starting hit compound 1. The structure-activity relationship was also discussed. These acetamides provided a new scaffold and lead compounds for the further development of clinically useful antitrypanosomal agents.


Assuntos
Acetamidas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Leucina-tRNA Ligase/antagonistas & inibidores , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Acetamidas/síntese química , Acetamidas/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Leucina-tRNA Ligase/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma brucei brucei/enzimologia
7.
Biosci Biotechnol Biochem ; 84(1): 25-30, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31516064

RESUMO

The Japanese orange fly, Bactrocera tsuneonis, infests various citrus crops. While male pheromone components accumulated in the rectal glands are well characterized for Bactrocera, but information regarding the chemical factors involved in the life cycles of B. tsuneonis remains scarce. Herein, several volatile chemicals including a γ-decalactone, (3R,4R)-3-hydroxy-4-decanolide [(3R,4R)-HD], were identified as major components, along with acetamide and spiroketals as minor components in the rectal gland complexes of male B. tsuneonis flies. The lactone (3R,4R)-HD was also identified in female rectal gland complexes. The amount of this compound in mature males was significantly higher than those observed in females and immature males. The lactone (3R,4R)-HD was detected in flies fed with sucrose only, indicating that this lactone is not derived from dietary sources during adulthood, but biosynthesized in vivo. The predominant accumulation of (3R,4R)-HD in mature males also suggests a possible role in reproductive behavior.


Assuntos
Lactonas/química , Glândula de Sal/química , Tephritidae/fisiologia , Acetamidas/síntese química , Acetamidas/química , Animais , Cromatografia Gasosa , Citrus , Dieta , Feminino , Furanos/síntese química , Furanos/química , Japão , Lactonas/síntese química , Masculino , Espectrometria de Massas , Reprodução/fisiologia , Atrativos Sexuais/química , Comportamento Sexual Animal/fisiologia , Compostos de Espiro/síntese química , Compostos de Espiro/química , Sacarose
8.
Analyst ; 144(22): 6578-6585, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31596276

RESUMO

Low-molecular-weight (LMW) thiols are important small molecules that regulate or maintain redox homeostasis in physiological and pathological processes. Assessing the concentrations of LMW thiols in biological systems may provide valuable information regarding physiological processes and the early diagnosis of some diseases. Here, we developed a method to simultaneously determine the concentrations of multiple LWM thiols in single cells by chemical derivatization assisted liquid chromatography-mass spectrometry (LC-MS). In this method, we synthesized a pair of stable isotope reagents, N-(acridin-9-yl)-2-bromoacetamide (AYBA) and N-(1,2,3,4-[2H4]-acridin-9-yl)-2-bromoacetamide ([2H4]AYBA). AYBA was used to derivatize LWM thiols in human cervical cancer (HeLa) cells, while [2H4]AYBA was used to derivatize standard LWM thiols to prepare internal standards for the LC-MS method development. The proposed AYBA derivatization greatly enhanced the detection sensitivity of LWM thiols by LC-MS, and thereby achieved the simultaneous detection of multiple LWM thiols by LC-MS in ∼1000 HeLa cells. Finally, the developed method was successfully utilized for the quantitative analysis of multiple LWM thiols in a single HeLa cell and the content changes of LWM thiols in a single HeLa cell before and after oxidative stress treatment. Accordingly, six LMW thiols were detected, including cysteamine, cysteine, glutathione, homocysteine, hydrogen sulfide, and pantetheine.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Compostos de Sulfidrila/análise , Espectrometria de Massas em Tandem/métodos , Acetamidas/síntese química , Acetamidas/química , Acridinas/síntese química , Acridinas/química , Células HeLa , Humanos , Indicadores e Reagentes/síntese química , Indicadores e Reagentes/química , Limite de Detecção , Peso Molecular , Compostos de Sulfidrila/química
9.
Eur J Med Chem ; 183: 111699, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31561045

RESUMO

The recent burst of explorations on heat shock protein 90 (HSP90) in virus research supports its emergence as a promising target to overcome the drawbacks of current antiviral therapeutic regimen. In continuation of our efforts towards the discovery of novel anti-retroviral molecules, we designed, synthesized fifteen novels 2-isoxazol-3-yl-acetamide based compounds (2a-o) followed by analysis of their anti-HIV activity and cytotoxicity studies. 2a-b, 2e, 2j, and 2l-m were found to be active with inhibitory potentials >80% at their highest non-cytotoxic concentration (HNC). Further characterization of anti-HIV activity of these molecules suggests that 2l has ∼3.5 fold better therapeutic index than AUY922, the second generation HSP90 inhibitor. The anti-HIV activity of 2l is a cell type, virus isolate and viral load independent phenomena. Interestingly, 2l does not significantly modulate viral enzymes like Reverse Transcriptase (RT), Integrase (IN) and Protease (PR) as compared to their known inhibitors in a cell free in vitro assay system at its HNC. Further, 2l mediated inhibition of HSP90 attenuates HIV-1 LTR driven gene expression. Taken together, structural rationale, modeling studies and characterization of biological activities suggest that this novel scaffold can attenuate HIV-1 replication significantly within the host and thus opens a new horizon to develop novel anti-HIV therapeutic candidates.


Assuntos
Acetamidas/farmacologia , Androstenóis/farmacologia , Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , HIV-1/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/química , Androstenóis/síntese química , Androstenóis/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , HIV-1/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
10.
Bioorg Chem ; 92: 103221, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31499261

RESUMO

A series of ten N-(3-(1H-tetrazole-5-yl)phenyl)acetamide derivatives (NM-07 to NM-16) designed from a lead molecule identified previously in our laboratory were synthesized and evaluated for protein tyrosine phosphatase 1B (PTP1B) inhibitory activity. Among the synthesized molecules, NM-14, a 5-Cl substituted benzothiazole analogue elicited significant PTP1B inhibition with an IC50 of 1.88 µM against reference standard suramin (IC50 ≥ 10 µM). Furthermore, this molecule also showed good in vivo antidiabetic activity which was comparable to that of standard antidiabetic drugs metformin and glimepiride. Overall, the results of the study clearly reveal that the reported tetrazole derivatives especially NM-14 are valuable prototypes for the development of novel non-carboxylic inhibitors of PTP1B with antidiabetic potential.


Assuntos
Acetamidas/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Tetrazóis/farmacologia , Acetamidas/síntese química , Acetamidas/química , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Ratos , Estreptozocina , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
11.
Bioorg Chem ; 91: 103153, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31382057

RESUMO

New sulfonamide-hydrazone derivatives (3a-3n) were synthesized to evaluate their inhibitory effects on purified human carbonic anhydrase (hCA) I and II. The inhibition profiles of the synthesized compounds on hCA I-II isoenzyme were investigated by comparing their IC50 and Ki values. Acetazolamide (5-acetamido-1,3,4-thiadiazole-2-sulfonamide, AZA) has also been used as a standard inhibitor. The compound 3e demonstrated the best hCA I inhibitory effect with a Ki value of 0.1676 ±â€¯0.017 µM. Besides, the compound 3m showed the best hCA II inhibitory effect with a Ki value of 0.2880 ±â€¯0.080 µM. Cytotoxicity of the compounds 3e and 3m toward NIH/3T3 mouse embryonic fibroblast cell line was observed and the compounds were found to be non-cytotoxic. Molecular docking studies were performed to investigate the interaction types between active compounds and hCA enzymes. Pharmacokinetic profiles of compounds were assessed by theoretical ADME predictions. As a result of this study a novel and potent class of CA inhibitors were identified with a good activity potential.


Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Animais , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Células NIH 3T3 , Relação Estrutura-Atividade
12.
Org Biomol Chem ; 17(33): 7694-7705, 2019 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-31328213

RESUMO

Membranous organelles are major endogenous sources of reactive oxygen and nitrogen species. When present at high levels, these species can cause macromolecular damage and disease. To better detect and scavenge free radical forms of the reactive species at their sources, we investigated whether nitrone spin traps could be selectively targeted to intracellular membranes using a bioorthogonal imaging approach. Electron paramagnetic resonance imaging demonstrated that the novel cyclic nitrone 5-dodecylcarbamoyl-5-N-dodecylacetamide-1-pyroline-N-oxide (diC12PO) could be used to target the nitrone moiety to liposomes composed of phosphatidyl choline. To test localization with authentic membranes in living cells, fluorophores were introduced via strain-promoted alkyne-nitrone cycloaddition (SPANC). Two fluorophore-conjugated alkynes were investigated: hexynamide-fluoresceine (HYA-FL) and dibenzylcyclooctyne-PEG4-5/6-sulforhodamine B (DBCO-Rhod). Computational and mass spectrometry experiments confirmed the cycloadduct formation of DBCO-Rhod (but not HYA-FL) with diC12PO in cell-free solution. Confocal microscopy of bovine aortic endothelial cells treated sequentially with diC12PO and DBCO-Rhod demonstrated clear localization of fluorescence with intracellular membranes. These results indicate that targeting of nitrone spin traps to cellular membranes is feasible, and that a bioorthogonal approach can aid the interrogation of their intracellular compartmentalization properties.


Assuntos
Acetamidas/química , Teoria da Densidade Funcional , Fluorescência , Imagem Óptica , Acetamidas/síntese química , Animais , Bovinos , Células Cultivadas , Espectroscopia de Ressonância de Spin Eletrônica , Estrutura Molecular
13.
Eur J Med Chem ; 180: 134-142, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31302446

RESUMO

In order to expand the arsenal of biologically active substances of anticonvulsive action by the interaction of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetic acid with the corresponding amines in the presence of N,N'-carbonyldiimidazole in the dioxane medium, a systematic series of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)-N-R-acetamides was obtained. A novel approach to synthesis of the key intermediate - 2-(2,4-dioxo-1,4-dihydro-quinazolin-3(2H)-yl)acetic acid was developed. The structure and purity of the resulting substances was confirmed by elemental analysis, 1H NMR, 13C NMR spectroscopy and LC/MS. Based on the results of docking studies using SCIGRESS software, selected compounds with the best affinity for anticonvulsant protein biomes (PDB codes: 4COF, 3F8E and 1 EOU) are promising for experimental studies of anticonvulsant activity. A comparative analysis of the results of molecular docking and in vivo results suggests that there is a positive correlation between scoring protein inhibition and experimental data. Pharmacological studies have revealed the leader compound 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)-N-[(2,4-dichlorophenyl)methyl]acet-amide, which improved all the experimental convulsive syndrome rates in mice without motor coordination impairment and may be recommended for further research. The lowest values of the scoring function of the ligand-peptide interaction are obtained for the synthesized compound and сarbonic anhydrase II (gene name CA2) (PDB code 1 EOU), so its inhibition is proposed by us as the most probable mechanism of the anticonvulsive effect of the leader compound.


Assuntos
Acetamidas/farmacologia , Anticonvulsivantes/farmacologia , Quinolinas/farmacologia , Convulsões/tratamento farmacológico , Acetamidas/síntese química , Acetamidas/química , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
14.
Bioorg Med Chem ; 27(18): 4069-4080, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31353076

RESUMO

Translocator protein (TSPO) expression is closely related with neuroinflammation and neuronal damage which might cause several central nervous system diseases. Herein, a series of TSPO ligands (11a-c and 13a-d) with a 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide structure were prepared and evaluated via an in vitro binding assay. Most of the novel ligands exhibited a nano-molar affinity for TSPO, which was better than that of DPA-714. Particularly, 11a exhibited a subnano-molar TSPO binding affinity with suitable lipophilicity for in vivo brain studies. After radiolabeling with fluorine-18, [18F]11a was used for a dynamic positron emission tomography (PET) study in a rat LPS-induced neuroinflammation model; the inflammatory lesion was clearly visualized with a superior target-to-background ratio compared to [18F]DPA-714. An immunohistochemical examination of the dissected brains confirmed that the uptake location of [18F]11a in the PET study was consistent with a positively activated microglia region. This study proved that [18F]11a could be employed as a potential PET tracer for detecting neuroinflammation and could give possibility for diagnosis of other diseases, such as cancers related with TSPO expression.


Assuntos
Acetamidas/síntese química , Ligantes , Pirimidinas/síntese química , Humanos
15.
ChemMedChem ; 14(14): 1329-1335, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31188540

RESUMO

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 µm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.


Assuntos
Acetamidas/farmacologia , Antimaláricos/farmacologia , Acetamidas/síntese química , Acetamidas/farmacocinética , Animais , Antimaláricos/síntese química , Antimaláricos/farmacocinética , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium berghei/efeitos dos fármacos , Plasmodium cynomolgi/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade
16.
Bioorg Chem ; 88: 102956, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31054432

RESUMO

Multitargeted therapy is considered a successful approach to cancer treatment. The development of small molecule multikinase inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. A library of N-alkyl-2-[(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio]acetamide derivatives 5-18 was designed and synthesized. The synthesized compounds were screened for cytotoxic activity against MDA-MB-231 breast cancer cell line and showed IC50 in the range of 0.34-149.10 µM. The inhibition percentage of VEGFR-2 was measured for all the compounds and found to be in the range of 90.09-20.44%. The promising compounds 8, 12, 13, 16 and 17 were selected to measure their possible multikinase inhibitory activity against VEGFR-2 and EGFR. IC50 of the promising compounds were in the range of 247-793 nM for VEGFR-2 in reference to sunitinib (IC50 320 nM), and 369-725 nM for EGFR in reference to erlotinib (IC50 568 nM). Compounds 12 and 13 showed the most potent activity towards VEGFR-2 & EGFR, respectively. Measuring the cytotoxicity of 12 and 13 against MCF-10 normal breast cell line indicates their relative safety to normal breast cells (IC50 37 & 97 µM, respectively). As radiotherapy is considered the primary treatment for some types of solid tumors, the radiosensitizing ability of 12 and 13 was measured by subjecting the MDA-MB-231 cells to a single dose of 8 Gy of gamma radiation. IC50 of 12 and 13 decreased from 1.91 & 0.51 µM to 0.79 & 0.43 µM, respectively. Molecular docking was performed to gain insights into the ligand-binding interactions of 12 inside VEGFR-2 and EGFR binding sites in comparison to their co-crystallized ligands.


Assuntos
Acetamidas/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/terapia , Radiossensibilizantes/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Raios gama , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Radiossensibilizantes/síntese química , Radiossensibilizantes/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
17.
Arch Pharm (Weinheim) ; 352(7): e1800310, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31125474

RESUMO

Sixteen novel coumarin-based compounds are reported as potent acetylcholinesterase (AChE) inhibitors. The most active compound in this series, 5a (IC50 0.04 ± 0.01 µM), noncompetitively inhibited AChE with a higher potency than tacrine and galantamine. Compounds 5d, 5j, and 5 m showed a moderate antilipid peroxidation activity. The compounds showed cytotoxicity in the same range as the standard drugs in HEK-293 cells. Molecular docking demonstrated that 5a acted as a dual binding site inhibitor. The coumarin moiety occupied the peripheral anionic site and showed π-π interaction with Trp278. The tertiary amino group displayed significant cation-π interaction with Phe329. The aromatic group showed π-π interaction with Trp83 at the catalytic anionic site. The long chain of methylene lay along the gorge interacting with Phe330 via hydrophobic interaction. Molecular docking was applied to postulate the selectivity toward AChE of 5a in comparison with donepezil and tacrine. Structural insights into the selectivity of the coumarin derivatives toward huAChE were explored by molecular docking and 3D QSAR and molecular dynamics simulation for 20 ns. ADMET analysis suggested that the 2-(2-oxo-2H-chromen-4-yl)acetamides showed a good pharmacokinetic profile and no hepatotoxicity. These coumarin derivatives showed high potential for further development as anti-Alzheimer agents.


Assuntos
Acetamidas/farmacologia , Inibidores da Colinesterase/farmacologia , Acetamidas/síntese química , Acetamidas/química , Acetilcolinesterase/metabolismo , Sítios de Ligação/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Cinética , Ácido Linoleico/antagonistas & inibidores , Ácido Linoleico/metabolismo , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade
18.
Bioorg Med Chem ; 27(12): 2572-2578, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30910475

RESUMO

A series of novel 2-hydroxyphenyl substituted aminoacetamides was designed by molecular hybridization of the aminoacetamide scaffold and 2-hydroxyphenyl motif. The target compounds were synthesized and their fungicidal activities were evaluated. Some of the target compounds showed excellent antifungal activities against S. sclerotiorum and P. capsici. Significantly, compounds 5e displayed the most potent activity against S. sclerotiorum with EC50 = 2.89 µg/mL, which was lower than that of commercial chlorothalonil. The systematic studies provided strong confidence that the hydroxyl group and the carbonyl group are crucial for the fungicidal activity. Molecular docking studies suggest that SDH enzyme could be one of the potential action targets of our compounds.


Assuntos
Acetamidas/química , Antifúngicos/síntese química , Desenho de Fármacos , Simulação de Acoplamento Molecular , Acetamidas/síntese química , Acetamidas/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Ascomicetos/efeitos dos fármacos , Sítios de Ligação , Proteínas Fúngicas/antagonistas & inibidores , Proteínas Fúngicas/metabolismo , Relação Estrutura-Atividade , Succinato Desidrogenase/antagonistas & inibidores , Succinato Desidrogenase/metabolismo
19.
Bioorg Chem ; 86: 459-472, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30772647

RESUMO

The present research was designed for the selective synthesis of novel bi-heterocyclic acetamides, 9a-n, and their tyrosinase inhibition to overwhelm the problem of melanogenesis. The structures of newly synthesized compounds were confirmed by spectral techniques such as 1H NMR, 13C NMR, and EI-MS along with elemental analysis. The inhibitory effects of these bi-heterocyclic acetamides (9a-n) were evaluated against tyrosinase and all these molecules were recognized as potent inhibitors relative to the standard used. The Kinetics mechanism was analyzed by Lineweaver-Burk plots which explored that compound, 9h, inhibited tyrosinase competitively by forming an enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.0027 µM. The computational study was coherent with the experimental records and these ligands exhibited good binding energy values (kcal/mol). The hemolytic analysis revealed their mild cytotoxicity towards red blood cell membranes and hence, these molecules can be pondered as nontoxic medicinal scaffolds for skin pigmentation and related disorders.


Assuntos
Acetamidas/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/farmacologia , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/química , Agaricales/enzimologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Cinética , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Relação Estrutura-Atividade
20.
Bioorg Med Chem Lett ; 29(6): 791-796, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30718161

RESUMO

The present study describes the discovery and characterization of a series of 5-aryl-2H-tetrazol-3-ylacetamides as G protein-gated inwardly-rectifying potassium (GIRK) channels activators. Working from an initial hit discovered during a high-throughput screening campaign, we identified a tetrazole scaffold that shifts away from the previously reported urea-based scaffolds while remaining effective GIRK1/2 channel activators. In addition, we evaluated the compounds in Tier 1 DMPK assays and have identified a (3-methyl-1H-pyrazol-1-yl)tetrahydrothiophene-1,1-dioxide head group that imparts interesting and unexpected microsomal stability compared to previously-reported pyrazole head groups.


Assuntos
Acetamidas/farmacologia , Descoberta de Drogas , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/agonistas , Pirazóis/farmacologia , Tetrazóis/farmacologia , Acetamidas/síntese química , Acetamidas/química , Animais , Células HEK293 , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...