Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.239
Filtrar
1.
Molecules ; 25(19)2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33036293

RESUMO

A novel series of some hydrazones bearing thiazole moiety were generated via solvent-drop grinding of thiazole carbohydrazide 2 with various carbonyl compounds. Also, dehydrative-cyclocondensation of 2 with active methylene compounds or anhydrides gave the respective pyarzole or pyrazine derivatives. The structures of the newly synthesized compounds were established based on spectroscopic evidences and their alternative syntheses. Additionally, the anti-viral activity of all the products was tested against SARS-CoV-2 main protease (Mpro) using molecular docking combined with molecular dynamics simulation (MDS). The average binding affinities of the compounds 3a, 3b, and 3c (-8.1 ± 0.33 kcal/mol, -8.0 ± 0.35 kcal/mol, and -8.2 ± 0.21 kcal/mol, respectively) are better than that of the positive control Nelfinavir (-6.9 ± 0.51 kcal/mol). This shows the possibility of these three compounds to effectively bind to SARS-CoV-2 Mpro and hence, contradict the virus lifecycle.


Assuntos
Antivirais/síntese química , Betacoronavirus/enzimologia , Hidrazonas/síntese química , Inibidores de Proteases/síntese química , Pirazinas/síntese química , Pirazóis/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/farmacologia , Betacoronavirus/química , Betacoronavirus/efeitos dos fármacos , Sítios de Ligação , Infecções por Coronavirus/tratamento farmacológico , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Descoberta de Drogas , Humanos , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/farmacologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Pirazinas/farmacologia , Pirazóis/farmacologia , Termodinâmica , Interface Usuário-Computador , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
2.
Eur J Med Chem ; 206: 112702, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798789

RESUMO

SARS-CoV-2 3C-like protease is the main protease of SARS-CoV-2 and has been considered as one of the key targets for drug discovery against COVID-19. We identified several N-substituted isatin compounds as potent SARS-CoV-2 3C-like protease inhibitors. The three most potent compounds inhibit SARS-CoV-2 3C-like protease with IC50's of 45 nM, 47 nM and 53 nM, respectively. Our study indicates that N-substituted isatin compounds have the potential to be developed as broad-spectrum anti-coronavirus drugs.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Isatina/uso terapêutico , Inibidores de Proteases/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/farmacologia , Cisteína Endopeptidases , Humanos , Isatina/análogos & derivados , Isatina/síntese química , Modelos Moleculares , Simulação de Acoplamento Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade
3.
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
4.
J Med Chem ; 63(9): 4562-4578, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: covidwho-613484

RESUMO

The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.


Assuntos
Antivirais/farmacologia , Coronavirus/efeitos dos fármacos , Enterovirus/efeitos dos fármacos , Lactamas/farmacologia , Peptidomiméticos/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Chlorocebus aethiops , Coronavirus/enzimologia , Cristalografia por Raios X , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Desenho de Fármacos , Enterovirus/enzimologia , Humanos , Lactamas/síntese química , Lactamas/metabolismo , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Ligação Proteica , Células Vero , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/química , Proteínas Virais/metabolismo
5.
J Med Chem ; 63(9): 4562-4578, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: covidwho-326341

RESUMO

The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.


Assuntos
Antivirais/farmacologia , Coronavirus/efeitos dos fármacos , Enterovirus/efeitos dos fármacos , Lactamas/farmacologia , Peptidomiméticos/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Chlorocebus aethiops , Coronavirus/enzimologia , Cristalografia por Raios X , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Desenho de Fármacos , Enterovirus/enzimologia , Humanos , Lactamas/síntese química , Lactamas/metabolismo , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Ligação Proteica , Células Vero , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/química , Proteínas Virais/metabolismo
6.
J Med Chem ; 63(9): 4562-4578, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32045235

RESUMO

The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.


Assuntos
Antivirais/farmacologia , Coronavirus/efeitos dos fármacos , Enterovirus/efeitos dos fármacos , Lactamas/farmacologia , Peptidomiméticos/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Chlorocebus aethiops , Coronavirus/enzimologia , Cristalografia por Raios X , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Desenho de Fármacos , Enterovirus/enzimologia , Humanos , Lactamas/síntese química , Lactamas/metabolismo , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Ligação Proteica , Células Vero , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/química , Proteínas Virais/metabolismo
7.
J Med Chem ; 63(4): 1576-1596, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32003991

RESUMO

Human cathepsin D (CatD), a pepsin-family aspartic protease, plays an important role in tumor progression and metastasis. Here, we report the development of biomimetic inhibitors of CatD as novel tools for regulation of this therapeutic target. We designed a macrocyclic scaffold to mimic the spatial conformation of the minimal pseudo-dipeptide binding motif of pepstatin A, a microbial oligopeptide inhibitor, in the CatD active site. A library of more than 30 macrocyclic peptidomimetic inhibitors was employed for scaffold optimization, mapping of subsite interactions, and profiling of inhibitor selectivity. Furthermore, we solved high-resolution crystal structures of three macrocyclic inhibitors with low nanomolar or subnanomolar potency in complex with CatD and determined their binding mode using quantum chemical calculations. The study provides a new structural template and functional profile that can be exploited for design of potential chemotherapeutics that specifically inhibit CatD and related aspartic proteases.


Assuntos
Catepsina D/antagonistas & inibidores , Catepsina D/metabolismo , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Sítios de Ligação , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Materiais Biomiméticos/metabolismo , Materiais Biomiméticos/toxicidade , Células CACO-2 , Catepsina D/química , Ensaios Enzimáticos , Humanos , Cinética , Estrutura Molecular , Pepstatinas/química , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/toxicidade , Inibidores de Proteases/síntese química , Inibidores de Proteases/toxicidade , Ligação Proteica , Relação Estrutura-Atividade
8.
Chemistry ; 26(1): 49-88, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31483909

RESUMO

Drugs in the chemical space beyond the rule of 5 (bRo5) can modulate targets with difficult binding sites while retaining cell permeability and oral absorption. Reviewing the syntheses of bRo5 drugs approved since 1990 highlights synthetic chemistry's contribution to drug discovery in this space. Initially, bRo5 drugs were mainly natural products and semi-synthetic derivatives. Later, peptidomimetics and de novo designed compounds, that include up to seven chiral centres and macrocyclic rings became dominant. These drugs are prepared by total synthesis, sometimes by routes of more than 25 steps with stereocentres originating from the chiral pool, or being installed by chiral induction or enzymatic resolution. Interestingly, ring-closing metathesis proved to be the method of choice for macrocyclisation in hepatitis C virus protease inhibitors. We conclude that structural simplification, planning of synthetic routes regarding incorporation of stereocentres and macrocyclisation, as well as incorporation of structural knowledge and consideration of chameleonic properties in design, should facilitate drug discovery in bRo5 space.


Assuntos
Descoberta de Drogas , Preparações Farmacêuticas/síntese química , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Hepacivirus/enzimologia , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/metabolismo , Peptidomiméticos , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Ribossomos/química , Ribossomos/metabolismo , Proteínas Virais/química , Proteínas Virais/metabolismo
9.
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
10.
J Med Chem ; 63(1): 103-121, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31841350

RESUMO

ERAP1 is an endoplasmic reticulum-resident zinc aminopeptidase that plays an important role in the immune system by trimming peptides for loading onto major histocompatibility complex proteins. Here, we report discovery of the first inhibitors selective for ERAP1 over its paralogues ERAP2 and IRAP. Compound 1 (N-(N-(2-(1H-indol-3-yl)ethyl)carbamimidoyl)-2,5-difluorobenzenesulfonamide) and compound 2 (1-(1-(4-acetylpiperazine-1-carbonyl)cyclohexyl)-3-(p-tolyl)urea) are competitive inhibitors of ERAP1 aminopeptidase activity. Compound 3 (4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid) allosterically activates ERAP1's hydrolysis of fluorogenic and chromogenic amino acid substrates but competitively inhibits its activity toward a nonamer peptide representative of physiological substrates. Compounds 2 and 3 inhibit antigen presentation in a cellular assay. Compound 3 displays higher potency for an ERAP1 variant associated with increased risk of autoimmune disease. These inhibitors provide mechanistic insights into the determinants of specificity for ERAP1, ERAP2, and IRAP and offer a new therapeutic approach of specifically inhibiting ERAP1 activity in vivo.


Assuntos
Aminopeptidases/antagonistas & inibidores , Compostos de Fenilureia/farmacologia , Inibidores de Proteases/farmacologia , Sulfonamidas/farmacologia , Triptaminas/farmacologia , Aminopeptidases/genética , Aminopeptidases/metabolismo , Domínio Catalítico/genética , Descoberta de Drogas , Células HeLa , Humanos , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/metabolismo , Polimorfismo de Nucleotídeo Único , Inibidores de Proteases/síntese química , Inibidores de Proteases/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo , Triptaminas/síntese química , Triptaminas/metabolismo
11.
Eur J Med Chem ; 184: 111747, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31604164

RESUMO

The present study reports on evaluation of anti-HCV activity and QSAR of certain arylidenethiazolidinone derivatives as potential inhibitors of HCV-NS5B polymerase. The pursued compounds involving, 5-aryliden-3-arylacetamidothiazolidin-2,4-diones 4-6(a-f), 5-arylidine-2-(N-arylacetamido)-iminothiazolidin-4-one (10) and their rigid counterparts 5-arylidinethiazolotriazines 13-15(a-f), were synthesized and their structures confirmed by spectral and elemental analyses. The results of NS5B polymerase inhibition assay revealed compound 4e, as the most active inhibitor (IC50 = 0.035 µM), which is four folds greater than that of the reference agent, VCH-759, (IC50 = 0.14 µM). Meanwhile, compounds 4b, 4c, 5a, and 5c, and 13b, 14e and 15c displayed equipotency to 2 folds higher activity than VCH-759 (IC50 values: 0.085, 0.14, 0.14, 0.10, 0.12, 0.09 and 0.07 µM, respectively). Assessment of the anti-HCV activity (GT1a) using human hepatoma cell line (Huh-7.5) illustrates superior activity of 4e (EC50 = 3.80 µM) relative to VCH-759 (EC50 = 5.29 µM). Cytotoxicity evaluation on, Transformed normal cell lines (Human Liver Epithelial-2, THLE-2 and Proximal Tubular Epithelial, RPTEC/TERT1), demonstrate enhanced safety profile of 4e (CC50 = 102.77, 161.37 µM, respectively) compared to VCH-759 (CC50 = 61.83, 81.28 µM, respectively). Molecular docking of the synthesized derivatives to NS5B polymerase allosteric site (PDB: 2HWH) showed similar binding modes to that of the co-crystallized ligand. Moreover, QSAR models were established for the studied thiazolidinones and thiazolotriazines to investigate the molecular characteristics contributing to the observed NS5B polymerase inhibition activity. The obtained results inspire further investigations of thiazolidinones and thiazolotriazine aiming at affording more potent, safe and orally active non-nucleoside NS5B polymerase inhibitors as anti-HCV drug candidates.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Relação Quantitativa Estrutura-Atividade , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hepacivirus/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia , Tiazolidinas/síntese química , Tiazolidinas/química , Tiazolidinas/farmacologia , Triazinas/síntese química , Triazinas/química , Triazinas/farmacologia , Proteínas não Estruturais Virais/metabolismo
12.
Adipocyte ; 8(1): 240-253, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31264515

RESUMO

Adipose tissue expansion involves angiogenesis to remodel its capillary network. The enzymemethionine aminopeptidase 2(MetAP2) promotes angiogenesis.MetAP2 inhibitors suppress angiogenesis and have potential anti-obesity effect. However, impairment in adipose tissue expansion is also linked with impaired glycemic control.This study investigated the effect of BL6, a MetAP2 inhibitor, on adipogenesis and glucose disposal.To test effect on angiogenesis, Human Umbilical Vein Endothelial Cells(HUVECs) were treated with BL6 for 24h to determine tube formation. Further, to test effect on adipogenesis and glucose disposal,3T3-L1 pre-adipocytes were treated with BL6(0 µM, 20µM, 50 µM or 100µM) during differentiation. Differentiated cells were stained with Oil Red O for determining lipid accumulation, and glucose uptake assay. Protein levels and RNA expression for key genes involved in the adipogenic cascade were determined.BL6 treatment of HUVECs dose dependently blocked angiogenesis. During differentiation of pre-adipocytes, 50µM and 100µM BL6 significantly reduced lipid accumulation. Treatment with 100µM BL6 significantly decreased expression of adipogenic genes. Interestingly, BL6 treatment dose dependently increased glucose uptake by 3T3-L1 cells.MetAP2 inhibitor blocks angiogenesis, attenuates adipogenesis, yet increases cellular glucose uptake. Collectively this proof of concept study supports a possible role for MetAP2 inhibitor BL6, as a putative anti-obesity therapeutic agent.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia , Glucose/metabolismo , Metionil Aminopeptidases/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Células 3T3 , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Metabolismo dos Lipídeos , Camundongos , Neovascularização Fisiológica , Inibidores de Proteases/síntese química
13.
Org Biomol Chem ; 17(30): 7124-7127, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31313793

RESUMO

Proteolysis mediated by ClpXP is a crucial cellular process linked to bacterial pathogenesis. The development of specific inhibitors has largely focused on ClpP. However, this focus was challenged by a recent finding showing that conformational control by ClpX leads to a rejection of ClpP binders. Thus, we here follow up on a hit molecule from a high throughput screen performed against the whole ClpXP complex and demonstrate that stable inhibition with high potency is possible. Further investigations revealed that the small molecule binds to ClpP without affecting its activity. Likewise, the molecule does not inhibit ClpX and retains the overall oligomeric state of ClpXP upon binding. Structure activity relationship studies confirmed structural constraints in all three parts of the molecule suggesting binding into a defined stereospecific pocket. Overall, the inhibition of ClpXP without affecting the individual components represents a novel mechanism with perspectives for further optimization for in situ applications.


Assuntos
Endopeptidase Clp/antagonistas & inibidores , Endopeptidase Clp/química , Hidantoínas/farmacologia , Inibidores de Proteases/farmacologia , Endopeptidase Clp/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Hidantoínas/síntese química , Hidantoínas/química , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Domínios Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Carbohydr Polym ; 217: 232-239, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31079681

RESUMO

Heparan sulfate (HS) and heparin, representative members of the glycosaminoglycans, possess distinct biological functions in terms of their specific interactions with hundreds of binding proteins. However, the structural properties of HS and heparin are complex due to their variable repeating motifs, different chain lengths and sulfation patterns. A concise chemoenzymatic approach has been developed to obtain well-defined low molecular weight (LMW) HS analogues. Pasteurella multocida heparosan synthase-2 (PmHS2) was utilized to fabricate the HS backbones with controllable chain lengths ranging from 14mer to 26mer. Moreover, regioselective and overall sulfation were conducted by chemical approach. The persulfated HS analogues exhibited more potent beta-site amyloid precursor protein (APP)-cleaving enzyme-1 (BACE-1) inhibitory activity than heparin and enoxaparin, and enhanced BACE-1 inhibitions were also found with the increasing molecular size of the HS analogues. This approach supplies the promising LMW HS analogues for the potential development of novel anti-Alzheimer's drugs.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Heparitina Sulfato/análogos & derivados , Inibidores de Proteases/química , Sequência de Carboidratos , Glicosiltransferases/química , Heparitina Sulfato/síntese química , Humanos , Peso Molecular , Pasteurella multocida/enzimologia , Inibidores de Proteases/síntese química
15.
Eur J Med Chem ; 168: 447-460, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30844608

RESUMO

A new series of 4-phenylcoumarin derivatives was synthesized starting from (2-oxo-4-phenyl-2H-chromen-7-yloxy) acetic acid hydrazide 3. Evaluation of the target compounds for their antiviral activity against hepatitis A virus revealed that the ethylthiosemicarbazide derivative 7b was the most potent virucidal agent (IC50 = 3.1 µg/ml, TI = 83). The Schiff's bases 14c and 14b demonstrated the highest virustatic effects against viral adsorption and replication, respectively (14c; IC50 = 8.5 µg/ml, TI = 88 and 14b; IC50 = 10.7 µg/ml, TI = 91). Furthermore, compounds 7b, 14b and 14c were tested against HAV 3C protease and showed significant inhibition effects (Ki = 1.903, 0.104 and 0.217 µM, respectively). The remarkable inhibitory effect expressed by the three target compounds against HAV 3C protease prompted us to expand our research on HRV 3C protease, a structurally related enzyme of the same family, and interestingly, the three target compounds displayed significant inhibitory effect against HRV 3C protease (IC50 = 16.10, 4.13 and 6.30 µM, respectively). Moreover, the active compounds 7b, 14b and 14c were docked within the pocket site of HAV 3C protease (PDB code: 2HAL) illustrating a strong H-profile with the key amino acids Gly170 and Cys172 similar to the co-crystallized ligand. Furthermore, 3D-pharmacophore and quantitative structure activity relationship (QSAR) models were generated to explore the structural requirements for the observed antiviral activity.


Assuntos
Antivirais/farmacologia , Cumarínicos/farmacologia , Desenho de Fármacos , Vírus da Hepatite A/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Proteínas Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Cumarínicos/síntese química , Cumarínicos/química , Cisteína Endopeptidases/metabolismo , Relação Dose-Resposta a Droga , Vírus da Hepatite A/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Relação Quantitativa Estrutura-Atividade , Proteínas Virais/metabolismo
16.
Bioorg Med Chem ; 27(6): 1034-1042, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30773420

RESUMO

Selective proteinase inhibitors have demonstrated utility in the investigation of cartilage degeneration mechanisms and may have clinical use in the management of osteoarthritis. The cysteine protease cathepsin K (CatK) is an attractive target for arthritis therapy. Here we report the synthesis of two cathepsin K inhibitors (CKIs): racemic azanitrile derivatives CKI-E and CKI-F, which have better inhibition properties on CatK than the commercial inhibitor odanacatib (ODN). Their IC50 values and inhibition constants (Ki) have been determined in vitro. Inhibitors demonstrate differential selectivity for CatK over cathepsin B, L and S in vitro, with Ki amounting to 1.14 and 7.21 nM respectively. We analyzed the effect of these racemic inhibitors on viability in different cell types. The human osteoblast-like cell line MG63, MOVAS cells (a murine vascular smooth muscle cell line) or murine primary chondrocytes, were treated either with CKI-E or with CKI-F, which were not toxic at doses of up to 5 µM. Primary chondrocytes subjected to several passages were used as a model of phenotypic loss of articular chondrocytes, occurring in osteoarthritic cartilage. The efficiency of CKIs regarding CatK inhibition and their specificity over other proteases were validated in primary chondrocytes subjected to several passages. Racemic CKI-E and CKI-F at 0.1 and 1 µM significantly inhibited CatK activity in dedifferentiated chondrocytes, even better than the commercial CatK inhibitor ODN. The enzymatic activity of other proteases such as matrix metalloproteinases or aggrecanases were not affected. Taken together, these findings support the possibility to design CatK inhibitors for preventing cartilage degradation in different pathologies.


Assuntos
Catepsina K/antagonistas & inibidores , Desdiferenciação Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Nitrilos/farmacologia , Inibidores de Proteases/farmacologia , Animais , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Catepsina K/metabolismo , Linhagem Celular , Células Cultivadas , Condrócitos/citologia , Condrócitos/enzimologia , Desenho de Fármacos , Humanos , Camundongos , Nitrilos/síntese química , Nitrilos/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/química
17.
Bioorg Med Chem ; 27(6): 978-990, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30737134

RESUMO

Aminopeptidase N (APN) has been proved to be deeply associated with cancer angiogenesis, metastasis and invasion. Therefore, APN gains increasing attention as a promising anti-tumor target. In the current study, we report the design, synthesis, biological evaluation and structure-activity relationship of one new series of leucine ureido derivatives containing the 1,2,3-triazole moiety. Among them, compound 31f was identified as the best APN inhibitor with IC50 value being two orders of magnitude lower than that of the positive control bestatin. Compound 31f possessed selective cytotoxicity to several tumor cell lines over the normal cell line human umbilical vein endothelial cells (HUVECs). Notably, when combined with 5-fluorouracil (5-Fu), 31f exhibited synergistic anti-proliferation effect against several tumor cell lines. At the same concentration, 31f exhibited much better anti-angiogenesis activities than bestatin in the HUVECs capillary tube formation assay and the rat thoracic aorta rings test. In the in vitro anti-invasion assay, 31f also exhibited superior potency over bestatin. Moreover, considerable in vivo antitumor potencies of 31f alone or in combination with 5-Fu were observed without significant toxic signs in a mouse heptoma H22 tumor transplant model.


Assuntos
Antígenos CD13/antagonistas & inibidores , Leucina/análogos & derivados , Leucina/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antígenos CD13/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Química Click , Desenho de Fármacos , Humanos , Leucina/síntese química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteases/síntese química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologia
18.
J Pept Sci ; 25(4): e3154, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30734395

RESUMO

Cathepsin D (Cath D) is overexpressed and hypersecreted by malignant tumors and involved in the progress of tumor invasion, proliferation, metastasis, and apoptosis. Cath D has been considered as a potential target to treat cancer. Our previous studies revealed that tasiamide B derivatives TB-9 and TB-11 exhibited high potent inhibition against Cath D and other aspartic proteases, but their molecular weights are still high, and the role of each residue is unknown yet. Based on this, two series of tasiamide B derivatives have been designed, synthesized, and evaluated for their inhibitory activity against Cath D/Cath E/BACE1. Enzymatic assays revealed that the target compound 1 with lower molecule weight showed good inhibitory activity against Cath D with IC50 of 3.29 nM and satisfactory selectivity over Cath E (72-fold) and BACE1 (295-fold), which could be a valuable template for the design of highly potent and selective Cath D inhibitors.


Assuntos
Catepsina D/antagonistas & inibidores , Desenho de Fármacos , Oligopeptídeos/farmacologia , Inibidores de Proteases/farmacologia , Catepsina D/metabolismo , Relação Dose-Resposta a Droga , Estrutura Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Relação Estrutura-Atividade
19.
PLoS One ; 14(1): e0210869, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30677071

RESUMO

Dengue virus Type 2 (DENV-2) is predominant serotype causing major dengue epidemics. There are a number of studies carried out to find its effective antiviral, however to date, there is still no molecule either from peptide or small molecules released as a drug. The present study aims to identify small molecules inhibitor from National Cancer Institute database through virtual screening. One of the hits, D0713 (IC50 = 62 µM) bearing thioguanine scaffold was derivatised into 21 compounds and evaluated for DENV-2 NS2B/NS3 protease inhibitory activity. Compounds 18 and 21 demonstrated the most potent activity with IC50 of 0.38 µM and 16 µM, respectively. Molecular dynamics and MM/PBSA free energy of binding calculation were conducted to study the interaction mechanism of these compounds with the protease. The free energy of binding of 18 calculated by MM/PBSA is -16.10 kcal/mol compared to the known inhibitor, panduratin A (-11.27 kcal/mol), which corroborates well with the experimental observation. Results from molecular dynamics simulations also showed that both 18 and 21 bind in the active site and stabilised by the formation of hydrogen bonds with Asn174.


Assuntos
Antivirais/química , Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Antivirais/síntese química , Domínio Catalítico , Chalconas/química , Chalconas/farmacologia , Vírus da Dengue/classificação , Vírus da Dengue/enzimologia , Estabilidade de Medicamentos , Humanos , Ligação de Hidrogênio , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/síntese química , Serina Endopeptidases/efeitos dos fármacos , Tioguanina/química , Interface Usuário-Computador , Proteínas não Estruturais Virais/antagonistas & inibidores
20.
Chem Biol Drug Des ; 93(5): 926-933, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30667164

RESUMO

A series of novel aminopyrimidine and diaminopyrimidine derivatives were designed and optimized to improve their potency and permeability relative to lead compound 1 (IC50  = 37.4 µM), which was discovered in a previous virtual screening. The potency of the optimized compound, 13g (IC50  = 1.4 µM), was 26-fold greater than that of 1 based on a fluorescence resonance energy transfer assay, and a parallel artificial membrane permeability assay suggested that it could pass through the blood-brain barrier. Additionally, several compounds containing selenium showed good potencies and deserve further investigation as anti-Alzheimer's agents.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Proteases/síntese química , Pirimidinas/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Permeabilidade/efeitos dos fármacos , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA