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1.
RSC Adv ; 14(13): 9020-9031, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38500630

RESUMO

Integrase plays an important role in the life cycle of HIV-1, and integrase strand transfer inhibitors (INSTIs) can effectively impair the viral replication. However, drug resistance mutations have been confirmed to decrease the efficacy of INSTI during the antiviral therapy. Herein, indole-2-carboxylic acid (1) was found to inhibit the strand transfer of integrase, and the indole nucleus of compound 1 was observed to chelate with two Mg2+ ions within the active site of integrase. Through optimization of compound 1, a series of indole-2-carboxylic acid derivatives were designed and synthesized, and compound 17a was proved to markedly inhibit the effect of integrase, with IC50 value of 3.11 µM. Binding mode analysis of 17a demonstrated that the introduced C6 halogenated benzene ring could effectively bind with the viral DNA (dC20) through π-π stacking interaction. These results indicated that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.

2.
Molecules ; 28(24)2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38138510

RESUMO

As an important antiviral target, HIV-1 integrase plays a key role in the viral life cycle, and five integrase strand transfer inhibitors (INSTIs) have been approved for the treatment of HIV-1 infections so far. However, similar to other clinically used antiviral drugs, resistance-causing mutations have appeared, which have impaired the efficacy of INSTIs. In the current study, to identify novel integrase inhibitors, a set of molecular docking-based virtual screenings were performed, and indole-2-carboxylic acid was developed as a potent INSTI scaffold. Indole-2-carboxylic acid derivative 3 was proved to effectively inhibit the strand transfer of HIV-1 integrase, and binding conformation analysis showed that the indole core and C2 carboxyl group obviously chelated the two Mg2+ ions within the active site of integrase. Further structural optimizations on compound 3 provided the derivative 20a, which markedly increased the integrase inhibitory effect, with an IC50 value of 0.13 µM. Binding mode analysis revealed that the introduction of a long branch on C3 of the indole core improved the interaction with the hydrophobic cavity near the active site of integrase, indicating that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.


Assuntos
Infecções por HIV , Inibidores de Integrase de HIV , Integrase de HIV , HIV-1 , Humanos , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/química , Simulação de Acoplamento Molecular , Integrase de HIV/metabolismo , Infecções por HIV/tratamento farmacológico , Indóis/farmacologia , Indóis/uso terapêutico , Domínio Catalítico , Farmacorresistência Viral , Mutação
3.
Eur J Med Chem ; 222: 113573, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34091209

RESUMO

A series of 2,4-diamino pyrimidine (DAPY) derivatives were designed, synthesized, and evaluated as inhibitors of focal adhesion kinase (FAK) with antitumor and anti-angiogenesis activities. Most compounds effectively suppressed the enzymatic activities of FAK, and the IC50s of 11b and 12f were 2.75 and 1.87 nM, respectively. 11b and 12f exhibited strong antiproliferative effects against seven human cancer cells, with IC50 values against two FAK-overexpressing pancreatic cancer cells (PANC-1 and BxPC-3) of 0.98 µM, 0.55 µM, and 0.11 µM, 0.15 µM, respectively. Moreover, 11b and 12f obviously suppressed the colony formation, migration, and invasion of PANC-1 cells in a dose-dependent manner. Meanwhile, these two compounds could induce the apoptosis of PANC-1 cells and arrest the cell cycle in G2/M phase according to the flow cytometry assay. Western blot revealed that 11b and 12f effectively inhibited the FAK/PI3K/Akt signal pathway and significantly decreased the expression of cyclin D1 and Bcl-2. In addition, compounds 11b and 12f potently inhibited the antiproliferative of HUVECs and obviously altered the cell morphology. 11b and 12f also significantly inhibited the migration, tube formation of HUVECs and severely impaired the angiogenesis in the zebrafish model. Overall, these results revealed the potential of compounds 11b and 12f as promising candidates for further preclinical studies.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Quinase 1 de Adesão Focal/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Quinase 1 de Adesão Focal/metabolismo , Humanos , Estrutura Molecular , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 129: 310-324, 2017 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-28235704

RESUMO

Viral infectivity factor (Vif) is protective against APOBEC3G (A3G)-mediated viral cDNA hypermutations, and development of molecules that inhibit Vif mediated A3G degradation is a novel strategy for blocking HIV-1 replication. Through optimizations of the central ring of N-(2-methoxyphenyl)-2-((4-nitrophenyl)thio)benzamide (RN-18), we found a potent compound 12c with EC50 value of 1.54 µM, enhancing the antiviral activity more than 150-fold compared with RN-18 in nonpermissive H9 cells. 12c protected A3G from degradation by inhibiting Vif function. Besides, 12c suppressed different HIV-1 clinical strains (HIV-1KM018, HIV-1TC-1 and HIV-1WAN) and drug-resistant strains (NRTI, NNRTI, PI, and FI) with relatively high activities. Amidation of 12c with glycine gave a prodrug 13a, improving the water solubility about 2600-fold compared with 12c. Moreover, 13a inhibited the virus replication efficiently with an EC50 value of 0.228 µM. These results suggested that the prodrug 13a is a promising candidate agent for the treatment of AIDS.


Assuntos
Fármacos Anti-HIV/síntese química , Benzamidas/farmacologia , Produtos do Gene vif do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Desaminase APOBEC-3G/metabolismo , Fármacos Anti-HIV/farmacologia , Benzamidas/síntese química , Linhagem Celular , Farmacorresistência Viral , Humanos , Simulação de Acoplamento Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Replicação Viral/efeitos dos fármacos
5.
Yi Chuan ; 25(1): 14-6, 2003 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-15639811

RESUMO

In this paper, authors re-calculated the data of ZHENG Lian-bin et al. in 1996 (Hand-clasping, Arm-folding and Handedness) by log-linear model. The results demonstrated both agreement and disagreement with the published data. The results show as follows: (1) There are no relations between hand-clasping and populations, sex; (2) There are obvious correlation between arm-folding and sex, but no relation between arm-folding and populations; (3) There are three factorial effects among handedness, populations and sex; (4) In our study, we found association between handedness and hand-clasping, arm-folding and non-association between hand-clasping and arm-folding.

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