Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.747
Filtrar
1.
J Med Chem ; 63(9): 4837-4848, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32293182

RESUMO

The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Tiofenos/farmacologia , Animais , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacocinética , Linhagem Celular Tumoral , Ensaios Enzimáticos , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Mutação , Ligação Proteica , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacocinética , Tiofenos/metabolismo , Tiofenos/farmacocinética
2.
Eur J Med Chem ; 194: 112255, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32244098

RESUMO

Human immunodeficiency virus type 1 (HIV-1) is a public health problem that affects over 38 million people worldwide. Although there are highly active antiretroviral therapies, emergence of antiviral resistant strains is a problem which leads to almost a million death annually. Thus, the development of new drugs is necessary. The viral enzyme reverse transcriptase (RT) represents a validated therapeutic target. Because the oxoquinolinic scaffold has substantial biological activities, including antiretroviral, a new series of 4-oxoquinoline ribonucleoside derivatives obtained by molecular hybridization were studied here. All synthesized compounds were tested against human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT), and 9a and 9d displayed the highest antiviral activities, with IC50 values of 1.4 and 1.6 µM, respectively. These compounds were less cytotoxic than AZT and showed CC50 values of 1486 and 1394 µM, respectively. Molecular docking studies showed that the most active compounds bound to the allosteric site of the enzyme, suggesting a low susceptibility to the development of antiviral resistance. In silico pharmacokinetic and toxicological evaluations reinforced the potential of the active compounds as anti-HIV candidates for further exploration. Overall, this work showed that compounds 9a and 9d are promising scaffold for future anti-HIV-1 RT drug design.


Assuntos
4-Quinolonas/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Ribonucleosídeos/farmacologia , 4-Quinolonas/síntese química , 4-Quinolonas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Transcriptase Reversa do HIV/metabolismo , HIV-1/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Ribonucleosídeos/síntese química , Ribonucleosídeos/química , Relação Estrutura-Atividade
3.
Eur J Med Chem ; 193: 112237, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32200201

RESUMO

HIV-1 RT has been considered as one of the most important targets for the development of anti-HIV-1 drugs for their well-solved three-dimensional structure and well-known mechanism of action. In this study, with HIV-1 RT as target, we used miniaturized parallel click chemistry synthesis via CuAAC reaction followed by in situ biological screening to discover novel potent HIV-1 NNRTIs. A 156 triazole-containing inhibitor library was assembled in microtiter plates and in millimolar scale. The enzyme inhibition screening results showed that 22 compounds exhibited improved inhibitory activity. Anti-HIV-1 activity results demonstrated that A3N19 effected the most potent activity against HIV-1 IIIB (EC50 = 3.28 nM) and mutant strain RES056 (EC50 = 481 nM). The molecular simulation analysis suggested that the hydrogen bonding interactions of A3N19 with the main chain of Lys101 and Lys104 was responsible for its potency. Overall, the results indicated the in situ click chemistry-based strategy was rational and might be amenable for the future discovery of more potent HIV-1 NNRTIs.


Assuntos
Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Triazóis/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Sítios de Ligação/efeitos dos fármacos , Química Click , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
4.
J Med Chem ; 63(11): 5625-5663, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32031378

RESUMO

The use of an acetylene (ethynyl) group in medicinal chemistry coincides with the launch of the Journal of Medicinal Chemistry in 1959. Since then, the acetylene group has been broadly exploited in drug discovery and development. As a result, it has become recognized as a privileged structural feature for targeting a wide range of therapeutic target proteins, including MAO, tyrosine kinases, BACE1, steroid receptors, mGlu5 receptors, FFA1/GPR40, and HIV-1 RT. Furthermore, a terminal alkyne functionality is frequently introduced in chemical biology probes as a click handle to identify molecular targets and to assess target engagement. This Perspective is divided into three parts encompassing: (1) the physicochemical properties of the ethynyl group, (2) the advantages and disadvantages of the ethynyl group in medicinal chemistry, and (3) the impact of the ethynyl group on chemical biology approaches.


Assuntos
Acetileno/química , Química Farmacêutica , Alquinos/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Química Click , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Meia-Vida , Humanos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Inibidores da Transcriptase Reversa/química
5.
Eur J Med Chem ; 189: 112071, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32004936

RESUMO

From an aqueous decoction of the traditional Chinese medicine "ban lan gen" (the Isatis indigotica root), an antiviral natural product CI - 39 was isolated as an NNRTI (non-nucleoside reverse transcriptase inhibitor) (EC50 = 3.40 µM). Its novel structure was determined as methyl (1-methoxy-1H-indol-3-yl)acetamidobenzoate by spectroscopic data and confirmed by single crystal X-ray diffraction. Through synthesis and structure-activity relationship (SAR) investigation of CI - 39 and 57 new derivatives (24 with EC50 values of 0.06-8.55 µM), two optimized derivatives 10f and 10i (EC50: 0.06 µM and 0.06 µM) having activity comparable to that of NVP (EC50 = 0.03 µM) were obtained. Further evaluation verified that 10f and 10i were RT DNA polymerase inhibitors and exhibited better activities and drug resistance folds compared to NVP against seven NNRTI-resistant strains carrying different mutations. Especially, 10i (EC50 = 0.43 µM) was more active to the L100I/K103N double-mutant strain as compared to both NVP (EC50 = 0.76 µM) and EFV (EC50 = 1.08 µM). The molecular docking demonstrated a possible binding pattern between 10i and RT and revealed activity mechanism of 10i against the NNRTI-resistant strains.


Assuntos
Descoberta de Drogas , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Indóis/síntese química , Indóis/farmacologia , Isatis/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Farmacorresistência Viral , Células HEK293 , Infecções por HIV/virologia , HIV-1/enzimologia , Humanos , Ácidos Indolacéticos/química , Estrutura Molecular , Mutação , Extratos Vegetais/farmacologia , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 188: 111987, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31893549

RESUMO

Infection by human immunodeficiency virus still represents a continuous serious concern and a global threat to human health. Due to appearance of multi-resistant virus strains and the serious adverse side effects of the antiretroviral therapy administered, there is an urgent need for the development of new treatment agents, more active, less toxic and with increased tolerability to mutations. Quinoxaline derivatives are an emergent class of heterocyclic compounds with a wide spectrum of biological activities and therapeutic applications. These types of compounds have also shown high potency in the inhibition of HIV reverse transcriptase and HIV replication in cell culture. For these reasons we propose, in this work, the design, synthesis and biological evaluation of quinoxaline derivatives targeting HIV reverse transcriptase enzyme. For this, we first carried out a structure-based development of target-specific compound virtual chemical library of quinoxaline derivatives. The rational construction of the virtual chemical library was based on previously assigned pharmacophore features. This library was processed by a virtual screening protocol employing molecular docking and 3D-QSAR. Twenty-five quinoxaline compounds were selected for synthesis in the basis of their docking and 3D-QSAR scores and chemical synthetic simplicity. They were evaluated as inhibitors of the recombinant wild-type reverse transcriptase enzyme. Finally, the anti-HIV activity and cytotoxicity of the synthesized quinoxaline compounds with highest reverse transcriptase inhibitory capabilities was evaluated. This simple screening strategy led to the discovery of two selective and potent quinoxaline reverse transcriptase inhibitors with high selectivity index.


Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Quinoxalinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinoxalinas/síntese química , Quinoxalinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 186: 111900, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31771827

RESUMO

Since dual inhibitors may yield lower toxicity and reduce the likelihood of drug resistance, as well as inhibitors of HIV-1 PR and RT constitute the core of chemotherapy for AIDS treatment, we herein designed and synthesized new coumarin derivatives characterized by various linkers that exhibited excellent potency against PR and a weak inhibition of RT. Among which, compounds 6f and 7c inhibited PR with IC50 values of 15.5 and 62.1 nM, respectively, and weakly affected also RT with IC50 values of 241.8 and 188.7 µM, respectively, showing the possibility in the future of developing dual HIV-1 PR/RT inhibitors. Creative stimulation for further research of more potent dual HIV-1 inhibitors was got according to the molecular docking studies.


Assuntos
Fármacos Anti-HIV/farmacologia , Cumarínicos/farmacologia , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
8.
Eur J Med Chem ; 186: 111864, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31767136

RESUMO

A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC50 values ranging from 1.5 to 0.0064 µM. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC50 = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC50 = 0.077 µM), Y181C (EC50 = 0.11 µM), E138K (EC50 = 0.057 µM), and moderate activity against double mutants RES056 (EC50 = 8.7 µM). Moreover, the structure-activity relationships (SARs) were summarized, and the molecular docking was performed to investigate the binding mode of IPAPYs and HIV-1 reverse transcriptase.


Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV/efeitos dos fármacos , Indazóis/farmacologia , Piperidinas/farmacologia , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Humanos , Indazóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Pirimidinas/síntese química , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
9.
Antiviral Res ; 174: 104671, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31812637

RESUMO

The management of Human Immunodeficiency Virus type 1 (HIV-1) infection requires life-long treatment that is associated with chronic toxicity and possible selection of drug-resistant strains. A new opportunity for drug intervention is offered by antivirals that act as allosteric inhibitors targeting two viral functions (dual inhibitors). In this work, we investigated the effects of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derivatives on both HIV-1 Integrase (IN) and Reverse Transcriptase associated Ribonuclease H (RNase H) activities. Among the tested compounds, the dihydroxyindole-carboxamide 5 was able to inhibit in the low micromolar range (1-18 µM) multiple functions of IN, including functional IN-IN interactions, IN-LEDGF/p75 binding and IN catalytic activity. Docking and site-directed mutagenesis studies have suggested that compound 5 binds to a previously described HIV-1 IN allosteric pocket. These observations indicate that 5 is structurally and mechanistically distinct from the published allosteric HIV-1 IN inhibitors. Moreover, compound 5 also inhibited HIV-1 RNase H function, classifying this molecule as a dual HIV-1 IN and RNase H inhibitor able to impair the HIV-1 virus replication in cell culture. Overall, we identified a new scaffold as a suitable platform for the development of novel dual HIV-1 inhibitors.


Assuntos
Ácidos Carboxílicos/farmacologia , Inibidores de Integrase de HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Ácidos Carboxílicos/química , Linhagem Celular , Descoberta de Drogas , Infecções por HIV/virologia , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
10.
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
11.
Commun Biol ; 2: 469, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31872074

RESUMO

Emtricitabine (FTC) and lamivudine (3TC), containing an oxathiolane ring with unnatural (-)-stereochemistry, are widely used nucleoside reverse transcriptase inhibitors (NRTIs) in anti-HIV therapy. Treatment with FTC or 3TC primarily selects for the HIV-1 RT M184V/I resistance mutations. Here we provide a comprehensive kinetic and structural basis for inhibiting HIV-1 RT by (-)-FTC-TP and (-)-3TC-TP and drug resistance by M184V. (-)-FTC-TP and (-)-3TC-TP have higher binding affinities (1/K d) for wild-type RT but slower incorporation rates than dCTP. HIV-1 RT ternary crystal structures with (-)-FTC-TP and (-)-3TC-TP corroborate kinetic results demonstrating that their oxathiolane sulfur orients toward the DNA primer 3'-terminus and their triphosphate exists in two different binding conformations. M184V RT displays greater (>200-fold) K d for the L-nucleotides and moderately higher (>9-fold) K d for the D-isomers compared to dCTP. The M184V RT structure illustrates how the mutation repositions the oxathiolane of (-)-FTC-TP and shifts its triphosphate into a non-productive conformation.


Assuntos
Farmacorresistência Viral , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , Nucleotídeos/química , Inibidores da Transcriptase Reversa/química , Alelos , Substituição de Aminoácidos , Bases de Dados Genéticas , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Mutação , Nucleotídeos/farmacologia , Inibidores da Transcriptase Reversa/farmacologia
12.
J Agric Food Chem ; 67(43): 11942-11947, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31622090

RESUMO

Manilkara zapota, usually known as Sapodilla, is a fairly slow-growing evergreen tropical tree which belongs to the genus Manilkara (Sapotaceae), indigenous to Central America, southern Mexico, and the Caribbean. The ripe fruits of M. zapota have been widely consumed as an uniquely flavored tropical fruit and verified to hold a variety of health benefits. In order to investigate the potential health-promoting chemical compositions from the fruits of M. zapota cultivated in Hainan Island of China, a systematic and in-depth phytochemical study on this fruit was accordingly implemented. In our current study, three new prenylated coumarins, manizapotins A-C (1-3), together with seven known prenylated coumarins (4-10), were separated from the fruits of M. zapota. The chemical structures of new prenylated coumarins 1-3 were unambiguously established by means of comprehensive spectroscopic analyses, and the known compounds 4-10 were determined by comparing their experimental spectral data with those described data in the literature. This is the first time to discover prenylated coumarins occurring in M. zapota. The potential anti-inflammatory effects and anti-HIV (human immunodeficiency virus) activities of all these separated prenylated coumarins were assessed. Prenylated coumarins 1-10 dispalyed remarkable inhibitory effects against nitric oxide production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells with the IC50 values equivalent to that of hydrocortisone in vitro. Meanwhile, prenylated coumarins 1-10 exhibited pronounced anti-HIV-1 reverse transcriptase activities with the EC50 values in range of 0.12-8.69 µM. These results suggest that appropriate and reasonable consumption of the fruits of M. zapota might assist people to prevent and reduce the occurrence of inflammatory diseases together with the infection of HIV. Furthermore, the discovery of these prenylated coumarins from the fruits of M. zapota holding pronounced anti-inflammatory effects along with anti-HIV activities could be of great significance to the research and development of new natural anti-inflammatory and anti-HIV agents.


Assuntos
Fármacos Anti-HIV/química , Anti-Inflamatórios/química , Cumarínicos/química , Manilkara/química , Extratos Vegetais/química , Animais , Fármacos Anti-HIV/isolamento & purificação , Fármacos Anti-HIV/farmacologia , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , China , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Frutas/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Estrutura Molecular , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Prenilação , Células RAW 264.7
13.
J Med Chem ; 62(21): 9996-10002, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31603676

RESUMO

HIV-1 reverse transcriptase (RT) is an essential enzyme, targeting half of approved anti-AIDS drugs. While nucleoside RT inhibitors (NRTIs) are DNA chain terminators, the nucleotide-competing RT inhibitor (NcRTI) INDOPY-1 blocks dNTP binding to RT. Lack of structural information hindered INDOPY-1 improvement. Here we report the HIV-1 RT/DNA/INDOPY-1 crystal structure, revealing a unique mode of inhibitor binding at the polymerase active site without involving catalytic metal ions. The structure may enable new strategies for developing NcRTIs.


Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Indóis/química , Indóis/farmacologia , Nitrilos/química , Nitrilos/farmacologia , Piridonas/química , Piridonas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Transcriptase Reversa do HIV/química , Modelos Moleculares , Conformação Proteica
14.
Molecules ; 24(21)2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31652782

RESUMO

BACKGROUND: HIV is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), an infectious disease with increasing incidence worldwide. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in the treatment of AIDS. Although, many compounds are already being used as anti-HIV drugs, research for the development of new inhibitors continues as the virus develops resistant strains. METHODS: The best features of available NNRTIs were taken into account for the design of novel inhibitors. PASS (Prediction of activity spectra for substances) prediction program and molecular docking studies for the selection of designed compounds were used for the synthesis. Compounds were synthesized using conventional and microwave irradiation methods and HIV RT inhibitory action was evaluated by colorimetric photometric immunoassay. RESULTS: The evaluation of HIV-1 RT inhibitory activity revealed that seven compounds have significantly lower ΙC50 values than nevirapine (0.3 µΜ). It was observed that the activity of compounds depends not only on the nature of substituent and it position in benzothiazole ring but also on the nature and position of substituents in benzene ring. CONCLUSION: Twenty four of the tested compounds exhibited inhibitory action lower than 4 µΜ. Seven of them showed better activity than nevirapine, while three of the compounds exhibited IC50 values lower than 5 nM. Two compounds 9 and 10 exhibited very good inhibitory activity with IC50 1 nM.


Assuntos
Síndrome de Imunodeficiência Adquirida , Fármacos Anti-HIV , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Simulação de Acoplamento Molecular , Inibidores da Transcriptase Reversa , Tiazóis , Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida/enzimologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Transcriptase Reversa do HIV/metabolismo , Humanos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia
15.
Antiviral Res ; 171: 104613, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31550450

RESUMO

Ribonucleases H (RNases H) are endonucleolytic enzymes, evolutionarily related to retroviral integrases, DNA transposases, resolvases and numerous nucleases. RNases H cleave RNA in RNA/DNA hybrids and their activity plays an important role in the replication of prokaryotic and eukaryotic genomes, as well as in the replication of reverse-transcribing viruses. During reverse transcription, the RNase H activity of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) degrades the viral genomic RNA to facilitate the synthesis of viral double-stranded DNA. HIV and HBV reverse transcriptases contain DNA polymerase and RNase H domains that act in a coordinated manner to produce double-stranded viral DNA. Although RNase H inhibitors have not been developed into licensed drugs, recent progress has led to the identification of a number of small molecules with inhibitory activity at low micromolar or even nanomolar concentrations. These compounds can be classified into metal-chelating active site inhibitors and allosteric inhibitors. Among them, α-hydroxytropolones, N-hydroxyisoquinolinediones and N-hydroxypyridinediones represent chemotypes active against both HIV and HBV RNases H. In this review we summarize recent developments in the field including the identification of novel RNase H inhibitors, compounds with dual inhibitory activity, broad specificity and efforts to decrease their toxicity.


Assuntos
Antivirais/farmacologia , HIV/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Ribonuclease H/antagonistas & inibidores , Substituição de Aminoácidos , Antivirais/química , Domínio Catalítico , Ativação Enzimática , HIV/enzimologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/química , Vírus da Hepatite B/enzimologia , Humanos , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Ribonuclease H/química , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
16.
SAR QSAR Environ Res ; 30(10): 697-714, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31542957

RESUMO

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) remain the most promising anti-AIDS agents that target the HIV-1 reverse transcriptase enzyme (RT). However, the efficiency of approved NNRTI drugs has decreased by the appearance of drug-resistant viruses and side effects upon long-term usage. Thus, there is an urgent need for developing new, potent NNRTIs with broad spectrum against HIV-1 virus and with improved properties. In this study, a series of thiazolidinone derivatives was designed based on a butterfly mimicking scaffold consisting of a substituted benzothiazolyl moiety connected with a substituted phenyl ring via a thiazolidinone moiety. The most promising derivatives were selected using molecular docking analysis and PASS prediction program, synthesized and evaluated for HIV-1 RT inhibition. Five out of fifteen tested compounds exhibited good inhibitory action. It was observed that the presence of Cl or CN substituents at the position 6 of the benzothiazole ring in combination with two fluoro atoms at the ortho-positions or a hydrogen acceptor substituent at the 4-position of the phenyl ring are favourable for the HIV RT inhibitory activity.


Assuntos
Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Simulação de Acoplamento Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 183: 111714, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557609

RESUMO

In our continuing efforts to find novel anti-HIV compounds, we have synthesized sixteen novel pyrazolo[4,3-c]pyridin-4-one derivatives. All the synthesized compounds were screened for anti-HIV activity against HIV-1VB59 (R5, subtype C). Compounds 12a-12c and 12e were also tested against HIV-1UG070 (X4, subtype D) in TZM-bl cell line. Compound 12c was found to be the most active against HIV-1VB59 and HIV-1UG070 with IC50 value 3.67 µM and 2.79 µM, and therapeutic indices 185 and 243, respectively. The lead compound 12c inhibited the HIV-192/BR/018 (R5, subtype B) and drug resistant isolates, NIH-119 (X4/R5, subtype B) and NARI-DR (R5, subtype C) effectively. The activity of the lead compound was further confirmed by PBMC assays. The molecular docking data showed that the most active compound 12c binds in the non-nucleoside binding pocket of HIV-1 reverse transcriptase, which was confirmed by the ToA assay. Thus the study indicated that 12c may be considered as a NNRTI and further explored as a lead for anti-HIV drug development.


Assuntos
Fármacos Anti-HIV/síntese química , Transcriptase Reversa do HIV/antagonistas & inibidores , Pirazóis/síntese química , Piridinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Fármacos Anti-HIV/farmacologia , Barreira Hematoencefálica/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Pirazóis/farmacologia , Piridinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
18.
Eur J Med Chem ; 182: 111619, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31434039

RESUMO

For more in-depth exploration of the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing different chiral N-substituted pyrrolidine, azetidine or substituted sulfonamide groups at indole-2-carboxamide were designed and synthesized as potent HIV NNRTIs by structure-guided scaffold morphing approach. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC50 values ranging from 0.0043 µM to 4.42 µM. Notably, compound 27 (EC50 = 4.7 nM, SI = 5183) and 33 (EC50 = 4.3 nM, SI = 7083) were identified as the most potent compounds, which were more active than nevirapine, lamivudine and efavirenz, and also reached the same order of etravirine. Furthermore, some compounds maintained excellent activity against various single HIV-1 mutants (L100I, K103 N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC50 values in low-micromolar concentration ranges. Notably, 34 displayed outstanding potency against F227L/V106A (EC50 = 0.094 µM), and also showed exceptional activity against E138K (EC50 = 0.014 µM), L100I (EC50 = 0.011 µM) and K103 N (EC50 = 0.025 µM). Additionally, most compounds showed markedly reduced cytotoxicity (CC50) compared to lead compounds, especially 36 (CC50 > 234.91 µM, SI > 18727) and 37 (CC50 > 252.49 µM, SI > 15152). Preliminary SARs and molecular modeling studies were also discussed in detail, which may provide valuable insights for further optimization.


Assuntos
Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Indóis/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Sulfonas/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , HIV-1/genética , Humanos , Indóis/síntese química , Indóis/química , Masculino , Camundongos , Camundongos Endogâmicos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química
19.
Eur J Med Chem ; 182: 111603, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421633

RESUMO

Conformational restriction is a promising strategy in the development of DAPY-type non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, eighteen thiophene-biphenyl-DAPY derivatives were designed and synthesized as potent HIV-1 NNRTIs in which halogen and methyl groups were introduced to explore the conformationally constrained effects. Molecular docking and dynamic simulation analysis indicated that substituents on different positions of the biphenyl ring induced different dihedral angles and binding conformations, further explaining their anti-viral activities. The 2'-fluoro and 3'-chloro substitutions could form electrostatic or halogen-bonding interactions with adjacent residues of the RT enzyme. The 2'-methyl group contributed to enlarge the dihedral angle of biphenyl ring and was positioned to a space-filling hydrophobic pocket. Notably, compounds 22 and 23 with two methyl groups exhibited potent biological activity against WT HIV-1-infected MT-4 cells (EC50 = 14 and 17 nM, respectively) and RT enzyme (EC50 = 27 and 42 nM, respectively). In particular, 23 exhibited much lower cytotoxicity (CC50 = 264.19 µM) and higher selectivity index (SI = 18,564) than etravirine. Taken together, a rational conformational model for further design of DAPYs is proposed, providing a new guidance for the development of NNRTIs.


Assuntos
Fármacos Anti-HIV/farmacologia , Compostos de Bifenilo/farmacologia , Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Tiofenos/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Compostos de Bifenilo/química , Linhagem Celular , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Tiofenos/química
20.
J Chem Inf Model ; 59(9): 3635-3644, 2019 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-31453694

RESUMO

A lot of high quality data on the biological activity of chemical compounds are required throughout the whole drug discovery process: from development of computational models of the structure-activity relationship to experimental testing of lead compounds and their validation in clinics. Currently, a large amount of such data is available from databases, scientific publications, and patents. Biological data are characterized by incompleteness, uncertainty, and low reproducibility. Despite the existence of free and commercially available databases of biological activities of compounds, they usually lack unambiguous information about peculiarities of biological assays. On the other hand, scientific papers are the primary source of new data disclosed to the scientific community for the first time. In this study, we have developed and validated a data-mining approach for extraction of text fragments containing description of bioassays. We have used this approach to evaluate compounds and their biological activity reported in scientific publications. We have found that categorization of papers into relevant and irrelevant may be performed based on the machine-learning analysis of the abstracts. Text fragments extracted from the full texts of publications allow their further partitioning into several classes according to the peculiarities of bioassays. We demonstrate the applicability of our approach to the comparison of the endpoint values of biological activity and cytotoxicity of reference compounds.


Assuntos
Mineração de Dados/métodos , Descoberta de Drogas/métodos , Bases de Dados Factuais , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , PubMed , Inibidores da Transcriptase Reversa/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA