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1.
Eur J Med Chem ; 190: 112085, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-32066010

RESUMO

HIV-1 CA is involved in different stages of the viral replication cycle, performing essential roles in both early (uncoating, reverse transcription, nuclear import, integration) and late events (assembly). Recent efforts have demonstrated HIV-1 CA protein as a prospective therapeutic target for the development of new antivirals. The most extensively studied CA inhibitor, PF-3450074 (PF-74, discovered by Pfizer), that targets an inter-protomer pocket within the CA hexamer. Herein we reported the design, synthesis, and biological evaluation of a series of 4-phenyl-1H-1,2,3-triazole phenylalanine derivatives as HIV-1 CA inhibitors based on PF-74 scaffold. Most of the analogues demonstrated potent antiviral activities, among them, the anti-HIV-1 activity of 6a-9 (EC50 = 3.13 µM) is particularly prominent. The SPR binding assay of selected compounds (6a-9, 6a-10, 5b) suggested direct and effective interaction with recombinant CA proteins. The mechanism of action studies also demonstrated that 6a-9 displays the effects in both the early and late stages of HIV-1 replication. To explore the potential binding mode of the here presented analogues, 6a-9 was analyzed by MD simulation to predict its binding to the active site of HIV-1 CA monomer. In conclusion, this novel series of antivirals can serve as a starting point for the development of a new generation of HIV-1 treatment regimen and highlights the potentiality of CA as a therapeutic target.

2.
Org Lett ; 22(1): 11-15, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31680527

RESUMO

Three novel gnidimacrin related macrocyclic daphnanes (GMDs), daphneodorins A-C (2-4), were isolated from Daphne odora Thunb., together with gnidimacrin (1). Their structures were established by extensive physicochemical and spectroscopic analyses. Compounds 2 and 3 potently inhibited HIV-1 replication at subnanomolar concentrations (EC50 0.16 and 0.25 nM, respectively). Compounds 2-4 represent a novel type of GMDs that are highly oxygenated on the macrocyclic ring, suggesting good potential for anti-HIV drug development by further chemical modification.

3.
J Nat Prod ; 83(1): 134-141, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31860304

RESUMO

Daphnane diterpenes with a 5/7/6-tricyclic ring system exhibit potent anti-HIV activity but are found in low abundance as plant natural products. In this study, an effective approach based on mass spectrometric fragmentation pathways was conducted to specifically recognize and isolate anti-HIV compounds of this type from Daphne genkwa. Briefly, the fragmentation pathways of reference analogues were elucidated based on characteristic ion fragments of m/z 323 → 295 → 267 or m/z 253 → 238 → 197 by ultra-high-performance liquid chromatography-ion trap tandem mass spectrometry (UPLC-IT-MSn) and then applied to the differentiations of substances with or without an oxygenated group at C-12. Twenty-seven daphnane diterpenes were successfully recognized from a petroleum ether extract of D. genkwa, including some potential new compounds and isomers that could not be identified accurately only from the ion fragments. Further separation of these target compounds using high-speed countercurrent chromatography (HSCCC) and preparative HPLC led to the isolation of three new (11, 25, and 27) and 14 known compounds, whose structures were identified and confirmed based on MS, NMR, and electronic circular dichroism (ECD) spectroscopy. The isolates exhibited anti-HIV activities at nanomolar concentrations. The results demonstrated that this strategy is feasible and reliable to rapidly recognize and isolate daphnane diterpenes from D. genkwa.

4.
Eur J Med Chem ; 183: 111696, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31541869

RESUMO

Cell division cycle 25 (Cdc25) protein phosphatases play key roles in the transition between the cell cycle phases and their association with various cancers has been widely proven, which makes them ideal targets for anti-cancer treatment. Though several Cdc25 inhibitors have been developed, most of them displayed low activity and poor subtype selectivity. Therefore, it is extremely important to discover novel small molecule inhibitors with potent activities and significant selectivity for Cdc25 subtypes, not only served as drugs to treat cancer but also to probe its mechanism in transitions. In this study, miniaturized parallel click chemistry synthesis via CuAAC reaction followed by in situ biological screening were used to discover selective Cdc25 inhibitors. The bioassay results showed that compound M2N12 proved to be the most potent Cdc25 inhibitor, which also act as a highly selective Cdc25C inhibitor and was about 9-fold potent than that of NSC 663284. Moreover, M2N12 showed remarkable anti-growth activity against the KB-VIN cell line, equivalent to that of PXL and NSC 663284. An all-atom molecular dynamics (MD) simulation approach was further employed to probe the significant selectivity of M2N12 for Cdc25C relative to its structural homologs Cdc25A and Cdc25B. Overall, above results make M2N12 a promising lead compound for further investigation and structural modification.


Assuntos
Antineoplásicos/farmacologia , Técnicas de Química Combinatória , Inibidores Enzimáticos/farmacologia , Fosfatases cdc25/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Química Click , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Fosfatases cdc25/metabolismo
5.
J Med Chem ; 62(15): 6958-6971, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31343875

RESUMO

Currently, due to the HIV latency mechanism, the search continues for effective drugs to combat this issue and provide a cure for AIDS. Gnidimacrin activates latent HIV-1 replication and inhibits HIV-1 infection at picomolar concentrations. This natural diterpene was able to markedly reduce the latent HIV-1 DNA level and the frequency of latently infected cells. Therefore, gnidimacrin is an excellent lead compound, and its anti-HIV potential merits further investigation. Twenty-nine modified gnidimacrin derivatives were synthesized and evaluated in assays for HIV replication and latency activation to establish which molecular structures must be maintained and which can tolerate changes that may be needed for better pharmacological properties. The results indicated that hydroxyl substituents at C-5 and C-20 are essential, while derivatives modified at 3-OH with aromatic esters retain anti-HIV replication and latent activation activities. The half-lives of the potent GM derivatives are over 20 h, which implies that they are stable in the plasm even though they contain ester linkages. The established structure-activity relationship should be useful in the development of gnidimacrin or structurally related compounds as clinical trial candidates.

6.
J Nat Prod ; 82(6): 1587-1592, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31184480

RESUMO

Two new (1 and 2) and 14 known (3-16) ingenane diterpenoids were isolated from the roots of Euphorbia ebracteolata by bioassay-guided fractionation together with UPLC-MS n analysis. The absolute configurations of the new diterpenoids were established from electronic circular dichroism (ECD) data and ECD calculations. Except for ingenol (16), the ingenane diterpenoids with long aliphatic chain substituents (1-15) exhibited potent activities against HIV-1, with IC50 values of 0.7 to 9.7 nM and selectivity index values of 96.2 to 20 263. From the results, it was concluded that long aliphatic chain substituents are required for the enhanced anti-HIV activity of ingenane diterpenoids.

7.
Eur J Med Chem ; 166: 159-166, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30703659

RESUMO

In this study, 12 known cycloartane triterpenoids (1-12) with four different skeletons isolated from the roots of Souliea vaginata were screened for the first time for in vitro anti-HIV activity using AZT as a standard. Among the compounds, beesioside I (1) showed the highest potency against HIV-1NL4-3 with an EC50 value of 2.32 µM (CC50 > 40 µM). Preliminary structure-activity relationship (SAR) studies on 1 indicated that simple modification of its aglycone (13) could significantly influence the antiviral activity. Particularly, the introduction of an acyl group at the C-3 position of 13 led to significant improvement in both anti-HIV potency and selectivity index. Among all synthetically modified derivatives, compound 13g was the most potent compound with an EC50 value of 0.025 µM and TI value greater than 800, comparable to those of 3-O-(3',3'-dimethylsuccinyl)-betulinic acid (DSB, bevirimat). Other analogues exhibited strong to weak inhibition of HIV-1 replication in MT-4 cells. The length, carboxylic terminus, and C-3' dimethyl substitution of the C-3 side chain substantially affected the anti-HIV activity. Finally, compound 13g was an effective agent against HIV with high potential for further investigation.


Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Desenho de Drogas , HIV-1/efeitos dos fármacos , Triterpenos/síntese química , Triterpenos/farmacologia , Fármacos Anti-HIV/química , Técnicas de Química Sintética , HIV-1/fisiologia , Relação Estrutura-Atividade , Triterpenos/química , Replicação Viral/efeitos dos fármacos
8.
J Med Chem ; 62(3): 1484-1501, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30624934

RESUMO

To address drug resistance to HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel diarylpyrimidine (DAPY) derivatives targeting "tolerant region I" and "tolerant region II" of the NNRTIs binding pocket (NNIBP) were designed utilizing a structure-guided scaffold-hopping strategy. The dihydrofuro[3,4- d]pyrimidine derivatives 13c2 and 13c4 proved to be exceptionally potent against a wide range of HIV-1 strains carrying single NNRTI-resistant mutations (EC50 = 0.9-8.4 nM), which were remarkably superior to that of etravirine (ETV). Meanwhile, both compounds exhibited comparable activities with ETV toward the virus with double mutations F227L+V106A and K103N+Y181C. Furthermore, the most active compound 13c2 showed favorable pharmacokinetic properties with an oral bioavailability of 30.96% and a half-life of 11.1 h, which suggested that 13c2 is worth further investigation as a novel NNRTI to circumvent drug resistance.

9.
Chem Biol Drug Des ; 93(4): 582-589, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30560566

RESUMO

Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains as the only enzyme encoded within the viral genome not targeted by current antiviral drugs. In this work, we report the design, synthesis, and biologic evaluation of a novel series of galloyl derivatives with HIV-1 RNase H inhibitory activity. Most of them showed IC50 s at sub- to low-micromolar concentrations in enzymatic assays. The most potent compound was II-25 that showed an IC50 of 0.72 ± 0.07 µM in RNase H inhibition assays carried out with the HIV-1BH 10 RT. II-25 was 2.8 times more potent than ß-thujaplicinol in these assays. Interestingly, II-25 and other galloyl derivatives were also found to inhibit the HIV IN strand transfer activity in vitro. Structure-activity relationships (SAR) studies and molecular modeling analysis predict key interactions with RT residues His539 and Arg557, while providing helpful insight for further optimization of selected compounds.


Assuntos
Fármacos Anti-HIV/síntese química , Desenho de Drogas , HIV-1/enzimologia , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Tropolona/análogos & derivados , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Ácido Benzoico/química , Sítios de Ligação , Domínio Catalítico , HIV-1/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo , Relação Estrutura-Atividade , Tropolona/síntese química , Tropolona/química , Tropolona/farmacologia
10.
Molecules ; 25(1)2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31888067

RESUMO

Two new carbazole alkaloids (1,2) and six known carbazole alkaloids (3-8) were isolated from Clausena anisum-olens. Their structures were elucidated based on extensive spectroscopic analysis. All isolated compounds (1-8) were evaluated for their anti-HIV effects on virus replication in MT-4 lymphocytes infected by HIV-1NL4-3 Nanoluc-sec virus, and new carbazole alkaloid 1 exhibited anti-HIV activity with an EC50 value of 2.4 µg/mL and SI of 7.1.

11.
Eur J Med Chem ; 158: 478-492, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30243152

RESUMO

The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of HIV-1 replication and is considered an important, clinically unexploited therapeutic target. As such, small drug-like molecules that inhibit this critical HIV-1 protein have become a priority for several groups. Therefore, in this study we explore small molecule targeting of the CA protein, and in particular a very attractive inter-protomer pocket. We report the design, parallel synthesis, and anti-HIV-1 activity evaluation of a series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors synthesized via Cu(I)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reaction. We demonstrate robust inhibitory activity over a range of potencies against the HIV-1 NL4-3 reference strain. In particular, compound 13m exhibited the greatest potency and lowest toxicity within this new series with an EC50 value of 4.33 µM and CC50 value of >57.74 µM (SI > 13.33). These values are very similar to the lead compound PF-74 (EC50 = 5.95 µM, CC50 > 70.50 µM, SI > 11.85) in our assay, despite significant structural difference. Furthermore, we demonstrate via surface plasmon resonance (SPR) binding assays that 13m interacts robustly with recombinant HIV-1 CA and exhibits antiviral activity in both the early and late stages of HIV-1 replication. Overall, the novel parallel synthesis and structure-activity relationships (SARs) identified within this study set the foundation for further rational optimization and discovery of CA-targeting compounds with improved potency.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Capsídeo/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Fármacos Anti-HIV/síntese química , Química Click , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Simulação de Dinâmica Molecular , Fenilalanina/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
12.
J Nat Prod ; 81(7): 1619-1627, 2018 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-30010341

RESUMO

A novel cycloartane triterpenoid alkaloid, kleinhospitine E (1), six new cycloartane triterpenoids (2-7), three known cycloartane triterpenoids (8-10), and taraxerone (11) were isolated from a methanol extract of Kleinhovia hospita. Their structures were elucidated by 1D- and 2D-NMR spectroscopy as well as HRMS analysis. The absolute configurations of all isolated compounds were determined from their ECD spectra by comparison with theoretical values. Kleinhospitine E (1) is the first cycloartane alkaloid possessing an unusual γ-lactam with an oxopropylidene side chain. Compounds 2, 3, and 6 were assigned as cycloartane triterpenoids with a 9α,10α-cyclopropyl ring, which is found rarely among naturally occurring compounds, while 4 and 5 were established as isomers of compound 3 containing a 21,23-diacetal side chain. Biological evaluation revealed that compounds 4 and 9 exhibited more potent antiproliferative activities against a multidrug-resistant tumor cell line compared with its parent chemosensitive cell line. Furthermore, compound 6 exhibited submicromolar anti-HIV activity.


Assuntos
Malvaceae/química , Extratos Vegetais/farmacologia , Triterpenos/isolamento & purificação , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Fármacos Anti-HIV/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Extratos Vegetais/química , Triterpenos/química , Triterpenos/farmacologia
13.
Eur J Med Chem ; 156: 618-627, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30031972

RESUMO

Euphorbia kansui showed potent anti-HIV-1 activity during screening of a library composed of plant extracts from Euphorbiaceae and Thymelaeaceae families. Bioassay-guided isolation led to identification of ingenane esters as the active compounds. Further chemical modification resulted in 3-(2-naphthoyl)ingenol (23), which exhibited the most potent anti-HIV-1 activity. Compound 23 also acted as an HIV-1-latency-reversing agent on activation of HIV-1 replication in a latently infected U1 cell model and a T cell latent HIV-1 model JLat-A2.


Assuntos
Diterpenos/química , Diterpenos/farmacologia , Euphorbia/química , HIV-1/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Replicação Viral/efeitos dos fármacos , Antivirais/química , Antivirais/isolamento & purificação , Antivirais/farmacologia , Linhagem Celular , Diterpenos/isolamento & purificação , Ésteres/química , Ésteres/isolamento & purificação , Ésteres/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Humanos , Extratos Vegetais/isolamento & purificação
14.
Sci Rep ; 8(1): 8812, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29891956

RESUMO

The association between mucosal microbiota and HIV-1 infection has garnered great attention in the field of HIV-1 research. Previously, we reported a receptor-independent HIV-1 entry into epithelial cells mediated by a Gram-negative invasive bacterium, Porphyromonas gingivalis. Here, we present evidence showing that P. gingivalis outer membrane vesicles (OMVs) promote mucosal transmission of HIV-1. We demonstrated, using the Dynabeads technology, a specific interaction between HIV-1 and P. gingivalis OMVs which led to an OMV-dependent viral entry into oral epithelial cells. HIV-1 was detected in human oral keratinocytes (HOKs) after a 20 minute exposure to the HIV-vesicle complexes. After entry, most of the complexes appeared to dissociate, HIV-1 was reverse-transcribed, and viral DNA was integrated into the genome of HOKs. Meanwhile, some of the complexes exited the original host and re-entered neighboring HOKs and permissive cells of HIV-1. Moreover, P. gingivalis vesicles enhanced HIV-1 infection of MT4 cells at low infecting doses that are not able to establish an efficient infection alone. These findings suggest that invasive bacteria and their OMVs with ability to interact with HIV-1 may serve as a vehicle to translocate HIV through the mucosa, establish mucosal transmission of HIV-1, and enhance HIV-1 infectivity.


Assuntos
Transmissão de Doença Infecciosa , Células Epiteliais/virologia , Vesículas Extracelulares/metabolismo , Infecções por HIV/transmissão , HIV-1/fisiologia , Porphyromonas gingivalis/metabolismo , Internalização do Vírus , Células Cultivadas , Humanos , Modelos Teóricos
15.
Eur J Med Chem ; 151: 339-350, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29635166

RESUMO

Inspired by our previous efforts on the modifications of diarylpyrimidines as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) and reported crystallography study, novel diarylnicotinamide derivatives were designed with a "triazole tail" occupying the entrance channel in the NNRTI binding pocket of the reverse transcriptase to afford additional interactions. The newly designed compounds were then synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds showed excellent to good activity against wild-type HIV-1 strain with EC50 of 0.02-1.77 µM. Evaluations of selected compounds against more drug-resistant strains showed these compounds had advantage of inhibiting E138K mutant virus which is a key drug-resistant mutant to the new generation of NNRTIs. Among this series, propionitrile (3b2, EC50(IIIB) = 0.020 µM, EC50(E138K) = 0.015 µM, CC50 = 40.15 µM), pyrrolidin-1-ylmethanone (3b8, EC50(IIIB) = 0.020 µM, EC50(E138K) = 0.014 µM, CC50 = 58.09 µM) and morpholinomethanone (3b9, EC50(IIIB) = 0.020 µM, EC50(E138K) = 0.027 µM, CC50 = 180.90 µM) derivatives are the three most promising compounds which are equally potent to the marketed drug Etravirine against E138K mutant strain but with much lower cytotoxicity. Furthermore, detailed SAR, inhibitory activity against RT and docking study of the representative compounds are also discussed.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Niacinamida/farmacologia , Triazóis/farmacologia , Fármacos Anti-HIV/química , Desenho de Drogas , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/genética , HIV-1/fisiologia , Humanos , Simulação de Acoplamento Molecular , Niacinamida/análogos & derivados , Mutação Puntual , Relação Estrutura-Atividade , Triazóis/química
16.
ACS Med Chem Lett ; 9(3): 268-273, 2018 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-29541372

RESUMO

We have previously reported gnidimacrin (GM), a protein kinase C (PKC) agonist, significantly reduces the frequency of HIV-1 latently infected cells in peripheral blood mononuclear cells (PBMCs) from patients undergoing successful antiretroviral therapy at low picomolar concentrations ex vivo, which is distinct from other latency reversing agents. In this study, we demonstrate that strong viral reactivation by GM is a mechanism for elimination of latently infected cells, and a histone deacetylase inhibitor (HDACI), a thiophenyl benzamide (TPB), further potentiated the efficacy of GM against latent HIV-1. The effect of GM on latent HIV-1 activation was potentiated by TPB in cell models by 2-3-fold. The GM/TPB combination further decreased the frequency of HIV-infected cells in latently infected patient PBMCs over 3-fold when compared with GM alone, which caused a 5-fold reduction compared with the solvent control. Thus, GM/TPB is a unique combination that may reduce latent HIV-1 reservoirs at nontoxic concentrations.

17.
Chem Biodivers ; 15(5): e1700560, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29569369

RESUMO

Three new compounds (1 - 3), including two euphane type triterpenes, 24,24-dimethoxy-25,26,27-trinoreuphan-3ß-ol (1) and (24S)-24-hydroperoxyeupha-8,25-dien-3ß-ol (2), and an ent-atisine diterpene, ent-atisane-3α,16α,17-triol (3), were isolated from an acetone extract of the stems of Euphorbia antiquorum, together with eight known diterpenes (4 - 11). The structures of compounds (1 - 11) were elucidated using NMR and MS spectroscopic methods. Compound 7 showed moderate activity against HIV-1 replication in vitro (EC50 = 1.38 µm).


Assuntos
Fármacos Anti-HIV/farmacologia , Euphorbia/química , HIV-1/efeitos dos fármacos , Terpenos/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Linhagem Celular Transformada , Transformação Celular Viral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Terpenos/química , Terpenos/isolamento & purificação , Replicação Viral/efeitos dos fármacos
18.
Phytochemistry ; 145: 40-47, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29080411

RESUMO

Six previously undescribed diterpenoids, named euphorantins S-T and euphorneroids A-D, including ingol and ent-atisane types, along with eleven known diterpenoids, were isolated from Euphorbia neriifolia. Their structures were elucidated on the basis of extensive NMR analysis and high resolution mass spectrometry. Euphorneroid D and ent-3-oxoatisan-16α,17-acetonide exhibited moderate anti-HIV-1 activities, with EC50 values of 34 µM (SI = 2.3) and 24 µM (SI = 1.9), respectively.


Assuntos
Fármacos Anti-HIV/farmacologia , Diterpenos/farmacologia , Euphorbia/química , HIV-1/efeitos dos fármacos , Casca de Planta/química , Caules de Planta/química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Linhagem Celular , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
19.
ACS Med Chem Lett ; 8(11): 1199-1203, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29152054

RESUMO

As a step toward developing novel anti-HIV agents, we have identified a class of quinolizidines, including aloperine, that inhibit HIV at 1-5 µM by blocking viral entry. In this study, we have optimized the structure of aloperine and derived compounds with markedly improved activity. Our structural optimization has yielded an aloperine derivative 19 with approximately a 15-fold increase in anti-HIV-1 activity. Our mechanism of action study reveals that compound 19 does not inhibit binding of HIV-1 to receptors but arrests the virus from fusion with the membrane. Binding of the compound to HIV-1gp120 might be responsible for its anti-HIV-1 entry activity.

20.
Planta Med ; 83(17): 1368-1373, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28662527

RESUMO

Three new compounds (1 - 3), including a sesterterpenoid, aspterpenacid C (1), with an unusual 5/3/7/6/5 pentacyclic skeleton, together with seven known ones (4 - 10), were isolated from the ethanol extract of the traditional Chinese medicinal plant Swertia bimaculata. Their structures were elucidated on the basis of the methods of spectroscopic NMR, MS, and computational chemistry. The structure of 1 was further confirmed by single-crystal X-ray diffraction analysis. Compounds 1 - 10 were tested for activities on the inhibition of nitric oxide production and HIV-1 replication in vitro. Compound 1 exhibited moderate activity in inhibiting nitric oxide production (IC50 = 16.1 µM) and HIV-1 replication (EC50 = 1.35 µM).


Assuntos
Fármacos Anti-HIV/isolamento & purificação , Fármacos Anti-HIV/farmacologia , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , HIV-1/efeitos dos fármacos , Swertia/química , Animais , Fármacos Anti-HIV/química , Anti-Inflamatórios/química , China , Medicamentos de Ervas Chinesas/química , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Células RAW 264.7 , Replicação Viral/efeitos dos fármacos
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