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1.
Chem Commun (Camb) ; 56(8): 1179-1182, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31868184

RESUMO

We report unprecedented Friedel-Crafts arylation of chlorofullerenes C60Cl6 and C70Cl8 with unprotected carboxylic acids as an efficient single-step synthesis of the inherently stable water-soluble fullerene derivatives. Using this method, a series of previously unaccessible compounds was obtained without chromatographic purification in almost quantitative yields. Promising anti-HIV activity comparable to characteristics of commercial drugs was demonstrated for some of these compounds.


Assuntos
Fármacos Anti-HIV/farmacologia , Ácidos Carboxílicos/farmacologia , Fulerenos/farmacologia , Água/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Fulerenos/química , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Solubilidade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia
2.
Chem Biodivers ; 16(12): e1900495, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31755643

RESUMO

Fifteen diterpenoids (1-15), including three undescribed ones with ent-atisane skeleton, eupnerias G-I (1-3), were obtained from Euphorbia neriifolia. Compounds 1-3 were established through comprehensive spectroscopic analysis. Compounds 4 and 5 exhibited obvious anti-HIV-1 effect, and their EC50 were 6.6±3.2 and 6.4±2.5 µg mL-1 , respectively. Compound 6 exhibited moderate cytotoxicity on HepG2 and HepG2/Adr cells with IC50 at 13.70 and 15.57 µm, respectively. In addition, compound 15 exhibited significant cytotoxicity on HepG2 cell lines (IC50 =0.01 µm), while it did not show any cytotoxicity against HepG2/Adr cell lines.


Assuntos
Fármacos Anti-HIV/química , Diterpenos/química , Euphorbia/química , Fármacos Anti-HIV/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Euphorbia/metabolismo , HIV-1/efeitos dos fármacos , Humanos , Conformação Molecular , Relação Estrutura-Atividade
3.
Chem Commun (Camb) ; 55(98): 14729-14732, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690911

RESUMO

A palladium-promoted oxidative annulation reaction for the synthesis of structurally diverse naphthoquinone-containing heterocycles has been developed, providing switchable access to 1,2-naphthofuroquinones and densely functionalized cyclobutene-fused 1,4-naphthofuroquinones by selective enol/enolate-directed processes. The synthetic application was extended by late-stage functionalization of an anti-HIV drug. The practical value of 1,2-naphthofuroquinone synthesis was highlighted in endothelial protective lead compound development.


Assuntos
Naftoquinonas/química , Paládio/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Apoptose/efeitos dos fármacos , Catálise , Ciclização , Células Endoteliais da Veia Umbilical Humana , Humanos , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Oxirredução
5.
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
6.
Eur J Pharm Biopharm ; 144: 91-100, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31521715

RESUMO

We have previously demonstrated that the ester conjugation of zidovudine (AZT) with ursodeoxycholic acid (UDCA) allows to obtain a prodrug (U-AZT) which eludes the active efflux transporters (AET). This allows the prodrug to more efficiently permeates and remains in murine macrophages than the parent compound. Here we demonstrate that U-AZT can be formulated, by a nanoprecipitation method, as nanoparticle cores coated by bile acid salt (taurocholate or ursodeoxycholate) corona, without any other excipients. The U-AZT nanoparticles appeared spherical with a mean diameter of ∼200 nm and a zeta potential of ∼-55 mV. During the incubation (5 h) in fetal bovine serum, the ursodeoxycholate-coated nanoparticle size did not change. Differently, taurocholate-coated particle size was firstly reduced and then increased up to 800 µm, thus suggesting the high aptitude of these nanoparticles to interact with serum proteins. The in vitro uptake of taurocholate coated particles by murine macrophages was strongly higher than that of ursodeoxycholate-coated particles or free U-AZT (∼500% and ∼7000%, respectively). AZT was also detected in macrophages following the prodrug uptake, with the greatest amounts observed after the taurocholate-coated nanoparticle incubation. As macrophages in the subarachnoid spaces of cerebrospinal fluid (CSF) constitute one of the most unreachable HIV sanctuaries in the body, we also tested the ability of taurocholate-coated nanoparticles (i.e., nanoparticles highly internalized by macrophages) to reach them after their nasal administration in the presence or absence of chitosan. The results indicate that chitosan allowed to obtain a relatively high uptake (up to 4 µg/ml) of U-AZT in CSF. Taking into account that chitosan may promote the direct brain nanoparticle uptake, these findings can be considered an initial step toward the in vivo targeting of the subarachnoid macrophages by U-AZT prodrug.


Assuntos
Ácidos e Sais Biliares/química , Encéfalo/metabolismo , Macrófagos/efeitos dos fármacos , Nanopartículas/química , Mucosa Nasal/metabolismo , Pró-Fármacos/farmacologia , Zidovudina/farmacologia , Administração Intranasal , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Quitosana/química , Portadores de Fármacos/química , Excipientes/química , Camundongos , Nariz , Tamanho da Partícula , Ácido Ursodesoxicólico/química
7.
Eur J Med Chem ; 183: 111699, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31561045

RESUMO

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


Assuntos
Acetamidas/farmacologia , Androstenóis/farmacologia , Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , HIV-1/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/química , Androstenóis/síntese química , Androstenóis/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , HIV-1/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
8.
Molecules ; 24(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31489889

RESUMO

HIV protease inhibitors against the viral protease are often hampered by drug resistance mutations in protease and in the viral substrate Gag. To overcome this drug resistance and inhibit viral maturation, targeting Gag alongside protease rather than targeting protease alone may be more efficient. In order to successfully inhibit Gag, understanding of its drug resistance mutations and the elicited structural changes on protease binding needs to be investigated. While mutations on Gag have already been mapped to protease inhibitor resistance, there remain many mutations, particularly the non-cleavage mutations, that are not characterized. Through structural studies to unravel how Gag mutations contributes to protease drug resistance synergistically, it is thus possible to glean insights to design novel Gag inhibitors. In this review, we discuss the structural role of both novel and previously reported Gag mutations in PI resistance, and how new Gag inhibitors can be designed.


Assuntos
Farmacorresistência Viral , HIV-1/metabolismo , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Desenho de Drogas , Protease de HIV/genética , Protease de HIV/metabolismo , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Modelos Moleculares , Mutação , Conformação Proteica , Relação Estrutura-Atividade
9.
Molecules ; 24(17)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484419

RESUMO

Chemical investigation of Cordia millenii, Baker resulted in the isolation of a new depsidone, cordidepsine (1), along with twelve known compounds including cyclooctasulfur (2), lup-20(29)-en-3-triacontanoate (3), 1-(26-hydroxyhexacosanoyl)glycerol (4), glyceryl-1-hexacosanoate (5) betulinic acid (6), lupenone (7), ß-amyrone (8), lupeol (9), ß-amyrin (10), allantoin (11), 2'-(4-hydroxyphenyl)ethylpropanoate (12) and stigmasterol glycoside (13). Hemi-synthetic reactions were carried out on two isolated compounds (5 and 6) to afford two new derivatives, that is, cordicerol A (14) and cordicerol B (15), respectively. The chemical structures of all the compounds were established based on analysis and interpretation of spectroscopic data such as electron ionization mass spectrometry (EI-MS), high resolution electrospray ionization mass spectrometry (HR-ESI-MS), fast atom bombardment mass spectrometry (FAB-MS), one dimension and two dimension nuclear magnetic resonance (1D and 2D-NMR) spectral data as well as X-ray crystallography (XRC). Lupeol ester derivatives [Lup-20(29)-en-3-triacontanoate (3)], monoglycerol derivatives [1-(26-hydroxyhexacosanoyl)glycerol (4) and glyceryl-1 hexacosanoate (5)] were isolated for the first time from Cordia genus while sulfur allotrope [cyclooctasulfur (2)] was isolated for the first time from plant origin. Biological assays cordidepsine (1) exhibited significant anti-HIV integrase activity with IC50 = 4.65 µM; EtOAc extract of stem barks, EtOAc fraction of roots and leaves were not toxic against 3T3 cells.


Assuntos
Fármacos Anti-HIV/química , Cordia/química , Depsídeos/química , Lactonas/química , Extratos Vegetais/química , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Espectrometria de Massas
10.
Eur J Med Chem ; 181: 111566, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31401538

RESUMO

The worldwide increase of AIDS, an epidemic infection in constant development has an essential and still requires potent antiretroviral chemotherapeutic agents for reducing the integer of deaths caused by HIV. Thus, there is an urgent need for new anti-HIV drug candidates with increased strength, new targets, superior pharmacokinetic properties, and compact side effects. From this viewpoint, we first review present strategies of anti-HIV drug innovation and the synthesis of heterocyclic or natural compound as anti-HIV agents for facilitating the development of more influential and successful anti-HIV agents.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Técnicas de Química Sintética/métodos , Desenho de Drogas , Descoberta de Drogas , Humanos , Modelos Moleculares , Relação Estrutura-Atividade
11.
Curr Top Med Chem ; 19(18): 1650-1675, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424369

RESUMO

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.


Assuntos
Amidas/farmacologia , Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/farmacologia , Pirróis/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Amidas/química , Fármacos Anti-HIV/química , Descoberta de Drogas , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/química , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Pirróis/química , Bibliotecas de Moléculas Pequenas/química
12.
Curr Top Med Chem ; 19(18): 1599-1620, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424370

RESUMO

Viral entry, the first process in the reproduction of viruses, primarily involves attachment of the viral envelope proteins to membranes of the host cell. The crucial components that play an important role in viral entry include viral surface glycoprotein gp120, viral transmembrane glycoprotein gp41, host cell glycoprotein (CD4), and host cell chemokine receptors (CCR5 and CXCR4). Inhibition of the multiple molecular interactions of these components can restrain viruses, such as HIV-1, from fusion with the host cell, blocking them from reproducing. This review article specifically focuses on the recent progress in the development of small-molecule HIV-1 entry inhibitors and incorporates important aspects of their structural modification that lead to the discovery of new molecular scaffolds with more potency.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Proteína gp41 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Fármacos Anti-HIV/química , Proteína gp120 do Envelope de HIV/metabolismo , Proteína gp41 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/química , Humanos , Bibliotecas de Moléculas Pequenas/química
13.
Curr Top Med Chem ; 19(18): 1621-1649, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424371

RESUMO

The history of the human immunodeficiency virus (HIV)/AIDS therapy, which spans over 30 years, is one of the most dramatic stories of science and medicine leading to the treatment of a disease. Since the advent of the first AIDS drug, AZT or zidovudine, a number of agents acting on different drug targets, such as HIV enzymes (e.g. reverse transcriptase, protease, and integrase) and host cell factors critical for HIV infection (e.g. CD4 and CCR5), have been added to our armamentarium to combat HIV/AIDS. In this review article, we first discuss the history of the development of anti-HIV drugs, during which several problems such as drug-induced side effects and the emergence of drug-resistant viruses became apparent and had to be overcome. Nowadays, the success of Combination Antiretroviral Therapy (cART), combined with recently-developed powerful but nonetheless less toxic drugs has transformed HIV/AIDS from an inevitably fatal disease into a manageable chronic infection. However, even with such potent cART, it is impossible to eradicate HIV because none of the currently available HIV drugs are effective in eliminating occult "dormant" HIV cell reservoirs. A number of novel unique treatment approaches that should drastically improve the quality of life (QOL) of patients or might actually be able to eliminate HIV altogether have also been discussed later in the review.


Assuntos
Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/química , Farmacorresistência Viral/efeitos dos fármacos , Humanos
14.
Eur J Med Chem ; 182: 111617, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31442684

RESUMO

A number of compounds targeting different processes of the Human Immunodeficiency Virus type 1 (HIV-1) life cycle have been developed in the continuing fight against AIDS. Coumarin-based molecules already proved to act as HIV-1 Protease (PR) or Integrase (IN) inhibitors and also to target HIV-1 reverse transcriptase (RT), blocking the DNA-dependent DNA-polymerase activity or the RNA-dependent DNA-polymerase activity working as common NNRTIs. In the present study, with the aim to exploit a coumarin-based scaffold to achieve the inhibition of multiple viral coded enzymatic functions, novel 4-hydroxy-2H, 5H-pyrano (3, 2-c) chromene-2, 5-dione derivatives were synthesized. The modeling studies calculated the theoretical binding affinity of the synthesized compounds on both HIV-1 IN and RT-associated Ribonuclease H (RNase H) active sites, which was confirmed by biological assays. Our results provide a basis for the identification of dual HIV-1 IN and RT RNase H inhibitors compounds.


Assuntos
Fármacos Anti-HIV/farmacologia , Cumarínicos/farmacologia , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , HIV-1/enzimologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo , Relação Estrutura-Atividade
15.
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
16.
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 Drogas , 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
17.
Int J Pharm ; 569: 118574, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31352053

RESUMO

With a dapivirine-releasing vaginal ring having successfully completed late-stage clinical testing for HIV prevention and currently undergoing regulatory review, there is now growing interest in next-generation multipurpose prevention technologies that seek to combine antiretroviral and contraceptive drugs within a single product. Here, we focus on ongoing efforts to develop a silicone elastomer vaginal ring releasing both dapivirine and levonorgestrel. Specifically, we evaluate various strategies aimed at both better understanding and reducing the tendency of levonorgestrel to bind with the elastomer, including: (i) formulation and post-manufacturing strategies aimed at reducing the extent of levonorgestrel reaction with addition-cure silicone elastomers; (ii) evaluation of a simple silicone system to model the complex elastomer; (iii) use of model compounds representing the enone and ethinyl moieties of levonorgestrel to probe the mode of addition of levonorgestrel to addition-cure silicone elastomers; and (iv) solution and solid-state 13C NMR analysis to probe the structural features of the levonorgestrel-silicone system. The results demonstrate that both the enone and ethinyl groups within levonorgestrel undergo hydrosilylation reactions with the hydrosiloxane groups in the silicone elastomer leading to covalent binding. The results also highlight potential strategies for further optimising the dapivirine + levonorgestrel silicone vaginal ring formulation to ensure that the levonorgestrel is available for release.


Assuntos
Fármacos Anti-HIV/química , Anticoncepcionais Femininos/química , Dispositivos Anticoncepcionais Femininos , Levanogestrel/química , Pirimidinas/química , Elastômeros de Silicone/química
18.
Eur J Med Chem ; 180: 562-612, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31344615

RESUMO

Heterocycles occupy a salient place in chemistry due to their wide range of activity in the fields of drug design, photochemistry, agrochemicals, dyes, and so on. Amongst all, indole scaffold is considered as one of the most promising heterocycles found in natural and synthetic sources and has been shown to possess various biological activity, including anti-inflammatory, anti-HIV, antitubercular, antimalarial, anticonvulsant, antidiabetic, antihypertensive, analgesics, antidepressant, anticancer, antioxidant, antifungal, and antimicrobial, etc. All the reported indole molecules bind to multiple receptors with high affinity, thus expedite the research on the development of novel biologically active compounds through the various approach. In this review, we aimed to highlight synthetic and medicinal perspective on the development of indole-based analogs. In addition, structural activity relationship (SAR) study to correlate for their biological activity also discussed.


Assuntos
Indóis/síntese química , Indóis/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Indóis/química , Estrutura Molecular , Relação Estrutura-Atividade
19.
Arch Pharm (Weinheim) ; 352(9): e1900045, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31274223

RESUMO

Acquired immune deficiency syndrome (AIDS)/human immunodeficiency virus (HIV) is one of the largest and most devastating public health pandemics throughout the world. The global pandemic of drug-sensitive HIV and the increasing threat from drug-resistant HIV result in an urgent need to develop more effective anti-HIV candidates. Quinolone represents a significant class of privileged heterocycles, and its derivatives possess promising in vitro and in vivo anti-HIV properties. The 4-quinolone elvitegravir has already been approved for the treatment of HIV; thus, quinolone derivatives might be promising candidates with anti-HIV activity. This review emphasizes quinolone derivatives with potential anti-HIV activity, covering articles published between 1992 and 2019. The structure-activity relationship is also discussed to provide insights for further development of more active quinolone derivatives.


Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Quinolonas/farmacologia , Fármacos Anti-HIV/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Descoberta de Drogas , Farmacorresistência Viral Múltipla/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/genética , Humanos , Estrutura Molecular , Quinolonas/química , Relação Estrutura-Atividade
20.
Int J Mol Sci ; 20(14)2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31336592

RESUMO

Human immunodeficiency virus type-1 and hepatitis C virus (HIV/HCV) coinfection occurs when a patient is simultaneously infected with both human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV), which is common today in certain populations. However, the treatment of coinfection is a challenge because of the special considerations needed to ensure hepatic safety and avoid drug-drug interactions. Multitarget inhibitors with less toxicity may provide a promising therapeutic strategy for HIV/HCV coinfection. However, the identification of one molecule that acts on multiple targets simultaneously by experimental evaluation is costly and time-consuming. In silico target prediction tools provide more opportunities for the development of multitarget inhibitors. In this study, by combining Naïve Bayes (NB) and support vector machine (SVM) algorithms with two types of molecular fingerprints, MACCS and extended connectivity fingerprints 6 (ECFP6), 60 classification models were constructed to predict compounds that were active against 11 HIV-1 targets and four HCV targets based on a multiple quantitative structure-activity relationships (multiple QSAR) method. Five-fold cross-validation and test set validation were performed to measure the performance of the 60 classification models. Our results show that the 60 multiple QSAR models appeared to have high classification accuracy in terms of the area under the ROC curve (AUC) values, which ranged from 0.83 to 1 with a mean value of 0.97 for the HIV-1 models and from 0.84 to 1 with a mean value of 0.96 for the HCV models. Furthermore, the 60 models were used to comprehensively predict the potential targets of an additional 46 compounds, including 27 approved HIV-1 drugs, 10 approved HCV drugs and nine selected compounds known to be active against one or more targets of HIV-1 or HCV. Finally, 20 hits, including seven approved HIV-1 drugs, four approved HCV drugs, and nine other compounds, were predicted to be HIV/HCV coinfection multitarget inhibitors. The reported bioactivity data confirmed that seven out of nine compounds actually interacted with HIV-1 and HCV targets simultaneously with diverse binding affinities. The remaining predicted hits and chemical-protein interaction pairs with the potential ability to suppress HIV/HCV coinfection are worthy of further experimental investigation. This investigation shows that the multiple QSAR method is useful in predicting chemical-protein interactions for the discovery of multitarget inhibitors and provides a unique strategy for the treatment of HIV/HCV coinfection.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antivirais/química , Antivirais/farmacologia , Aprendizado de Máquina , Relação Quantitativa Estrutura-Atividade , Algoritmos , Teorema de Bayes , Bases de Dados de Produtos Farmacêuticos , Descoberta de Drogas , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Polifarmacologia , Ligação Proteica
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