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1.
Curr Comput Aided Drug Des ; 17(1): 123-133, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-31878861

RESUMO

BACKGROUND: Studies on the interaction between bioactive molecules and HIV-1 virus have been the focus of recent research in the scope of medicinal chemistry and pharmacology. OBJECTIVE: Investigating the structural parameters and physico-chemical properties of elucidating and identifying the antiviral pharmacophore sites. METHODS: A mixed computational Petra/Osiris/Molinspiration/DFT (POM/DFT) based model has been developed for the identification of physico-chemical parameters governing the bioactivity of 22 3-hydroxy-indolin-2-one derivatives of diacetyl-L-tartaric acid and aromatic amines containing combined antiviral/antitumor/antibacterial pharmacophore sites. Molecular docking study was carried out with HIV-1 integrase (pdb ID: 5KGX) in order to provide information about interactions in the binding site of the enzyme. RESULTS: The POM analyses of physico-chemical properties and geometrical parameters of compounds 3a-5j, show that they are bearing a two combined (O,O)-pockets leading to a special platform which is able to coordinate two transition metals. The increased activity of series 3a-5j, as compared to standard drugs, contains (Osp2,O sp3,O sp2)-pharmacophore site. The increase in bioactivity from 4b (R1, R2 = H, H) to 3d (R1, R2 = 4-Br, 2-OCH3) could be attributed to the existence of π-charge transfer from para-bromo-phenyl to its amid group (COδ---NHδ+). Similar to the indole-based reference ligand (pdb: 7SK), compound 3d forms hydrogen bonding interactions between the residues Glu170, Thr174 and His171 of HIV-1 integrase in the catalytic core domain of the enzyme. CONCLUSION: Study confirmed the importance of oxygen atoms, especially from the methoxy group of the phenyl ring, and electrophilic amide nitrogen atom for the formation of interactions.


Assuntos
Fármacos Anti-HIV/farmacologia , Integrase de HIV/efeitos dos fármacos , Indóis/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Sítios de Ligação , Teoria da Densidade Funcional , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Indóis/síntese química , Indóis/química , Ligantes , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
2.
Molecules ; 23(8)2018 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-30049955

RESUMO

HIV-1 integrase (IN) inhibitors represent a new class of highly effective anti-AIDS therapeutics. Current FDA-approved IN strand transfer inhibitors (INSTIs) share a common mechanism of action that involves chelation of catalytic divalent metal ions. However, the emergence of IN mutants having reduced sensitivity to these inhibitors underlies efforts to derive agents that antagonize IN function by alternate mechanisms. Integrase along with the 96-residue multifunctional accessory protein, viral protein R (Vpr), are both components of the HIV-1 pre-integration complex (PIC). Coordinated interactions within the PIC are important for viral replication. Herein, we report a 7-mer peptide based on the shortened Vpr (69⁻75) sequence containing a biotin group and a photo-reactive benzoylphenylalanyl residue, and which exhibits low micromolar IN inhibitory potency. Photo-crosslinking experiments have indicated that the peptide directly binds IN. The peptide does not interfere with IN-DNA interactions or induce higher-order, aberrant IN multimerization, suggesting a mode of action for the peptide that is distinct from clinically used INSTIs and developmental allosteric IN inhibitors. This compact Vpr-derived peptide may serve as a valuable pharmacological tool to identify a potential new pharmacologic site.


Assuntos
Produtos do Gene vpr/química , Produtos do Gene vpr/metabolismo , Infecções por HIV/virologia , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV-1/fisiologia , Peptídeos/farmacologia , Sequência de Aminoácidos , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Peptídeos/síntese química , Peptídeos/química , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica
3.
Eur J Med Chem ; 155: 714-724, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29940462

RESUMO

We reported herein the design, synthesis and biological evaluation of a series of 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as HIV-1 reverse transcriptase (RT) ribonuclease H (RNase H) inhibitors using a privileged structure-guided scaffold refining strategy. In view of the similarities between the pharmacophore model of RNase H and integrase (IN) inhibitors as well as their catalytic sites, we also performed IN inhibition assays. Notably, the majority of these derivatives inhibited RNase H and IN at micromolar concentrations. Among them, compound 7a exhibited similar inhibitory activity against RNase H and IN (IC50RNase H = 1.77 µM, IC50IN = 1.18 µM, ratio = 1.50). To the best of our knowledge, this is the first reported dual HIV-1 RNase H-IN inhibitor based on a 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one structure. Molecular modeling has been used to predict the binding mode of 7a in complex with the catalytic cores of HIV-1 RNase H and IN. Taken together these results strongly support the feasibility of developing HIV-1 dual inhibitors from analog-based optimization of divalent metal ion chelators. Recently, the identification of dual inhibitors proved to be a highly effective strategy for novel antivirals discovery. Therefore, these compounds appear to be useful leads that can be further modified to develop more valuable anti-HIV-1 molecules with suitable drug profiles.


Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV/efeitos dos fármacos , Pirazinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Ribonuclease H/antagonistas & inibidores , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Ribonuclease H/metabolismo , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 28(12): 2124-2130, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29779976

RESUMO

BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials.


Assuntos
Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV/efeitos dos fármacos , Pirimidinas/farmacologia , Pirimidinonas/farmacologia , Tiazinas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinonas/síntese química , Pirimidinonas/química , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/química
5.
Curr Top Med Chem ; 18(31): 2664-2680, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30659539

RESUMO

HIV-1 integrase, a member of a polynucleotidyl transferases superfamily, catalyzes the insertion of the viral DNA into the genome of host cells. It has emerged as a potential target for developing anti-HIV agents. In the last two decades, a number of integrase inhibitors have been developed as potential anti-HIV therapeutics. Several integrase inhibitors have reached later stages of clinical trials including S-1360, L870,810, L870,812 and BMS-707035. Into the bargain, Raltegravir, Elvitegravir and Dolutegravir have been approved by FDA as anti-HIV agents. This review article summarizes the structural insights required for the inhibition of the HIV1 integrase in the context of clinically relevant HIV1 integrase inhibitors. Additionally, the structural features required for overcoming HIV resistance have been discussed. These insights will update the ongoing design of novel antiviral inhibitors.


Assuntos
Antivirais/farmacologia , Desenho de Fármacos , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/química , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
6.
Nat Prod Res ; 32(16): 1893-1901, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28748719

RESUMO

Drawing inspiration from the structural features of some natural polyphenols, the synthesis of two different model compounds as potential inhibitors of HIV integrase (IN) has been described. The former was characterised by a diketo acid (DKA) bioisostere, such as a ß-hydroxycarbonyl moiety, between two fragments containing aromatic groups, while in the latter an epoxide linked two polyoxygenated aromatic residues. The moieties present in the structures are thought to function by chelating divalent metal ions on the enzyme catalytic site. Overall, 10 compounds were prepared and some of that submitted to molecular modelling studies (to investigate their interactions with the active site of IN), to metal titration studies (to detect their chelating capability) and to biological assays.


Assuntos
Inibidores de Integrase de HIV/síntese química , Modelos Moleculares , Domínio Catalítico , Quelantes/química , Integrase de HIV/química , Inibidores de Integrase de HIV/química , Humanos , Metais/química , Polifenóis/química , Relação Estrutura-Atividade
7.
Bioorg Med Chem ; 25(20): 5779-5789, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28951095

RESUMO

A small library containing 3-hydroxyquinazoline-2,4(1H,3H)-dione and 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one scaffolds was obtained via the copper(I)-catalyzed azidealkyne cycloaddition (CuAAC) reaction and evaluated for their anti-HIV activity in MT-4 cells. Among the synthesized compounds, several 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one derivatives showed remarkable anti-HIV potency with EC50 values ranging from 0.92 to 26.85µM. The most active one, IIA-2, also showed remarkable and selective potency against HIV type 1 integrase (IN). To the best of our knowledge, this is the first report showing that 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones are selective HIV IN inhibitors. Preliminary structure-activity relationship (SAR) studies suggested that the divalent metal ion chelators and the nature and position of substituents around the core are important for antiviral potency. Molecular modeling has been used to predict the binding site of the pyrido[2,3-d]pyrimidin-2(1H)-one core in HIV type 1 IN and suggestions are made for improvement of its inhibitory activity.


Assuntos
Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Bioensaio , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , HIV/efeitos dos fármacos , HIV/enzimologia , Inibidores de Integrase de HIV/química , Humanos , Concentração Inibidora 50 , Modelos Biológicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinonas/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade
8.
J Pept Sci ; 23(2): 117-121, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28070909

RESUMO

We have recently reported the covalent inhibition of HIV-1 integrase by an N-terminal succinimide-modified lens epithelium-derived growth factor (361-370) peptide. We also showed that this peptide is proteolytically stable. Here, we show that this inhibitor is stored as fibrils that serve as a stock for the inhibitory monomers. The fibrils increase the local concentration of the peptide at the target protein. When the monomers bind integrase, the equilibrium between the fibrils and their monomers shifts towards the formation of peptide monomers. The combination of fibril formation and subsequent proteolytic stability of the peptide may bring to new strategy for developing therapeutic agents. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.


Assuntos
Inibidores de Integrase de HIV/química , Integrase de HIV/química , HIV-1/química , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos/química , Sequência de Aminoácidos , Inibidores de Integrase de HIV/síntese química , HIV-1/enzimologia , Humanos , Microscopia de Força Atômica , Peptídeos/síntese química , Multimerização Proteica , Estabilidade Proteica , Proteólise , Succinimidas/química
9.
Bioorg Med Chem ; 24(21): 5007-5016, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27658796

RESUMO

Reverse transcriptase (RT) and integrase (IN) are two indispensable enzymes in human immunodeficiency virus type 1 (HIV-1) replication. RT is responsible for the transformation of the single-stranded RNA viral genome into double-stranded DNA, and IN catalyzes the integration of viral DNA into the host DNA. Although highly active antiretroviral therapy (HAART) combining nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) with nonnucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) could suppress successfully HIV viral load and reduce evidently the mortality of HIV infected people, it involves the difficulty of perfect adherence, and other drawbacks such as viral rebound, toxicities and multi-drug resistances. Recently, rational drug design has become a dominant technique for the development of multi-target drugs. And the rationally designed dual inhibitors of HIV-1 RT and IN have become a hot topic of anti-HIV research. In this review, the advances in rationally designed dual inhibitors of HIV-1 RT and IN were summarized, including structurally diverse inhibitors, their structure-activity relationship (SAR) studies as well as binding mode analysis.


Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Inibidores de Integrase de HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Integrases/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , HIV/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
10.
ChemMedChem ; 11(18): 1987-94, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27331774

RESUMO

We present a new approach for the covalent inhibition of HIV-1 integrase (IN) by an LEDGF/p75-derived peptide modified with an N-terminal succinimide group. The covalent inhibition is mediated by direct binding of the succinimide to the amine group of a lysine residue in IN. The peptide serves as a specific recognition sequence for the target protein, while the succinimide serves as the binding moiety. The combination of a readily synthesizable peptide precursor with easy and efficient binding to the target protein makes this approach a promising new strategy for designing lead compounds.


Assuntos
Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , Peptídeos/farmacologia , Succinimidas/farmacologia , Relação Dose-Resposta a Droga , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Humanos , Modelos Moleculares , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Relação Estrutura-Atividade , Succinimidas/síntese química , Succinimidas/química
12.
Eur J Med Chem ; 106: 132-43, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26540494

RESUMO

The glycoprotein gp120 of the HIV-1 viral envelope has a high content in mannose residues, particularly α-1,2-mannose oligomers. Compounds that interact with these high-mannose type glycans may disturb the interaction between gp120 and its (co)receptors and are considered potential anti-HIV agents. Previously, we demonstrated that a tripodal receptor (1), with a central scaffold of 1,3,5-triethylbenzene substituted with three 2,3,4-trihydroxybenzoyl groups, selectively recognizes α-1,2-mannose polysaccharides. Here we present additional studies to determine the anti-HIV-1 activity and the mechanism of antiviral activity of this compound. Our studies indicate that 1 shows anti-HIV-1 activity in the low micromolar range and has pronounced gp120 binding and HIV-1 integrase inhibitory capacity. However, gp120 binding rather than integrase inhibition seems to be the primary mechanism of antiviral activity of 1.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Integrase de HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Mananas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/metabolismo , Mananas/síntese química , Mananas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
13.
Eur J Med Chem ; 104: 127-38, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26451771

RESUMO

The synthesis and antiviral evaluation of a series of dihydropyrimidinone and thiopyrimidine derivatives bearing aryl α,γ-diketobutanoic acid moiety are described using the Biginelli multicomponent reaction as key step. The most active among 20 synthesized novel compounds were 4c, 4d and 5b, which possess nanomolar HIV-1 integrase (IN) stand transfer (ST) inhibition activities. In order to understand their mode of interactions within the IN active site, we docked all the compounds into the previously reported X-ray crystal structure of IN. We observed that compounds 4c, 4d and 5b occupied an area close to the two catalytic Mg(2+) ions surrounded by their chelating triad (E221, D128 and D185), DC16, Y212 and the ß-diketo acid moiety of 4c, 4d and 5b chelating Mg(2+). As those compounds lack anti-HIV activities in cell, their prodrugs were synthetized. The prodrug 4c' exhibited an anti-HIV activity of 0.19 µM in primary human lymphocytes with some cytotoxicity. All together, these results indicate that the new analogs potentially interact within the catalytic site with highly conserved residues important for IN catalytic activity.


Assuntos
Fármacos Anti-HIV/farmacologia , Ácido Butírico/farmacologia , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Ácido Butírico/síntese química , Ácido Butírico/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Humanos , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Células Vero
14.
Eur J Med Chem ; 101: 288-94, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26150289

RESUMO

A series of N-aryl-naphthylamines, exemplified by the structures 11-16, were chosen for an in-house library screening to assay their ability to disrupt the interaction between the LEDGF cofactor and the HIV integrase. Structure modification led also to design and synthesize new compounds 17a-f. Compounds 11e,h,k,n, 13b, and 14 showed good activity in AlphaScreen assay. The most active compound 11e (IC50 = 2.5 µM) was selected for molecular modeling studies and showed a binding mode similar to the one of the known LEDGIN 8.


Assuntos
1-Naftilamina/análogos & derivados , Descoberta de Drogas , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , para-Aminobenzoatos/farmacologia , 1-Naftilamina/síntese química , 1-Naftilamina/química , 1-Naftilamina/farmacologia , Relação Dose-Resposta a Droga , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais Cultivadas , para-Aminobenzoatos/síntese química , para-Aminobenzoatos/química
15.
Molecules ; 20(7): 12623-51, 2015 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-26184144

RESUMO

HIV integrase, encoded at the 3'-end of the HIV pol gene, is essential for HIV replication. This enzyme catalyzes the incorporation of HIV DNA into human DNA, which represents the point of "no-return" in HIV infection. Integrase is a significant target in anti-HIV drug discovery. This review article focuses largely on the design of integrase inhibitors that are ß-diketo acids constructed on pyridinone scaffolds. Methodologies for synthesis of these compounds are discussed. Integrase inhibition data for the strand transfer (ST) step are compared with in vitro anti-HIV data. The review also examines the issue of the lack of correlation between the ST enzymology data and anti-HIV assay results. Because this disconnect appeared to be a problem associated with permeability, prodrugs of these inhibitors were designed and synthesized. Prodrugs dramatically improved the anti-HIV activity data. For example, for compound, 96, the anti-HIV activity (EC50) improved from 500 nM for this diketo acid to 9 nM for its prodrug 116. In addition, there was excellent correlation between the IC50 and IC90 ST enzymology data for 96 (6 nM and 97 nM, respectively) and the EC50 and EC90 anti-HIV data for its prodrug 116 (9 nM and 94 nM, respectively). Finally, it was confirmed that the prodrug 116 was rapidly hydrolyzed in cells to the active compound 96.


Assuntos
Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/química , HIV-1/efeitos dos fármacos , Cetoácidos/farmacologia , Pró-Fármacos/farmacologia , Piridonas/farmacologia , Transporte Biológico , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Desenho de Fármacos , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , HIV-1/enzimologia , HIV-1/crescimento & desenvolvimento , Humanos , Hidrólise , Concentração Inibidora 50 , Cetoácidos/síntese química , Cetoácidos/química , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/patologia , Leucócitos Mononucleares/virologia , Simulação de Acoplamento Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Piridonas/síntese química , Piridonas/química , Relação Estrutura-Atividade
16.
Angew Chem Int Ed Engl ; 54(24): 7144-8, 2015 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-25939331

RESUMO

A practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper-catalyzed acylation along with the implementation of the BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer.


Assuntos
Inibidores de Integrase de HIV/síntese química , Integrase de HIV/química , HIV/enzimologia , Acilação , Catálise , Cobre/química , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/química , Humanos , Ligantes , Estereoisomerismo , Sulfonamidas/química
17.
J Med Chem ; 58(4): 1915-28, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25629256

RESUMO

The development of HIV-1 dual inhibitors is a highly innovative approach aimed at reducing drug toxic side effects as well as therapeutic costs. HIV-1 integrase (IN) and reverse transcriptase-associated ribonuclease H (RNase H) are both selective targets for HIV-1 chemotherapy, and the identification of dual IN/RNase H inhibitors is an attractive strategy for new drug development. We newly synthesized pyrrolyl derivatives that exhibited good potency against IN and a moderate inhibition of the RNase H function of RT, confirming the possibility of developing dual HIV-1 IN/RNase H inhibitors and obtaining new information for the further development of more effective dual HIV-1 inhibitors.


Assuntos
Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV/efeitos dos fármacos , Pirróis/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Ribonuclease H/antagonistas & inibidores , Relação Dose-Resposta a Droga , HIV/enzimologia , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Estrutura Terciária de Proteína/efeitos dos fármacos , Pirróis/síntese química , Pirróis/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Ribonuclease H/metabolismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
18.
Bioorg Med Chem ; 22(19): 5446-53, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25150089

RESUMO

Raltegravir (RAL) is a first clinically approved integrase (IN) inhibitor for the treatment of HIV but rapid mutation of the virus has led to chemo-resistant strains. Therefore, there is a medical need to develop new IN inhibitors to overcome drug resistance. At present, several IN inhibitors are in different phases of clinical trials and few have been discontinued due to toxicity and lack of efficacy. The development of potent second-generation IN inhibitors with improved safety profiles is key for selecting new clinical candidates. In this article, we report the design and synthesis of potent 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide analogues as second-generation IN inhibitors. These compounds satisfy two structural requirements known for potent inhibition of HIV-1 IN catalysis: a metal chelating moiety and a hydrophobic functionality necessary for selectivity against the strand transfer reaction. Most of the new compounds described herein are potent and selective for the strand transfer reaction and show antiviral activity in cell-based assays. Furthermore, this class of compounds are drug-like and suitable for further optimization and preclinical studies.


Assuntos
Descoberta de Drogas , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV/efeitos dos fármacos , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
19.
J Med Chem ; 57(12): 5190-202, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24901667

RESUMO

There are currently three HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) approved by the FDA for the treatment of AIDS. However, the emergence of drug-resistant mutants emphasizes the need to develop additional agents that have improved efficacies against the existent resistant mutants. As reported herein, we modified our recently disclosed 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides IN inhibitors to develop compounds that have improved efficacies against recombinant IN in biochemical assays. These new compounds show single-digit nanomolar antiviral potencies against HIV vectors that carry wild-type (WT) IN in a single round replication assay and have improved potency against vectors harboring the major forms of drug resistant IN mutants. These compounds also have low toxicity for cultured cells, which in several cases, results in selectivity indices (CC50/EC50) of greater than 10000. The compounds have the potential, with additional structural modifications, to yield clinical agents that are effective against the known strains of resistant viruses.


Assuntos
Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/genética , HIV-1/efeitos dos fármacos , Naftiridinas/farmacologia , Pirrolidinonas/farmacologia , Linhagem Celular Tumoral , Farmacorresistência Viral , Células HEK293 , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , HIV-1/enzimologia , HIV-1/genética , Humanos , Mutação , Naftiridinas/síntese química , Naftiridinas/química , Raltegravir Potássico , Proteínas Recombinantes/química , Estereoisomerismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
20.
J Med Chem ; 57(11): 4640-60, 2014 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-24793360

RESUMO

We report herein further insight into the biological activities displayed by a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs). Substitution of the N-hydroxyimide two-metal binding pharmacophore at position 4 by carboxamido side chains was previously shown by us to be fruitful for this scaffold, since strong human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors in the low nanomolar range associated with low micromolar anti-HIV activities were obtained. We investigated the influence of substitution at position 7 on biological activity. Introduction of electron-withdrawing functional groups such as the nitro moiety at position 7 led to a noticeable improvement of antiviral activity, down to low nanomolar anti-HIV potencies, with advantageous therapeutic indexes going close to those of the clinically used raltegravir and retained potencies against a panel of IN mutants.


Assuntos
Inibidores de Integrase de HIV/síntese química , HIV-1/efeitos dos fármacos , Isoquinolinas/síntese química , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Linhagem Celular Tumoral , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Farmacorresistência Viral , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/genética , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Simulação de Acoplamento Molecular , Mutação , Relação Estrutura-Atividade
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