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1.
Bioorg Med Chem ; 22(19): 5241-8, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25199582

RESUMO

The presence of a structural recognition motif for the nucleoside P2 transporter in a library of pyrimidine and triazine non-nucleoside HIV-1 reverse transcriptase inhibitors, prompted for the evaluation of antitrypanosomal activity. It was demonstrated that the structure-activity relationship for anti-HIV and antitrypanosomal activity was different. Optimization in the diaryl triazine series led to 6-(mesityloxy)-N2-phenyl-1,3,5-triazine-2,4-diamine (69), a compound with potent in vitro and moderate in vivo antitrypanosomal activity.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Testes de Sensibilidade Parasitária , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química
2.
Nucleic Acids Res ; 40(7): 3018-30, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22156370

RESUMO

Ethionamide is an antituberculous drug for the treatment of multidrug-resistant Mycobacterium tuberculosis. This antibiotic requires activation by the monooxygenase EthA to exert its activity. Production of EthA is controlled by the transcriptional repressor EthR, a member of the TetR family. The sensitivity of M. tuberculosis to ethionamide can be artificially enhanced using synthetic ligands of EthR that allosterically inactivate its DNA-binding activity. Comparison of several structures of EthR co-crystallized with various ligands suggested that the structural reorganization of EthR resulting in its inactivation is controlled by a limited portion of the ligand-binding-pocket. In silico simulation predicted that mutation G106W may mimic ligands. X-ray crystallography of variant G106W indeed revealed a protein structurally similar to ligand-bound EthR. Surface plasmon resonance experiments established that this variant is unable to bind DNA, while thermal shift studies demonstrated that mutation G106W stabilizes EthR as strongly as ligands. Proton NMR of the methyl regions showed a lesser contribution of exchange broadening upon ligand binding, and the same quenched dynamics was observed in apo-variant G106W. Altogether, we here show that the area surrounding Gly106 constitutes the molecular switch involved in the conformational reorganization of EthR. These results also shed light on the mechanistic of ligand-induced allosterism controlling the DNA binding properties of TetR family repressors.


Assuntos
Proteínas Repressoras/química , Substituição de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , DNA/metabolismo , Ligantes , Modelos Moleculares , Mutagênese , Ressonância Magnética Nuclear Biomolecular , Dobramento de Proteína , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
3.
Bioorg Med Chem ; 19(20): 5924-34, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21930388

RESUMO

In this Letter, we report on diarylpyridinone, diarylpyridazinone and diarylphthalazinone analogs as potential inhibitors of HIV-1 nonnucleoside reverse transcriptase (NNRTIs). The most promising compounds in these series are three diarylpyridazinones 25a, 25l and 25n which demonstrated submicromolar activity against wild-type HIV-1 and moderate activity against the single mutant strain Ba-L V106A.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Ftalazinas/farmacologia , Piridazinas/farmacologia , Piridonas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/química , Humanos , Modelos Moleculares , Ftalazinas/química , Piridazinas/química , Piridonas/química , Inibidores da Transcriptase Reversa/química
4.
J Med Chem ; 54(8): 2994-3010, 2011 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-21417236

RESUMO

We report in this article an extensive structure-activity relationships (SAR) study with 58 thiophen-2-yl-1,2,4-oxadiazoles as inhibitors of EthR, a transcriptional regulator controling ethionamide bioactivation in Mycobacterium tuberculosis. We explored the replacement of two key fragments of the starting lead BDM31343. We investigated the potency of all analogues to boost subactive doses of ethionamide on a phenotypic assay involving M. tuberculosis infected macrophages and then ascertained the mode of action of the most active compounds using a functional target-based surface plasmon resonance assay. This process revealed that introduction of 4,4,4-trifluorobutyryl chain instead of cyanoacetyl group was crucial for intracellular activity. Replacement of 1,4-piperidyl by (R)-1,3-pyrrolidyl scaffold did not enhance activity but led to improved pharmacokinetic properties. Furthermore, the crystal structures of ligand-EthR complexes were consistent with the observed SAR. In conclusion, we identified EthR inhibitors that boost antibacterial activity of ethionamide with nanomolar potency while improving solubility and metabolic stability.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Etionamida/química , Etionamida/farmacologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Animais , Antituberculosos/síntese química , Sequência de Bases , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Primers do DNA , Relação Dose-Resposta a Droga , Etionamida/síntese química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Modelos Moleculares , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície
5.
ACS Chem Biol ; 5(11): 1007-13, 2010 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-20704273

RESUMO

In situ click chemistry has been successfully applied to probe the ligand binding domain of EthR, a mycobacterial transcriptional regulator known to control the sensitivity of Mycobacterium tuberculosis to several antibiotics. Specific protein-templated ligands were generated in situ from one azide and six clusters of 10 acetylenic fragments. Comparative X-ray structures of EthR complexed with either clicked ligand BDM14950 or its azide precursor showed ligand-dependent conformational impacts on the protein architecture. This approach revealed two mobile phenylalanine residues that control the access to a previously hidden hydrophobic pocket that can be further exploited for the development of structurally diverse EthR inhibitors. This report shows that protein-directed in situ chemistry allows medicinal chemists to explore the conformational space of a ligand-binding pocket and is thus a valuable tool to guide drug design in the complex path of hit-to-lead processes.


Assuntos
Antituberculosos/química , Azidas/química , Química Click/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Oxidiazóis/química , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/química , Antituberculosos/farmacologia , Azidas/farmacologia , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Ligantes , Mycobacterium tuberculosis/genética , Oxidiazóis/farmacologia , Conformação Proteica , Transcrição Gênica/efeitos dos fármacos
6.
Nat Med ; 15(5): 537-44, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19412174

RESUMO

The side effects associated with tuberculosis therapy bring with them the risk of noncompliance and subsequent drug resistance. Increasing the therapeutic index of antituberculosis drugs should thus improve treatment effectiveness. Several antituberculosis compounds require in situ metabolic activation to become inhibitory. Various thiocarbamide-containing drugs, including ethionamide, are activated by the mycobacterial monooxygenase EthA, the production of which is controlled by the transcriptional repressor EthR. Here we identify drug-like inhibitors of EthR that boost the bioactivation of ethionamide. Compounds designed and screened for their capacity to inhibit EthR-DNA interaction were co-crystallized with EthR. We exploited the three-dimensional structures of the complexes for the synthesis of improved analogs that boosted the ethionamide potency in culture more than tenfold. In Mycobacterium tuberculosis-infected mice, one of these analogs, BDM31343, enabled a substantially reduced dose of ethionamide to lessen the mycobacterial load as efficiently as the conventional higher-dose treatment. This provides proof of concept that inhibiting EthR improves the therapeutic index of thiocarbamide derivatives, which should prompt reconsideration of their use as first-line drugs.


Assuntos
Antituberculosos/uso terapêutico , Etionamida/uso terapêutico , Oxidiazóis/uso terapêutico , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/uso terapêutico , Tiofenos/uso terapêutico , Tuberculose/tratamento farmacológico , Animais , Sítios de Ligação , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Sinergismo Farmacológico , Ligação de Hidrogênio , Ligantes , Camundongos , Modelos Moleculares , Conformação Proteica , Proteínas Repressoras/química
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