RESUMO
Following our previous research on anti-inflammatory drugs (NSAIDs), we report here the synthesis of chiral 1,5-diarylpyrroles derivatives that were characterized for their in vitro inhibitory effects toward cyclooxygenase (COX) isozymes. Analysis of enzymatic affinity and COX-2 selectivity led us to the selection of one compound (+/-)-10b that was further tested in vitro in the human whole blood (HWB) and in vivo for its anti-inflammatory activity in mice. The affinity data have been rationalized through docking simulations.
Assuntos
Álcoois/química , Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Éteres/química , Modelos Químicos , Pirróis/farmacologia , Ácido Acético , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Sítios de Ligação , Carragenina , Células Cultivadas , Simulação por Computador , Ciclo-Oxigenase 1/efeitos dos fármacos , Ciclo-Oxigenase 2/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Isoenzimas/efeitos dos fármacos , Masculino , Camundongos , Estrutura Molecular , Dor/induzido quimicamente , Dor/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Pirróis/síntese química , Pirróis/química , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
As a continuation of our previous work that turned toward the identification of antimycobacterial compounds with innovative structures, two series of pyrazole derivatives were synthesized by parallel solution-phase synthesis and were assayed as inhibitors of Mycobacterium tuberculosis (MTB), which is the causative agent of tuberculosis. One of these compounds showed high activity against MTB (MIC = 4 microg/mL). The newly synthesized pyrazoles were also computationally investigated to analyze their fit properties to the pharmacophoric model for antitubercular compounds previously built by us and to refine structure-activity relationship analysis.
Assuntos
Antituberculosos , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazóis/farmacologia , Antituberculosos/síntese química , Antituberculosos/farmacologia , Testes de Sensibilidade Microbiana , Pirazóis/síntese química , Relação Estrutura-AtividadeRESUMO
The assignment of the absolute configuration of novel anti-inflammatory pyrrole derivatives has been accomplished by a combined strategy based on independent physical methods. The key step of our stereochemical characterization approach is the production at mg-scale of enantiomerically pure forms by HPLC on Chiralpak IA stationary phase.
Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Pirróis/química , Pirróis/isolamento & purificação , Dicroísmo Circular , Cristalografia por Raios X , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Espectrofotometria Ultravioleta , EstereoisomerismoRESUMO
The important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effect limitations of current COX-2 inhibitor drugs illustrates a need for the design of new compounds based on alternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selective COX-2 inhibitors and their affinity data were rationalized through docking simulations. In this paper, we describe the synthesis of new 1,5-diarylpyrrole derivatives that were assayed for their in vitro inhibitory effects toward COX isozymes. Among them, the ethyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-fluorophenyl]-1H-pyrrol-3-acetate (1d), which was the most potent and COX-2 selective compound, also showed a very interesting in vivo anti-inflammatory and analgesic activity, laying the foundations for developing new lead compounds that could be effective agents in the armamentarium for the management of inflammation and pain.
Assuntos
Acetatos/síntese química , Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Ciclo-Oxigenase 2/metabolismo , Pirróis/síntese química , Acetatos/química , Acetatos/farmacologia , Adulto , Animais , Carragenina , Linhagem Celular , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/sangue , Edema/induzido quimicamente , Edema/prevenção & controle , Feminino , Humanos , Masculino , Camundongos , Modelos Moleculares , Medição da Dor , Pirróis/química , Pirróis/farmacologia , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade , Proteínas com Domínio T/sangueRESUMO
On the basis of suggestions derived either from a pharmacophoric model for antitubercular agents or from a structure-activity relationship analysis of many pyrroles previously described by us, we report here the design and synthesis of new analogues of 1,5-(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM212). Various substituents with different substitution patterns were added to both positions 1 and 5 of the pyrrole nucleus to evaluate their influence on the activity toward Mycobacterium tuberculosis (MTB) and atypical mycobacteria. Biological data showed that, although some nontuberculosis mycobacterial strains were found to be sensitive, MIC values were higher than those found toward MTB. The best compound (1-(4-fluorophenyl)-2-methyl-3-(thiomorpholin-4-yl)methyl-5-(4-methylphenyl)-1H-pyrrole, 5) possessed a MIC of 0.4 microg/mL (better than BM212 and streptomycin) and a very high protection index (160), better than BM212, isoniazid, and streptomycin (6, 128, and 128, respectively). Finally, molecular modeling studies were performed to rationalize the activity of the new compounds in terms of both superposition onto a pharmacophoric model for antitubercular compounds and their hydrophobic character.