RESUMO
Eicosanoids like leukotrienes and prostaglandins play a considerable role in inflammation. Produced within the arachidonic acid (AA) cascade, these lipid mediators are involved in the pathogenesis of pain as well as acute and chronic inflammatory diseases like rheumatoid arthritis and asthma. With regard to the lipid cross-talk within the AA pathway, a promising approach for an effective anti-inflammatory therapy is the development of inhibitors targeting more than one enzyme of this cascade. Within this study, thirty N-4-diaryl-1,3-thiazole-2-amine based compounds with different substitution patterns were synthesized and tested in various cell-based assays to investigate their activity and selectivity profile concerning five key enzymes involved in eicosanoid metabolism (5-, 12-, 15-lipoxygenase (LO), cyclooxygenase-1 and -2 (COX-1/-2)). With compound 7, 2-(4-phenyl)thiazol-2-ylamino)phenol (ST-1355), a multi-target ligand targeting all tested enzymes is presented, whereas compound 9, 2-(4-(4-chlorophenyl)thiazol-2-ylamino)phenol (ST-1705), represents a potent and selective 5-LO and COX-2 inhibitor with an IC50 value of 0.9 ± 0.2 µM (5-LO) and a residual activity of 9.1 ± 1.1% at 10 µM (COX-2 product formation). The promising characteristics and the additional non-cytotoxic profile of both compounds reveal new lead structures for the treatment of eicosanoid-mediated diseases.
Assuntos
Aminofenóis/farmacologia , Eicosanoides/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Tiazóis/farmacologia , Proteínas Ativadoras de 5-Lipoxigenase/metabolismo , Aminofenóis/síntese química , Aminofenóis/química , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Eicosanoides/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células HeLa , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Células Tumorais Cultivadas , Células U937RESUMO
A class of 5-lipoxygenase (5-LO) inhibitors characterized by a central 5-benzylidene-2-phenyl-thiazolinone scaffold was synthesized as a new series of molecular modifications and extensions of a previously reported series. Compounds were tested in a cell-based and a cell-free assay and furthermore evaluated for their influence on cell viability. The presented substituted thiazolinone scaffold turned out to be essential for both the 5-LO inhibitory activity and the non-cytotoxic profile. With (Z)-5-(4-methoxybenzylidene)-2-(naphthalen-2-yl)-5H-thiazol-4-one (2k, ST1237), a potent, direct, non-cytotoxic 5-LO inhibitor with IC(50) of 0.08 µM and 0.12 µM (cell-free assay and intact cells), we present a promising lead optimization and development for further investigations as novel anti-inflammatory drug.
Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacologia , Tiazóis/química , Sobrevivência Celular/efeitos dos fármacos , Sistema Livre de Células , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Neutrófilos/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A novel class of potent direct 5-lipoxygenase (5-LO) inhibitors bearing a thiazolinone-scaffold identified by virtual screening is presented. A range of substitutions and the importance of the 2-phenyl moiety were evaluated. This series is characterized by high potency in intact polymorphonuclear leukocytes and a cell-free system, exemplified by (Z)-2-(4-chlorophenyl)-5-(4-methoxybenzylidene)-5H-thiazol-4-one (18, IC(50) = 0.28 and 0.09 µM). These disubstituted thiazolinones may possess potential for intervention with inflammatory and allergic diseases and certain cancer types.