RESUMO
Preliminary hit-to-lead optimization of a novel series of phenylsulfonyl hydrazide derivatives, which were derived from the high throughput screening hit compound 1 (IC50=5700nM against PGE2 production), for a potent suppressor of PGE2 production is described. Subsequent optimization led to the identification of the potent lead compound 8n with IC50 values of 4.5 and 6.9nM, respectively, against LPS-induced PGE2 production and NO production in RAW 264.7 macrophage cells. In addition, 8n was about 30- and >150-fold more potent against mPGES-1 enzyme in a cell-free assay (IC50=70nM) than MK-886 and hit compound 1, respectively. Molecular docking suggests that compound 8n could inhibit PGE2 production by blocking the PGH2 binding site of human mPGES-1 enzyme.
Assuntos
Dinoprostona/biossíntese , Inibidores Enzimáticos/farmacologia , Hidrazinas/farmacologia , Oxirredutases Intramoleculares/antagonistas & inibidores , Simulação de Acoplamento Molecular , Compostos de Sulfidrila/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Oxirredutases Intramoleculares/química , Oxirredutases Intramoleculares/metabolismo , Estrutura Molecular , Prostaglandina-E Sintases , Relação Estrutura-Atividade , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/químicaRESUMO
We present the synthesis and biological evaluation of a collection of s-triazine derivatives as a novel scaffold of compounds with the capability to inhibit the PGE2 production in LPS-induced RAW 264.7 macrophage cells. A total of 12 derivatives were synthesized and assayed for PGE2 reduction at 10 µM concentration. Two compounds (7b and 7i) exhibiting >90% inhibition of PGE2 production were found to have IC50 values of 5.76 and 5.52 µM, respectively. They were counter screened for inhibition on COX-2 activity in a cell free assay. Specifically, compound 7i (R¹ = 4-Bn-Ph, R² = Cl, R³ = Ph, R5 = CO2Me) was highly active in cells while maintaining little COX-2 inhibition (â¼0% at 10 µM). Molecular docking study provides the possibility that compound 7i could inhibit PGE2 production by blocking the PGH2 binding site of mPGES-1 instead of COX-2 enzyme. Based on this result, our synthetic efforts will focus on intensive structure-activity relationship (SAR) study of s-triazine scaffold to discovery a potential PGE2 synthesis inhibitor.