RESUMO
TLR7/8 agonists are versatile immune stimulators capable of treating various diseases such as viral infections, autoimmune, and cancer. Despite the structural similarity of TLR7/8, their immune stimulation mechanisms and time-course responses significantly differ. In this study, a new series of TLR7-selective agonists was synthesized utilizing the economical building block 2,6-dichloropurine. Compound 27b showed the most potent activity on hTLR7 with an EC50 of 17.53 nM and demonstrated high hTLR7 selectivity (224 folds against TLR8). 27b effectively stimulated the secretion of proinflammatory cytokines in mouse macrophages and enhanced intranasal vaccine efficacy against influenza A virus in vivo. Assessment of humoral and mucosal antibody titers confirmed that 27b elevates IgG and IgA levels, protecting against both homologous and heterologous influenza viral infections. These findings suggest that 27b is a promising candidate as a vaccine adjuvant to prevent viral infections or as a robust immunomodulator with prolonged activity for treating immune-suppressed diseases.
Assuntos
Administração Intranasal , Desenho de Fármacos , Vacinas contra Influenza , Purinas , Receptor 7 Toll-Like , Receptor 7 Toll-Like/agonistas , Animais , Camundongos , Humanos , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Purinas/farmacologia , Purinas/química , Adjuvantes de Vacinas/farmacologia , Adjuvantes de Vacinas/química , Relação Estrutura-Atividade , Camundongos Endogâmicos BALB C , Feminino , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/imunologia , Citocinas/metabolismo , Células RAW 264.7 , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/síntese química , Adjuvantes Imunológicos/químicaRESUMO
Tryptophan hydroxylase 1 (TPH1) has emerged as a target for the treatment of metabolic diseases including obesity and fatty liver disease. A series of xanthine derivatives were synthesized and evaluated for their TPH1 inhibition. Among the synthesized compounds, compound 40 showed good in vitro activity and liver microsomal stability. Docking studies revealed that compound 40 showed better binding to TPH1 via key intermolecular interactions involving the xanthine scaffold, imidazo-thiazolyl ring, and hydroxyl-containing phenacyl moiety. In addition, compound 40 effectively suppressed the adipocyte differentiation of 3 T3-L1 cells.
Assuntos
Alcaloides , Hepatopatia Gordurosa não Alcoólica , Humanos , Diuréticos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Triptofano Hidroxilase/antagonistas & inibidores , Xantinas/química , Xantinas/farmacologiaRESUMO
A series of aryl sulfide derivatives was synthesized and evaluated for their anti-melanogenic activities. Several compounds, including 3e, 3i and 3q exhibited good anti-melanogenic activities. Among the derivatives, compound 3i showed good inhibitory effects against melanin synthesis and showed no toxicity in reconstituted human eye and skin tissues.