Indirubin is an isomer of the blue dye indigo. It is widely used in Chinese medicine as part of therapy against many diseases and, thus, its skeleton becomes a promising candidate for new drug prototypes. Since it has low solubility, its properties could be improved through the insertion of hydrophilic and pharmacophoric groups, such as sugars bridged to 1,2,3-triazoles. Here, we report the synthesis of indirubin-based compounds evaluating two different routes: via the aldol condensation reaction of triazole-isatin derivatives with 3-acetoxyindole (pathway A) and reductive coupling of isatin, followed by N-propargylation of indirubin. We also performed reactivity studies guided by density functional theory (DFT) calculations (pathway B). As a demonstration, we simulate interactions with the glycogen synthase kinase 3β enzyme, which is associated with neurodegenerative diseases, through both molecular docking and molecular dynamics simulations. indigo thus prototypes solubility groups 1,2,3triazoles. 123triazoles triazoles 1,2,3 triazoles. 1 2 3 1,2,3-triazoles Here indirubinbased indirubin based routes triazoleisatin triazole isatin 3acetoxyindole acetoxyindole pathway A Npropargylation N propargylation DFT (DFT B. B . B) demonstration β enzyme simulations 3triazoles 1,2,3triazoles 123 1,2, 12 1,2 1,

Abstract The administration of medications on the skin through transcutaneous routes is a practice that has been used by mankind for millennia. Some studies have been reporting the use of terpenes and natural oils rich in terpenes as an enhancer of cutaneous penetration. Copaiba oil, due to its rich content of terpenes, presents itself as a great choice of penetration enhancer for drugs administered on the skin. In this study, we developed two cream formulations containing 5% of ibuprofen (IBU) and copaiba oil: IBCO5 and IBCO10 with 5% and 10% of copaiba oil respectively. Ex vivo cutaneous penetration/permeation studies of IBU were performed using pig ear skin as biological membrane in the Franz-type diffusion cells. The steady-state flux of IBU samples, IBCO5 (35.72 ± 6.35) and IBCO10 (29.78 ± 2.41) were significantly higher when compared with control without copaiba oil (10.32 ±1.52) and with a commercial product (14.44 ± 2.39). In the penetration analysis, the amount of IBU found in the samples IBCO5 and IBCO10 was markedly higher in the dermis than epidermis. Our results showed that copaiba oil possesses attracting properties in promoting skin penetration and permeation of IBU when added into cream formulations.