13-a

A series of 38 phthalazinone-triazole compounds were synthesized using Click chemistry to identify potential antidiabetic agents. These compounds were systematically tested for their ability to promote glucose transporter type 4 (GLUT4) translocation in skeletal muscle cells. Among the 38 derivatives, 11 compounds (i.e., 12k, 13a-13c, 13e-13i, 13s, and 13v) showed significant potential to stimulate GLUT4 translocation in skeletal muscle cells, with compound 13a exhibiting most promising activity. Further, treatment with 13a induced a concentration-dependent increase in GLUT4 translocation in L6 skeletal muscle cells through the activation of wortmannin-sensitive PI-3-K-dependent signaling and AMPK-dependent signaling pathways. The in vivo studies further demonstrated that compound 13a effectively lowered blood glucose levels in STZ-induced diabetic rats and displayed favorable pharmacokinetic properties, making it a promising candidate for further development as an antidiabetic agent.

To promote the development of the new generation of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel 2,4,5-trisubstituted pyrimidine derivatives targeting the "tolerant region I″ and "tolerant region II" of NNRTI binding pocket (NNIBP) were designed through multi-site binding strategy. Among them, 13a was demonstrated with an improved potency against wild-type (WT) and a panel of mutant HIV-1 strains with EC₅₀ values ranging from 0.0062 to 0.25 μM, being superior to that of efavirenz (EFV, EC₅₀ = 0.0080-0.37 μM). In addition, 13a was proved to have low cytotoxicity (CC₅₀ = 160.7 μM) and high SI values (SI = 25254). Further HIV-1 RT inhibition assay demonstrated that 13a is a classical NNRTI with an IC₅₀ value of 0.41 μM. Molecular docking and molecular dynamics simulations results illustrated its binding mode with HIV-1 RT. Overall, these enchanting results illuminated the potential of 13a as a promising lead for the development of the new generation HIV-1 NNRTIs drugs.