Synthesis and anti-diabetic activity evaluation of benzopyrimidine -7-azaindole derivatives targeting TXNIP/DYRK1A

Thioredoxin-interacting protein(TXNIP) inhibitors can inhibit the apoptosis of pancreatic β cells, while dual-specific tyrosine phosphatase regulator 1A (DYRK1A) inhibitors can promote the proliferation of pancreatic β cells. This study used 4-hydroxyquinazoline as the starting material to design and synthesize benzopyrimidine-7-azaindole scaffold derivatives targeting TXNIP/DYRK1A by linking it with variously substituted 7-azaindoles via carbon chains of different lengths. A total of 12 novel quinazoline-7-azaindole derivatives were designed and synthesized, their structures confirmed by ¹H NMR, ¹³C NMR, and ESI-MS, and their content was determined by HPLC. Pharmacological activity tests showed that all 12 compounds could inhibit β cell apoptosis, with YN-1~YN-3, YN-6 and YN-11exhibiting the strongest activity, achieving a cell survival rate greater than 70% (compared to 48.6% in the model group). Proliferative assays demonstrated that most compounds exhibit proliferative activity, with YN-1~YN-4 and YN-11 showing a proliferative activity greater than 120%. YN-3 exhibit the strongest inhibitory activity against apoptosis and the strongest proliferative activity, making them potential new chemical entities for anti-diabetic therapy.