Design, synthesis and biological evaluation of quinazoline-carbazole derivatives as dual TXNIP/DYRK1A inhibitors for the treatment of type 2 diabetes mellitus.

Abstract

TXNIP and DYRK1A are two novel drug targets for the treatment of type 2 diabetes (T2DM), and their respective inhibitors have been shown to suppress islet β-cell apoptosis and promote islet β-cell proliferation. The quinazoline scaffold constitutes the core pharmacophore of TXNIP inhibitors. Harmine, a prototypical DYRK1A inhibitor bearing a β-carboline scaffold, has demonstrated robust β-cell proliferative activity. Carbazole serves as a structurally simplified bioisostere of β-carboline. Guided by the principles of multi-target drug design and combinatorial chemistry, we designed and synthesized a series of quinazoline-carbazole hybrids as dual TXNIP/DYRK1A inhibitors. Compounds PF-5 and PF-6 markedly attenuated palmitic acid (PA)-induced β‑cell injury by suppressing the TXNIP-NLRP3-IL-1β signaling axis. Meanwhile, compounds PF-6 and PF-8 enhanced β-cell proliferation via DYRK1A inhibition. Molecular docking confirmed PF-6 bound with high affinity to both targets, and ADMET predictions supported its drug-like properties. Thus, PF-6 emerges as a potential dual-target therapeutics for T2DM. In conclusion, PF-6 can be used as a potential new chemical entity against T2DM.