Abstract: In order to find highly active antidiabetic agents, the 3-amino group of skeletal structure of thiazolidine-2,4-diones (TZDs) was modified to generate the new molecules TM1 and TM2 in the present research. The new molecules TM3-TM6 containing rhodanine structural units were designed based upon the bioisostere and combination principles. The target molecules TM7, which is similar to the traditional TZDs structurally, were designed by connecting the phenolic hydroxyl of the above target molecules to carbazole through a linker. All of these target compounds were synthesized successfully by selecting suitable synthetic routes with optimized procedures. The assay results of peroxisome proliferator activated receptor response element (PPRE) agonist activity revealed that the PPAR agonist activity was decreased due to the change of TZD ring. The assay of α-glucosidase inhibitory activity and protein tyrosine phosphatase-1B (PTP-1B) inhibitory activity showed that most of the seven serials target molecules have weak activities in vitro. However, 3 of the compounds exhibited strong PTP-1B inhibitory activities. TM2-6 exhibited the highest inhibitory activities, which reached 96.71% with IC₅₀ 1.48 mg·L^-1. In addition, the toxicity prediction disclosed that the highly active compounds were almost non-toxic. These results provide a hint for the development of new antidiabetic