In accordance with the structural characteristics of thiazolidinedione drugs and highly bioactive tyrosine derivatives, we tentatively designed the l-phenylglycine derivatives TM1 and TM2 based on basic principles of drug design and then synthesized them. The in vitro screening of peroxisome proliferator-activated receptor gamma (PPARγ) activated activity, α-glucosidase inhibitory and dipeptidyl peptidase-4 inhibitory activities showed that the novel molecule M5 had efficient PPAR response element (PPRE) activated activity (PPRE relative activity 105.04% at 10 μg·mL⁻¹ compared with the positive control pioglitazone, with 100% activity). Therefore, M5 was selected as the hit compound from which the TM3 and TM4 series of compounds were further designed and synthesized. Based on the PPRE relative activities of TM3 and TM4, we discovered another new molecule, TM4h, which had the strongest PPRE relative activity (120.42% at 10 μg·mL⁻¹). In addition, the concentration-dependent activity of the highly active compounds was determined by assaying their half-maximal effective concentration (EC₅₀) values. The molecular physical parameter calculation and the molecular toxicity prediction were used to theoretically evaluate the lead-likeness and safety of the active compounds. In conclusion, we identified a potential PPARγ lead molecule and developed a tangible strategy for antidiabetic drug development.

根据噻唑烷二酮类药物和具有高生物活性的酪氨酸衍生物的结构特征，我们根据药物设计的基本原理初步设计了1-苯基甘氨酸衍生物TM1和TM2，然后对其进行了合成。在体外过氧化物酶体增殖物激活受体γ（PPARγ）的激活的活动的筛选，α葡萄糖苷酶抑制和二肽基肽4的抑制活性表明，所述新型分子M5有高效的PPAR反应元件（PPRE）活化的活性（PPRE相对活性105.04％与阳性对照吡格列酮相比，浓度为10μg·mL ^-1，活性为100％）。因此，M5选择“ H2O3”作为命中化合物，从中进一步设计和合成TM3和TM4系列化合物。根据TM3和TM4的PPRE相对活性，我们发现了另一个新分子TM4h，其具有最强的PPRE相对活性（在10μg·mL ^-1时为120.42％）。此外，高活性化合物的浓度依赖性活性是通过测定其最大有效浓度的一半来确定的（EC ₅₀）值。通过分子物理参数计算和分子毒性预测从理论上评估了活性化合物的铅样和安全性。总之，我们确定了潜在的PPARγ前导分子，并为抗糖尿病药物开发制定了切实可行的策略。