In case of metabolic disorder like Diabetes mellitus (DM), a number of key enzymes are abnormally expressed and hence they might be excellent targets for antidiabetic drug design. Multi-target design strategy has recently attracted great attention to treat challenging diseases. We have previously reported a vanillin-thiazolidine-2,4-dione hybrid 3 as multitarget inhibitor of α-glucosidase, α-amylase, PTP-1B and DPP-4. The reported compound predominantly exhibited good in-vitro DPP-4 inhibition only. Current research describes the goal to optimize an early lead compound. The efforts were focused on enhancing the capability of manipulating multiple pathways at the same time for the treatment of diabetes. The central 5-benzylidinethiazolidine-2,4-dione for Lead compound (Z)-5-(4-hydroxy-3-methoxybenzylidene)-3-(2-morpholinoacetyl)thiazolidine-2,4-dione (Z-HMMTD) was left unchanged. While East and West moieties were altered by the introduction of different building blocks conceived by using a number of rounds of predictive docking studies performed on X-ray crystal structures of four target enzymes. This systematic SAR led to the syntheses of new potent multi-target antidiabetic compounds 47–49 and 55–57 with many fold increase in the in-vitro potency compared to Z-HMMTD. The potent compounds showed good in-vitro and in-vivo safety profile. Compound 56 emerged excellent as glucose-uptake promotor via hemi diaphragm of the rat. Moreover, the compounds demonstrated antidiabetic activity in STZ-induced diabetic animal model.

在糖尿病（DM）等代谢紊乱的情况下，许多关键酶会异常表达，因此它们可能是抗糖尿病药物设计的绝佳靶标。多靶点设计策略最近在治疗挑战性疾病方面引起了极大的关注。我们之前报道过香草醛-噻唑烷-2,4-二酮杂合体3作为 α-葡萄糖苷酶、α-淀粉酶、PTP-1B 和 DPP-4 的多靶点抑制剂。报道的化合物仅主要表现出良好的体外DPP-4 抑制作用。目前的研究描述了优化早期先导化合物的目标。这些努力的重点是增强同时操纵多个途径治疗糖尿病的能力。先导化合物 (Z)-5-(4-羟基-3-甲氧基亚苄基)-3-(2-吗啉代乙酰基)噻唑烷-2,4-二酮 (Z -HMMTD) 的中心 5-苄基噻唑烷-2,4-二酮为保持不变。同时，通过引入不同的构建块来改变东西方部分，这些构建块是通过对四种目标酶的 X 射线晶体结构进行多轮预测对接研究而构想的。这种系统的 SAR 导致合成了新的有效多靶点抗糖尿病化合物47-49和55-57，与 Z-HMMTD 相比，其体外效力增加了许多倍。这些有效的化合物表现出良好的体外和体内安全性。化合物56作为通过大鼠半隔膜的葡萄糖摄取促进剂表现出优异的表现。此外，这些化合物在 STZ 诱导的糖尿病动物模型中表现出抗糖尿病活性。