期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 258, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2023.115591
关键词
Thiazolidine-2; 4-dione; Diabetes; Multi-target drug design; DPP-4
Metabolic disorders like Diabetes mellitus (DM) can be treated by targeting abnormally expressed key enzymes. A vanillin-thiazolidine-2,4-dione hybrid compound was reported as a multitarget inhibitor, but only showed good in-vitro DPP-4 inhibition. Current research aims to optimize this lead compound for diabetes treatment by manipulating multiple pathways simultaneously.
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-2,4dione hybrid 3 as multitarget inhibitor of & alpha;-glucosidase, & alpha;-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 (ZHMMTD) 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 glucoseuptake promotor via hemi diaphragm of the rat. Moreover, the compounds demonstrated antidiabetic activity in STZ-induced diabetic animal model.
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