Design,Synthesis And Biological Evaluation Of Novel Bromophenol Derivatives As DPP-4 Inhibitors

Diabetes is a fast growing chronic metabolic disorder around the world.The risks of many micro-and macro-vascular complications are increased due to diabetes.Recently,many drugs are approved for the treatment of type 2 diabetes mellitus.Dipeptidyl peptidase-4?DPP-4?inhibitors could prevent the inactivation of glucagon-like peptide-1?GLP-1?and glucose-dependent insulinotropic polypeptide?GIP?which contributes to insulin secretion stimulation,glucagon secretion inhibition and thereby glucose control improvement.Synergistic activity is often attributed to molecular hybrids with different pharmacophores.By use of molecular hybrids and docking,we designed a series of novel bromophenol derivatives containing pyrimidinedione skeleton.Apart from pyrimidinedione core and bromophenol,the butynyl group,the fluorocyanobenzyl or?R?-3-aminopiperidine was determined as substituents.Predicted docking interactions of 36 and DPP-4 were also described in this article.The synthesis of?R?-6?3-aminopiperidin-1-yl?-3-?3-bromo-4,5-dimethoxybenzyl?-1-?but-2-yn-1-yl?pyrimidine-2,4?1H,3H?-dione,?R?-6?3-aminopiperidin-1-yl?-1-?but-2-yn-1-yl?-3-?2,3-dibromo-4,5-dimethoxybenzyl?pyrimidine-2,4?1H,3H?-dione,?R?-2-??6-?3-aminopiperidin-1-yl?-3-?3,4-dimethoxybenzyl?-2,4-dioxo-3,4-dihydropyrimidin-1?2H?-yl?methyl?-4-fluorobenzonitrile and other bromophenol derivatives was started from commercially available compound 6-chlorouracil.Then,the resulting compounds were transformed by a process including alkylation,the N-alkylation,and removal of Boc with TFA.We determined the structures of final compounds by¹H-NMR,¹³C-NMR.The purity and melt point of 18 compounds were also measured.We evaluated the in vitro DPP-4 inhibitory activity of 18 compounds.Among them,the representative compounds 35,39 and 40 showed potent inhibitory activity of DPP-4 with IC₅₀ values of 64.47 nM,188.7 nM and 65.36 nM,compared with Sitagliptin?37.96 nM?.Further studies showed that the blood glucose levels were reduced from the second week in compound 35-treated group.These results revealed that compound 35 has anti-diabetic potency with an effective blood glucose-lowing effect.Through molecular hybrids with different pharmacophores and computer-aided design of molecular docking,a series of novel bromophenol derivatives containing pyrimidinedione skeleton were designed and synthesized.The in vitro DPP-4inhibitory activity of 18 compounds and the anti-diabetic activities in vivo were evaluated.We provide experience and research methods for further study on DPP-4inhibitors.