Synthesis and discovery of triazolo-pyridazine-6-yl-substituted piperazines as effective anti-diabetic drugs; evaluated over dipeptidyl peptidase-4 inhibition mechanism and insulinotropic activities

被引：22

作者：

Bindu, B. ^{[1
]}

Vijayalakshmi, S. ^{[1
]}

Manikandan, A. ^{[2
]}

机构：

[1] Govt Arts Coll, Dept Chem, Coimbatore 641018, Tamil Nadu, India

[2] VIT Univ, Sch Biosci & Technol, Dept Biotech, Vellore 632014, Tamil Nadu, India

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 187卷

关键词：

Antioxidant; Diabetes; Dipeptidyl peptidase-4; Molecular docking; MTT assay; Piperazines; Pyridazine; OXIDATIVE STRESS; TYPE-2; SITAGLIPTIN; PLASMA; DNA;

D O I：

10.1016/j.ejmech.2019.111912

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A family of 12 triazolo-pyridazine-6-yl-substituted piperazines (5a-1) was synthesized and evaluated for their Dipeptidyl peptidase-4 (DPP-4) inhibition potentials in order to develop them as anti-diabetic medications. In the two-step synthesis process, 6-chloro-3-(m-tolyl)-[1,2,4]triazolo[4,3-b]pyridazine was synthesized with one-pot mode using pyridine, 3,6-dichloropyridazine 5-(3-methyl-phenyl)tetrazole in toluene. Conjugating corresponding 2 degrees amines with 6-chloro-3-(m-tolyl)-[1,2,4]triazolo[4,3-13] pyridazine afforded the target triazolo-pyridazine-6-yl-substituted piperazines (5a-1). DPP-4 inhibition potential of these compounds was testified in silico and in nitro along with their insulinotropic activities in 832/13 INS-1 cells. H2O2 radical scavenging assay and MTT assay were conducted to assess the anti-oxidant and cytotoxicity of these compounds respectively. Molecular docking and. ELBA based enzyme inhibition assay results revealed the strong inhibition potential of the target compounds. MTT assay results indicated a maximum dose of 2.5 nM (IC50 1.25 nM) could be used and above this level vital for the cells. Compounds 5a, 5c, 5g and 5i were found with excellent antioxidant and insulinotropic activity up to 99%. (C) 2019 Elsevier Masson SAS. All rights reserved.

引用

页数：8

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