Synthesis, biological evaluation and molecular modeling studies of imidazo[1,2-α]pyridines derivatives as protein kinase inhibitors

被引：28

作者：

Lawson, Marie ^{[1
]}

Rodrigo, Jordi ^{[1
]}

Baratte, Blandine ^{[2
]}

Robert, Thomas ^{[2
]}

Delehouze, Claire ^{[2
]}

Lozach, Olivier ^{[2
]}

Ruchaud, Sandrine ^{[2
]}

Bach, Stephane ^{[2
]}

Brion, Jean-Daniel ^{[1
]}

Alami, Mouad ^{[1
]}

Hamze, Abdallah ^{[1
]}

机构：

[1] Univ Paris Saclay, Equipe Labellisee Ligue Canc, CNRS, BioCIS,Univ Paris Sud, F-92290 Chatenay Malabry, France

[2] Univ Paris 06, Sorbonne Univ, CNRS,Stn Biol Roscoff, USR3151,Prot Phosphorylat & Human Dis Unit,Platef, Pl Georges Teissier, F-29688 Roscoff, France

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 123卷

关键词：

CLK1; DYRK1A; Kinase inhibitors; Imidazo[1,2-alpha]pyridines; POTENT INHIBITORS; DOWN-SYNDROME; DISCOVERY; DYRK1A; LEUCETTINES; LIGANDS; DISEASE; ANALOGS; TARGETS; CANCER;

D O I：

10.1016/j.ejmech.2016.07.040

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report here the synthesis, the biological evaluation and the molecular modeling studies of new imidazo[1,2-alpha]pyridines derivatives designed as potent kinase inhibitors. This collection was obtained from 2-aminopyridines and 2-bromoacetophenone which afforded final compound in only one step. The bioactivity of this family of new compounds was tested using protein kinase and ATP competition assays. The structure-activity relationship (SAR) revealed that six compounds inhibit DYRK1A and CLK1 at a micromolar range. Docking studies provided possible explanations that correlate with the SAR data. The most active compound 4c inhibits CLK1 (IC50 of 0.7 mu M) and DYRK1A (IC50 of 2.6 mu M). (C) 2016 Elsevier Masson SAS. All rights reserved.

引用

页码：105 / 114

页数：10

共 51 条

[1] Discovery of novel 2-phenyl-imidazo[1,2-a]pyridine analogues targeting tubulin polymerization as antiproliferative agents [J].

An, Weiteng ;

Wang, Wei ;

Yu, Ting ;

Zhang, Yongliang ;

Miao, Zehong ;

Meng, Tao ;

Shen, Jingkang .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2016, 112 :367-372

[2] Pyrido[2,3-d]pyrimidines: Discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors [J].

Anderson, Kevin ;

Chen, Yi ;

Chen, Zhi ;

Dominique, Romyr ;

Glenn, Kelli ;

He, Yang ;

Janson, Cheryl ;

Luk, Kin-Chun ;

Lukacs, Christine ;

Polonskaia, Ann ;

Qiao, Qi ;

Railkar, Aruna ;

Rossman, Pamela ;

Sun, Hongmao ;

Xiang, Qing ;

Vilenchik, Masha ;

Wovkulich, Peter ;

Zhang, Xiaolei .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (24) :6610-6615

[3] Roscovitine targets, protein kinases and pyridoxal kinase [J].

Bach, S ;

Knockaert, M ;

Reinhardt, J ;

Lozach, O ;

Schmitt, S ;

Baratte, B ;

Koken, M ;

Coburn, SP ;

Tang, L ;

Jiang, T ;

Liang, DC ;

Galons, H ;

Dierick, JF ;

Pinna, LA ;

Meggio, F ;

Totzke, F ;

Schächtele, C ;

Lerman, AS ;

Carnero, A ;

Wan, YQ ;

Gray, N ;

Meijer, L .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (35) :31208-31219

[4] A Medicinal Chemist's Guide to Molecular Interactions [J].

Bissantz, Caterina ;

Kuhn, Bernd ;

Stahl, Martin .

JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (14) :5061-5084

[5] Synthesis and biological evaluation of new 5-benzylated 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indoles as PI3Kα inhibitors [J].

Bruel, Amelie ;

Loge, Cedric ;

de Tauzia, Marie-Ludivine ;

Ravache, Myriam ;

Le Guevel, Remy ;

Guillouzo, Christiane ;

Lohier, Jean-Francois ;

Santos, Jana Sopkova-de Oliveira ;

Lozach, Olivier ;

Meijer, Laurent ;

Ruchaud, Sandrine ;

Benedetti, Helene ;

Robert, Jean-Michel .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2012, 57 :225-233

[6] Kinase Domain Insertions Define Distinct Roles of CLK Kinases in SR Protein Phosphorylation [J].

Bullock, Alex N. ;

Das, Sanjan ;

Debreczeni, Judit E. ;

Rellos, Peter ;

Fedorov, Oleg ;

Niesen, Frank H. ;

Guo, Kunde ;

Papagrigoriou, Evangelos ;

Amos, Ann L. ;

Cho, Suhyung ;

Turk, Benjamin E. ;

Ghosh, Gourisankar ;

Knapp, Stefan .

STRUCTURE, 2009, 17 (03) :352-362

[7]

Burgy G., 2014, J APP PHARM SCI, V4, P025

[8] 2-ARYLPYRROCOLINES AND 2-ARYLPYRIMIDAZOLES [J].

BUUHOI, NP ;

JACQUIGNON, P ;

XUONG, ND ;

LAVIT, D .

JOURNAL OF ORGANIC CHEMISTRY, 1954, 19 (08) :1370-1375

[9] Imidazo[1,2-α]pyridines.: Part 2:: SAR and optimisation of a potent and selective class of cyclin-dependent kinase inhibitors [J].

Byth, KF ;

Culshaw, JD ;

Green, S ;

Oakes, SE ;

Thomas, AP .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (09) :2245-2248

[10] NEW LEUKOTRIENE-B4 RECEPTOR ANTAGONIST - LEUCETTAMINE-A AND RELATED IMIDAZOLE ALKALOIDS FROM THE MARINE SPONGE LEUCETTA-MICRORAPHIS [J].

CHAN, GW ;

MONG, S ;

HEMLING, ME ;

FREYER, AJ ;

OFFEN, PH ;

DEBROSSE, CW ;

SARAU, HM ;

WESTLEY, JW .

JOURNAL OF NATURAL PRODUCTS, 1993, 56 (01) :116-121

← 1 2 3 4 5 6 →