Development of Kinase Inhibitors Via Metal-Catalyzed C⁻H Arylation of 8-Alkyl-thiazolo[5,4-]-quinazolin-9-ones Designed by Fragment-Growing Studies

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2018 Aug 31

PMID 30158487

Citations 3

Authors

Florence Couly

Marine Harari

Carole Dubouilh-Benard

Laetitia Bailly

Emilie Petit

Julien Diharce

Pascal Bonnet

Laurent Meijer

Corinne Fruit

Thierry Besson

Affiliations

Soon will be listed here.

Abstract

Efficient metal catalyzed C⁻H arylation of 8-alkyl-thiazolo[5,4-]-quinazolin-9-ones was explored for SAR studies. Application of this powerful chemical tool at the last stage of the synthesis of kinase inhibitors allowed the synthesis of arrays of molecules inspired by fragment-growing studies generated by molecular modeling calculations. Among the potentially active compounds designed through this strategy, () exhibits nanomolar IC values against some kinases, and is the best candidate for the development as a DYRK kinase inhibitor.

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References

Harari M, Couly F, Fruit C, Besson T . Pd-Catalyzed and Copper Assisted Regioselective Sequential C2 and C7 Arylation of Thiazolo[5,4-f]quinazolin-9(8H)-one with Aryl Halides. Org Lett. 2016; 18(13):3282-5. DOI: 10.1021/acs.orglett.6b01552. View

Loidreau Y, Deau E, Marchand P, Nourrisson M, Loge C, Coadou G . Synthesis and molecular modelling studies of 8-arylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines as multitarget Ser/Thr kinases inhibitors. Eur J Med Chem. 2015; 92:124-34. DOI: 10.1016/j.ejmech.2014.12.038. View

Loidreau Y, Marchand P, Dubouilh-Benard C, Nourrisson M, Duflos M, Loaec N . Synthesis and biological evaluation of N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues as dual inhibitors of CLK1 and DYRK1A kinases. Eur J Med Chem. 2012; 59:283-95. DOI: 10.1016/j.ejmech.2012.11.030. View

Foucourt A, Hedou D, Dubouilh-Benard C, Girard A, Taverne T, Casagrande A . Design and synthesis of thiazolo[5,4-f]quinazolines as DYRK1A inhibitors, part II. Molecules. 2014; 19(10):15411-39. PMC: 6271009. DOI: 10.3390/molecules191015411. View

Chabane H, Pierre A, Leonce S, Pfeiffer B, Renard P, Thiery V . Synthesis and cytotoxic activity of thiazolofluorenone derivatives. J Enzyme Inhib Med Chem. 2005; 19(6):567-75. DOI: 10.1080/14756360400004607. View

Chaikuad A, Diharce J, Schroder M, Foucourt A, Leblond B, Casagrande A . An Unusual Binding Model of the Methyl 9-Anilinothiazolo[5,4-f] quinazoline-2-carbimidates (EHT 1610 and EHT 5372) Confers High Selectivity for Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases. J Med Chem. 2016; 59(22):10315-10321. DOI: 10.1021/acs.jmedchem.6b01083. View

Primot A, Baratte B, Gompel M, Borgne A, Liabeuf S, Romette J . Purification of GSK-3 by affinity chromatography on immobilized axin. Protein Expr Purif. 2000; 20(3):394-404. DOI: 10.1006/prep.2000.1321. View

Loidreau Y, Marchand P, Dubouilh-Benard C, Nourrisson M, Duflos M, Lozach O . Synthesis and biological evaluation of N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amines and their pyrido and pyrazino analogues as Ser/Thr kinase inhibitors. Eur J Med Chem. 2012; 58:171-83. DOI: 10.1016/j.ejmech.2012.10.006. View

Martin L, Latypova X, Wilson C, Magnaudeix A, Perrin M, Yardin C . Tau protein kinases: involvement in Alzheimer's disease. Ageing Res Rev. 2012; 12(1):289-309. DOI: 10.1016/j.arr.2012.06.003. View

10.

Coutadeur S, Benyamine H, Delalonde L, de Oliveira C, Leblond B, Foucourt A . A novel DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro. J Neurochem. 2015; 133(3):440-51. DOI: 10.1111/jnc.13018. View

11.

Wu P, Nielsen T, Clausen M . Small-molecule kinase inhibitors: an analysis of FDA-approved drugs. Drug Discov Today. 2015; 21(1):5-10. DOI: 10.1016/j.drudis.2015.07.008. View

12.

Testard A, Loge C, Leger B, Robert J, Lozach O, Blairvacq M . Thiazolo[5,4-f]quinazolin-9-ones, inhibitors of glycogen synthase kinase-3. Bioorg Med Chem Lett. 2006; 16(13):3419-23. DOI: 10.1016/j.bmcl.2006.04.006. View

13.

Hedou D, Dubouilh-Benard C, Loaec N, Meijer L, Fruit C, Besson T . Synthesis of Bioactive 2-(Arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff Reaction or Cu- Catalyzed Intramolecular C-S Bond Formation. Molecules. 2016; 21(6). PMC: 6272913. DOI: 10.3390/molecules21060794. View

14.

Varjosalo M, Keskitalo S, van Drogen A, Nurkkala H, Vichalkovski A, Aebersold R . The protein interaction landscape of the human CMGC kinase group. Cell Rep. 2013; 3(4):1306-20. DOI: 10.1016/j.celrep.2013.03.027. View

15.

Nguyen T, Fruit C, Herault Y, Meijer L, Besson T . Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors: a survey of recent patent literature. Expert Opin Ther Pat. 2017; 27(11):1183-1199. DOI: 10.1080/13543776.2017.1360285. View

16.

Loge C, Testard A, Thiery V, Lozach O, Blairvacq M, Robert J . Novel 9-oxo-thiazolo[5,4-f]quinazoline-2-carbonitrile derivatives as dual cyclin-dependent kinase 1 (CDK1)/glycogen synthase kinase-3 (GSK-3) inhibitors: synthesis, biological evaluation and molecular modeling studies. Eur J Med Chem. 2007; 43(7):1469-77. DOI: 10.1016/j.ejmech.2007.09.020. View

17.

Hedou D, Godeau J, Loaec N, Meijer L, Fruit C, Besson T . Synthesis of Thiazolo[5,4-f]quinazolin-9(8H)-ones as Multi-Target Directed Ligands of Ser/Thr Kinases. Molecules. 2016; 21(5). PMC: 6273584. DOI: 10.3390/molecules21050578. View

18.

Patel K, Gadewar M, Tripathi R, Prasad S, Patel D . A review on medicinal importance, pharmacological activity and bioanalytical aspects of beta-carboline alkaloid ''Harmine''. Asian Pac J Trop Biomed. 2013; 2(8):660-4. PMC: 3609365. DOI: 10.1016/S2221-1691(12)60116-6. View

19.

Carles F, Bourg S, Meyer C, Bonnet P . PKIDB: A Curated, Annotated and Updated Database of Protein Kinase Inhibitors in Clinical Trials. Molecules. 2018; 23(4). PMC: 6017449. DOI: 10.3390/molecules23040908. View

20.

Smith B, Medda F, Gokhale V, Dunckley T, Hulme C . Recent advances in the design, synthesis, and biological evaluation of selective DYRK1A inhibitors: a new avenue for a disease modifying treatment of Alzheimer's?. ACS Chem Neurosci. 2012; 3(11):857-72. PMC: 3503344. DOI: 10.1021/cn300094k. View