Carole Dubouilh-Benard

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.

Novel N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines (1) and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues (2) were designed and prepared for the first time via microwave-accelerated multi-step synthesis. Various anilines were condensed with N-(2-cyanaryl)-N,N-dimethylformimidamide intermediates obtained by reaction of 3-amino-6-methoxybenzofuran-2-carbonitrile (3) and 3-amino-6-methoxybenzothiophene-2-carbonitrile (4) precursors with dimethylformamide dimethylacetal. The inhibitory potency of the final products against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) was estimated. Compounds (2a-z) turned out to be particularly promising for the development of new pharmacological dual inhibitors of CLK1 and DYRK1A kinases.

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.

A useful and rapid access to libraries of N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amines and their pyrido and pyrazino analogues was designed and optimized for the first time via microwave-accelerated condensation and Dimroth rearrangement of the starting anilines with N-(2-cyanoaryl)-N,N-dimethylformimidamides obtained by reaction of thiophene precursors with dimethylformamide dimethylacetal. The inhibitory potency of the final products against five protein kinases (CDK5/p25, CK1δ/ɛ, GSK3α/β, DYRK1A and CLK1) was estimated. N-arylpyrido[3,2:4,5]thieno[3,2-d]pyrimidin-4-amine series of compounds (4a-j) turned out to be particularly promising for the development of new pharmacological inhibitors of CK1 and CLK1 kinases.

Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part I

The convenient synthesis of a library of novel 6,6,5-tricyclic thiazolo[5,4-f] quinazolines (forty molecules) was achieved mainly under microwave irradiation. Dimroth rearrangement and 4,5-dichloro-1,2,3,-dithiazolium chloride (Appel salt) chemistry were associated for the synthesis of a novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (16) a versatile molecular platform for the synthesis of various bioactive derivatives. Kinase inhibition of the final compounds was evaluated on a panel of four Ser/Thr kinases (DYRK1A, CDK5, CK1 and GSK3) chosen for their strong implications in various regulation processes, especially Alzheimer’s disease (AD). In view of the results of this preliminary screening, thiazolo[5,4-f]quinazoline scaffolds constitutes a promising source of inspiration for the synthesis of novel bioactive molecules. Among the compounds of this novel chemolibrary, 7i, 8i and 9i inhibited DYRK1A with IC50 values ranging in the double-digit nanomolar range (40, 47 and 50 nM, respectively).

Synthesis of Bioactive 2-(Arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff Reaction or Cu- Catalyzed Intramolecular C-S Bond Formation

A library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient multistep synthesis of the key 6-amino-3-cyclopropylquinazolin-4(3H)-one (3) has been reinvestigated and performed on a multigram scale from the starting 5-nitroanthranilic acid. The inhibitory potency of the final products was evaluated against five kinases involved in Alzheimer’s disease and showed that some molecules of the 17 series described in this paper are particularly promising for the development of novel multi-target inhibitors of kinases.

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

Efficient metal catalyzed C–H arylation of 8-alkyl-thiazolo[5,4-f]-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, FC162 (4c) exhibits nanomolar IC50 values against some kinases, and is the best candidate for the development as a DYRK kinase inhibitor.

Synthesis of Bioactive 2-(arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff Reaction or Cu- Catalyzed Intramolecular C-S Bond Formation

The occurrence and properties of the thiazole ring in various natural and synthetic products have been the interest of many research groups on account of its useful biological properties [1]. In this context, our research group is mainly invested in the synthesis of C,N,S-containing bioactive molecules able to modulate the activity of deregulated kinases (CDK5, GSK-3, CLK1, CK1 and the dual-specificity kinase DYRK1A) involved to some extent in Alzheimer’s disease (AD) [2]. nA library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series I, II,III and IV) was prepared via the Hugershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient multistep synthesis of the keyxa0 6-amino-3-cyclopropylquinazolin-4(3H)-one has been reinvestigated and performed on a multigram scale from the starting 5-nitroanthranilic acid. The inhibitory potency of the final products was evaluated against five kinases involved in Alzheimer’s disease and showed that some molecules of the IV series described in this communication are particularly promising for the development of novel multi-target inhibitors of kinases, a new strategy for the development of powerful tools against neurodegenerative diseases [3]. nReferences n n(a) Wells, G.; Bradshaw, T.D.; Diana, P.; Seaton, A.; Shi, D.-F.; Westwell, A.D.; Stevens, M.F.G.xa0 Bioorg. Med. Chem. Lett. 2000, 10, 513; (b) Bradshaw, T.D.; Wrigley, S.; Shi, D.-F.; Schultz, R.J.; Paull, K.D.; Stevens, M.F.G.xa0 J. Cancer 1998, 77, 745; (c) Molinski, T.F. Chem. Rev. 1993, 93, 1825. n(a) Foucourt, A.; Hedou, D.; Dubouilh-Benard, C.; Desire, L.; Casagrande, -S.; Leblond, B.; Loaec, N.; Meijer, L.; Besson, T. Molecules 2014, 19, 15411; (b) Leblond, B.; Casagrande, A.-S.; Desire, L.; Foucourt A.; Besson, T. WO 2013026806. Chem. Abst. 2013, 158, 390018; (c) Loge, C.; Testard, A.; Thiery, V.; Lozach, O.; Blairvacq, M.; Robert, J.-M.; Meijer, L.; Besson, T.xa0 J. Med. Chem. 2008, 43, 1469; (d) Testard, A.; Picot, L.; Fruitier-Arnaudin, I.; Piot, J.M.; Chabane, H.; Domon, L.; Thiery, V.; Besson, T. . Enz. Inhib. Med. Chem. 2004, 19, 467. n(a) Hedou, D.; Godeau, J.; Loaec, N.; Meijer, L.; Fruit, C.; Besson, T. Molecules 2016, 21, 578; (b) Bajda, M.; Guzior, N.; Ignasik, M.; Malawska, B. Curr. Med. Chem. 2011, 18, 4949; (c) Cavalli, A.; Bolognesi, M.L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. J. Med. Chem. 2008, 51, 347.