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

Abstract

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.

Biological Characterization of 8-Cyclopropyl-2-(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-one, a Promising Inhibitor of DYRK1A

“…The complete synthesis of FC162 has been described in [27,34] (see SI for some Supplementary Materials). The target compound was obtained in eight steps from 5-nitroanthranilic acid in an overall yield of 14%, its percentage of purity was more than 99% (HPLC).…”

“…In the last 15 years, more than 40 kinases inhibitors have been approved by the US and Food and Drug Administration (FDA), mainly for cancer indications [10,11]. In the same period, our group has been dedicated to the conception and synthesis of bioactive heterocycles that can modulate the activity of deregulated kinases (Figure 1) [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27], with a particular focus on dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) which play a role in the development of diseases such as cancer, Alzheimer's disease (AD) and Down syndrome (DS) [28,29]. Figure 1.…”

“…Innovative microwave-assisted metal-catalysed chemical reactions were studied [33,34], allowing the synthesis of important arrays of 2-aryl-N8alkylthiazolo[5,4-f]quinazolin-9(8H)-ones which were screened on a panel of five kinases (CDK5/p25, CK1δ/ε (casein kinase 1), GSK-β, CLK1 and DYRK1A, according to standard methods [35,36]. Among the various thiazolo [5,4-f]quinazolin-9(8H)-ones tested, only the 8-cyclopropyl-2-(pyridin-3-yl)thiazolo [5,4-f]quinazolin-9(8H)-one (also called FC162) ( Figure 2) exhibited nanomolar IC50 values (11,18, and 68 nM, against DYRK1A, CLK1, and GSK3, respectively) [27]. Compared to data obtained for other compounds, FC162 was found to be the most promising candidate based on in vitro cell based assays.…”

“…Among the various thiazolo[5,4-f ]quinazolin-9(8H)-ones tested, only the 8-cyclopropyl-2-(pyridin-3-yl)thiazolo[5,4-f ]quinazolin-9(8H)-one (also called FC162) ( Figure 2) exhibited nanomolar IC 50 values (11,18, and 68 nM, against DYRK1A, CLK1, and GSK3, respectively) [27]. Compared to data obtained for other compounds, FC162 was found to be the most promising candidate based on in vitro cell based assays.…”

“…General aspect of the angular thiazolo[5,4-f ]quinazolin-9(8H)-ones studied in our group, including the DYRK1A inhibitor FC162[25][26][27].…”