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. 2018 Aug 29;23(9):2181.
doi: 10.3390/molecules23092181.

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

Florence Couly  1 , Marine Harari  2 , Carole Dubouilh-Benard  3 , Laetitia Bailly  4 , Emilie Petit  5 , Julien Diharce  6 , Pascal Bonnet  7 , Laurent Meijer  8 , Corinne Fruit  9 , Thierry Besson  10
Affiliations

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

Florence Couly et al. Molecules. .

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.

Keywords: CDK5; CK1; CLK1; C–H arylation; DYRK1A; GSK-3; microwave-assisted synthesis; protein kinases; thiazolo[5,4-f]quinazolin-9(8H)-ones.

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Conflict of interest statement

The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Scheme 1
Scheme 1
6-Aminobenzo[d]thiazole-2,7-dicarbonitrile, a versatile molecular platform for global chemistry strategy and structures of the five best DYRK1A/1B inhibitors. Harmine and Leucettine 41 (L41) are positive control inhibitors.
Figure 1
Figure 1
Results of molecular modeling studies (docking experiments) (left) and schematic representation (right) of the predicted binding modes of thiazolo[5,4-f]quinazolin-9(8H)-ones (Scheme 2, in DYRK1A).
Scheme 2
Scheme 2
Schematic access to thiazolo[5,4-f]quinazolin-9(8H)-ones, a family of multitarget kinase inhibitors.
Scheme 3
Scheme 3
Fragment-growing anchor points envisioned on the thiazolo[5,4-f]quinazolin-9(8H)-one scaffold (left). Schematic representation of the predicted binding modes and retrosynthetic route to C2-arylated derivatives suggested via C–H arylation of the former C2-H thiazole precursor (right).
Scheme 4
Scheme 4
Retrosynthetic pathway envisioned.
Scheme 5
Scheme 5
Six step synthesis of the key N8-benzylthiazolo[5,4-f]quinazoline (1) from 5-nitroanthranilic acid [16].
Scheme 6
Scheme 6
Selective C2-H arylation of 1 with aryl halides.
Scheme 7
Scheme 7
The two kinase active derivatives 3a and 3b and new compounds (series 4a–f) suggested by the first active products.
Scheme 8
Scheme 8
Retrosynthetic route of series 4 products using compound 5 as intermediate.
Scheme 9
Scheme 9
Synthesis of series 7a–f, 8a–f, and 4a–f.
Scheme 10
Scheme 10
Synthetic route to series 9a–j and 10 (R, X, and Y).
Figure 2
Figure 2
Predicted binding mode of FC162 by docking calculation. Left, first predicted binding mode (green), with the same orientation of the skeleton, but slightly shifted. Right, second predicted binding mode, in which the skeleton is flipped compared to its initial placement (in brown).
Figure 3
Figure 3
Comparative study of the activity of FC162 (4c) with related molecules.
See this image and copyright information in PMC

References

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