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Exploring Kinase Inhibition Properties of 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine Derivatives

Abstract : We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC50 values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave irradiation in an eco-friendly approach. In order to explore more in-depth the pharmacological interest in such tricyclic skeletons, the central five member ring, i.e., thiophène or furan, was replaced by a pyrrole to afford 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine derivatives inspired from harmine. The inhibitory potency of the final products was determined against four protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β and DYRK1A). As a result, we have identified promising compounds targeting CK1δ/ε and DYRK1A and displaying micromolar and submicromolar IC50 values.
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02612282
Contributor : Madeleine Roux-Merlin <>
Submitted on : Tuesday, May 19, 2020 - 8:29:04 AM
Last modification on : Friday, October 16, 2020 - 3:41:11 AM

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Yvonnick Loidreau, Carole Dubouilh-Benard, Marie-Renée Nourrisson, Nadège Loaëc, Laurent Meijer, et al.. Exploring Kinase Inhibition Properties of 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine Derivatives. Pharmaceuticals, MDPI, 2020, 13 (5), pp.89. ⟨10.3390/ph13050089⟩. ⟨hal-02612282⟩

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