Exploring Kinase Inhibition Properties of 9 H-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, CK1/ε, GSK3 and DYRK1A). As a result, we have identified promising compounds targeting CK1/ε and DYRK1A and displaying micromolar and submicromolar IC₅₀ values.

Keywords: CDK5; CK1; DYRK1A; GSK-3; microwave-assisted chemistry; protein kinases.

Figure 1

Previous benzo[b]thieno[3,2-d]pyrimidin-4-amines (A) and their pyrido (B) and pyrazino (C) analogues (left). The 9H-pyrimido[5,4-b]indol-4-amine derivatives (1 and 2) and their 9Hpyrimido[4,5-b]indole isomers (3 and 4) described in this work (right).

Scheme 1

Synthesis of 9H-pyrimido[5,4-b]indol-4-amines (series 1a–d and 2a–d) and their 9H-pyrimido[4,5-b]indoles isomers (series 3a–d and 4a–d).

Scheme 2

Microwave-assisted synthesis of N-alkylated harmine derivatives (compounds 11b–d).

Figure 2

Comparison between selected pyrimido[4,5-b or 5,4-b]indol-4-amines described in this work and some of their thieno[2,3-d]pyrimidin-4-amine congeners (12, 13, 14 and 15) described in preceding work.