Catalyst-free synthesis of quinazolin-4-ones from (hetero)aryl-guanidines: application to the synthesis of pyrazolo[4,3-f]quinazolin-9-ones, a new family of DYRK1A inhibitors

Abstract

A small library of heterocycle-fused quinazolin-4-ones was prepared and evaluated as kinase inhibitors. The key step of the two-step process involves the environmental friendly thermolysis of N-ethoxycarbonyl-N'-(hetero) arylguanidines at 130 °C in water. The cyclization is fully regioselective. The most active molecules, 7-(2-hydroxyethylamino)- and 7-(3-hydroxypropylamino)-pyrazolo[4,3-f]quinazolin-9-ones, inhibit DYRK1A and CLK1 at submicromolar concentrations, indicating the potential interest of this new heterocycle in drug design.

A direct access to heptasubstituted biguanides

“…The 1 H NMR spec- 13 C NMR spectrum of 5a exhibited 16 signals in accord with the proposed structure. The mass spectrum of 5a displayed the molecular ion signal at m/z = 397.…”

“…Structures of products 5a-m were assigned by IR, 1 H NMR, 13 C NMR, and mass spectral data. The 1 H NMR spec- 13 C NMR spectrum of 5a exhibited 16 signals in accord with the proposed structure.…”

“…Melting points (uncorrected) and IR spectra of all compounds were measured on an Electrothermal 9100 apparatus and a Shimadzu IR-460 spectrometer, respectively. The 1 H and 13 C spectra were obtained with a BRUKER DRX-500 AVANCE instrument using CDCl 3 as applied solvent and TMS as internal standard at 500.1 and 125.7 MHz, respectively. The abbreviations used for NMR signals: s = singlet, d = doublet, t = triplet, and m = multiplet.…”

Design and Synthesis of a Library of Lead-Like 2,4-Bisheterocyclic Substituted Thiophenes as Selective Dyrk/Clk Inhibitors

“…Several further inhibitor classes were published which potently inhibited Dyrk1A. However, these compounds were either not selective for the Dyrk family, or no selectivity data were provided [49], [55]–[60]. While it can be challenging to develop selective ATP-competitive kinase inhibitors, the example of harmine has demonstrated that in the case of the Dyrk isoforms, this might be achievable using very small, compact molecules.…”

Pyrazoloquinazolines: Synthetic strategies and bioactivities

“…et al gave a catalyst-free one pot microwave synthesis of pyrazolo[4,3-f]quinazolines derivatives (Figure 27) involving the thermolysis of N-(hetero) arylguanidines (85) at 130°C in water[102].…”