Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2

Abstract

a b s t r a c tHerein we describe the synthesis and properties of substituted phenylaminopyrrolo[1,2-a]quinoxalinecarboxylic acid derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 15 compounds was designed and synthesized using convenient and straightforward synthesis protocols. The compounds were tested for inhibition of human protein kinase CK2, which is a potential drug target for many diseases including inflammatory disorders and cancer. New inhibitors with IC 50 in the microand sub-micromolar range were identified. The most promising compound, the 4-[(3-chlorophenyl) amino]pyrrolo[1,2-a]quinoxaline-3-carboxylic acid 1c inhibited human CK2 with an IC 50 of 49 nM. Our findings indicate that pyrrolo[1,2-a]quinoxalines are a promising starting scaffold for further development and optimization of human protein kinase CK2 inhibitors.

Design, synthesis and antimalarial activity of novel bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives

“…These compounds have been reported as key intermediates for the assembly of several heterocycles including antipsychotic agents, anti-HIV agents, adenosine A 3 receptor modulators 19 , antiparasitic agents [20][21][22][23][24][25] and antitumor agents [26][27][28][29][30] . In the course of our work devoted to discover new compounds employed in the antiparasitic chemotherapy, we previously identified some series of substituted pyrrolo[1,2-a]quinoxaline derivatives designed as interesting bioactive isosteres of quinoline derivatives [20][21][22][23][24] .Thus, taking into account our experience in the field of the synthesis of new antimalarial heterocyclic compounds based on our pyrrolo[1,2-a]quinoxaline heterocyclic core [20][21][22][23][24][27][28][29][30] , we decided to incorporate a benzyl group in position 4 of the heterocyclic skeletonof our previously described bispyrrolo [1,2-a]quinoxalines C 20 to broaden the structural diversity of these derivatives, and mainly to increase the aromatic surface of these designed compounds ( Figure 1). …”

Living on pyrrolic foundations – Advances in natural and artificial bioactive pyrrole derivatives

“…Jean Guillon et al have reported on the synthesis and properties of a new class of substituted phenylaminopyrrolo[1,2-a]quinoxalinecarboxylic acid derivatives, found to be potent inhibitors of the human protein kinase CK2 [41]. The work details the design and synthesis of 15 selected compounds, the latter utilising remarkably simple procedures.…”

“…1c) form the foundation for design of a multitude of biologically active compounds. This is due to the fact that research has shown pyrrolo [1,2-a]quinoxalines to be promising starting systems for development of human CK2 protein kinase inhibitors [41]. V. A. Mamedov and A.…”

“…(3-Substituted-phenyl)aminopyrrolo[1,2-a]quinoxaline derivatives were prepared from 3-methyl-2-quinoxalinol, which in turn was obtained either from various substituted 1H-pyrrole-2-carboxylic acid alkyl esters, or from various 2-nitroanilines via their respective lactams [41]. Moreover, synthesis of 3-(4-alkyl-4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)-2H-chromen-2-one derivatives has also been achieved, in a novel one-pot three-component reaction of salicylaldehydes, b-ketoesters, and 1-(2-aminophenyl)pyrrole in the presence a dual catalyst system, consisting of piperidine-iodine [45].…”

Ninhydrin in synthesis of heterocyclic compounds

“…[410][411] Quinoxalines are very important compounds due to their wide spectrum of biological activities such as anticancer, [412][413] antibacterial 414 and activity as kinase inhibitors. 415 It was reported that the Kaupp and co-workers (Scheme 122). 419 The yields were quantitative and the solid state reaction gave pure crystalline products just by milling stoichiometric mixtures of the crystalline reagents.…”