Synthesis of New 5-Arylidene-1,3-thiazolidine-4-ones Bearing an (3-Aminopropylpiperazin-1-yl)propyl chain on N-3 Position by A "One-Pot Two Steps" Method under Microwave

Protein kinases are enzymes assuring the transfer of a phosphate group of molecule donors of high energy, such as ATP, in specific substrates. The disorder of these enzymes in cellular environment are involved in some pathologies such as cancer and Alzheimer's disease [1]. So the discovery of inhibitors became the key point for the research of new therapeutic agents. In our team, N,N'-bis(5-arylidene-4-oxo-4,5-dihydrothiazolin-2-yl)aminopropylpiperazine (IC50=40 nM) was identified as promising and selective inhibitor [2, 3] of DYRK1A (dual specificity, tyrosine phosphorylation regulated kinases), a protein kinase of interest for neurodegenerative diseases [4, 5] and also for cancer [6]. In order to understand the mechanism of action of this inhibitor towards DYRK1A but also towards GSK3a/b (who also plays an important role in malaria), we have developed a 4-steps synthesis from the commercial reagents N,N'-bis(3-aminopropyl)piperazine. The key step of this process is the construction of the 2-thioxo-1,3-thiazolidine-4-one platform under microwave irradiation from commercial bis(carboxymethyl)trithiocarbonate. Results for the synthesis will be presented and discussed in this presentation . References1. Debdab M., Carreaux F., Renault S., Meijer L., Bazureau J.-P. et al. J. Med. Chem. 2011, 54, 4172.2. Coulibaly W-K, Paquin L., Benie A., Bekro Y-A., Durieu E., Meijer L., Bazureau J-P. Eur. J. Med. Chem. 2012, 58, 581.3. Coulibaly W-K., Paquin L., Benie A., Bekro Y-A., Durieux E., Rucheau S., Meijer L., Le Guevel R., Corlu A., Bazureau J-P., Scienta Pharm. 2012, 80, 825.4. Tahtouh T., Burgy G., Carreaux F., Bazureau J-P., Meijer L. et al. J. Med. Chem. 2012, 55, 9312-9330.5. Burgy G., Limanton E., Meijer L., Carreaux F., Bazureau J-P. Eur. J. Med. Chem. 2013, 62, 728.6. Ionescu A., Dufrasne F., Gelbcke M., Jabin I., Kiss R., Lamoral-Theys D. Mini-Rev. Med. Chem. 2012, 12, 1315.