Original article Synthesis of N,N 0 -bis(5-arylidene-4-oxo-3,5-dihydro-4H-imidazol-2-yl)diamines bearing various linkers and biological evaluation as potential inhibitors of kinases Wacothon Karime Coulibaly a, b , Ludovic Paquin a , Anoubilé Bénie b , Yves-Alain Bekro b , Emilie Durieu c , Laurent Meijer d , Jean Pierre Bazureau a, * a Université de Rennes 1, Institut des Sciences Chimiques de Rennes (ISCR), UMR CNRS 6226, groupe Ingénierie Chimique et Molécules pour le Vivant (ICMV), Bât. 10A, Campus de Beaulieu, Avenue du Général Leclerc, CS 74205, 35042 Rennes Cedex, France b Université d’Abobo-Adjamé, Laboratoire de Chimie Bioorganique et de Substances Naturelles (LCBSN), BP 802, Abidjan 02 (CO), Cote d’Ivoire c Protein Phosphorylation and Human Disease Group, Station Biologique CNRS, Place G. Tessier, BP 74, 29682 Roscoff (F), France d ManRos Therapeutics (From Sea to Pharmacy), Hôtel de Recherche, Centre de Perharidy, 29680 Roscoff (F), France article info Article history: Received 4 May 2012 Received in revised form 29 August 2012 Accepted 30 August 2012 Available online 7 September 2012 Keywords: 5-Arylidene-imidazolinone Sulphur/nitrogen displacement Diamino linker N,N 0 -bis(5-arylidene-4-oxo-3,5-dihydro-4H- imidazol-2-yl)diamine Microwave irradiation Solvent-free Kinase inhibitors abstract The synthesis in 4 steps of new N,N 0 -bis(5-arylidene-4-oxo-3,5-dihydro-4H-imidazol-2-yl)diamines issued from various symmetric primary diamines as linkers was reported. The key step of our strategy has been the sulphur/nitrogen displacement of (5Z)-5-arylidene-2-ethylsulfanyl-3,5-dihydro-4H-imida- zol-4-ones 6 with respectively ethylenediamine 7a, piperazine 7b and N,N 0 -bis(3-aminopropyl)pipera- zine 7c using solvent-free reaction conditions under microwave irradiation with retention of configuration. These compounds were tested for their kinase inhibitory potencies toward four kinases (GSK-3a/b, DYRK1A, CLK1 and CLK3). Crown Copyright Ó 2012 Published by Elsevier Masson SAS. All rights reserved. 1. Introduction According to the World Heath Organisation (WHO), between 300 million and 500 million clinical case of malaria occur every year [1]. Malaria is one of the most severe infectious diseases, primarily affecting the world’s most disadvantaged populations. This parasite infection is estimated to kill more than 1 million people annually and possibly as many as 3 million, with most of the deaths among children under age six living in undeveloped sub- Saharian Africa [2]. Despite the presence of commercially avail- able anti-malarial drugs, the disease is gaining ground as the parasite’s resistance to drugs and the parasite-carrying mosquito’s resistance to insecticides expand. Of the four typically recognized Plasmodium species causing diseases in humans, which can be transmitted by about 60 species of Anopheles mosquito, Plasmodium falciparum causes most mortality, mainly in children below the age of 5, and Plasmodium vivax most morbidity additionally repre- senting a reservoir of latent infections [3]. The infection stages of the malaria parasite reside in the salivary glands of female mosquito that bite humans for a blood meal. The mosquito injects its saliva into the wound, then transferring approximatively 15e20 so-called sporozoites into the blood stream [4]. Anti-malarial agents are classified by the stages of the malaria life cycle that are targeted by the blood. Currently there are only limited safe drugs for the treatment of the disease, however, reports of emerging resistance against existing drugs warrant the introduc- tion of new drugs. Recently, the re-emergence of malaria as a public health problem demonstrates the urgent need for the discovery and development of new anti-malarial drugs. Traditionally, the chemotherapy of malaria involves killing of the asexual parasites and providing supportive therapy to the host to boots its immune system. In this context and prior to the 2nd world war, quinine and its derivatives (pamaquine, chloroquine) were used intensively. They were followed by proguanyl and amodiaquine in the 1940s, followed by primaquine and pyri- methamine (1950s), sulfadoxine (1960s) [5]. The use of medicinal * Corresponding author. Fax: þ33 (0)223 236 374. E-mail address: jean-pierre.bazureau@univ-rennes1.fr (J.P. Bazureau). Contents lists available at SciVerse ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Crown Copyright Ó 2012 Published by Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2012.08.044 European Journal of Medicinal Chemistry 58 (2012) 581e590