Original article Novel 9-oxo-thiazolo[5,4-f]quinazoline-2-carbonitrile derivatives as dual cyclin-dependent kinase 1 (CDK1)/glycogen synthase kinase-3 (GSK-3) inhibitors: Synthesis, biological evaluation and molecular modeling studies Ce ´dric Loge ´ a, * , Alexandra Testard b , Vale ´rie Thie ´ry b , Olivier Lozach c , Me ´lina Blairvacq c , Jean-Michel Robert a , Laurent Meijer c , Thierry Besson b, ** a Universite ´ de Nantes, Nantes Atlantique Universite ´s, Biomole ´cules et Cibles The ´rapeutiques, De ´partement de Pharmacochimie, BioCiT, UPRES EA 1155, UFR Sciences Pharmaceutiques, 1 rue Gaston Veil, F-44035 Nantes Cedex 1, France b Laboratoire de Biotechnologies et de Chimie Bio-organique, FRE CNRS 2766, UFR Sciences Fondamentales et Sciences pour l’Inge ´nieur, Universite ´ de La Rochelle, Ba ˆ timent Marie Curie, 17042 La Rochelle, France c Cell Cycle Group, UMR7150 & UPS2682, Station Biologique, B. P. 74, 29682 Roscoff Cedex, Bretagne, France Received 26 June 2007; received in revised form 13 September 2007; accepted 18 September 2007 Available online 29 September 2007 Abstract Continuous efforts in microwave-assisted synthesis and the structureeactivity relationships’ (SARs) studies of novel modified 9-oxo-thia- zolo[5,4-f]quinazoline-2-carbonitriles, allowed identification of new amidine and imidate derivatives as potent and dual CDK1/GSK-3 inhibitors. Combination of lead optimization and molecular modeling studies allowed identification of a dual CDK1/GSK-3 inhibitor (compound 13d) with submicromolar values. Ó 2007 Elsevier Masson SAS. All rights reserved. Keywords: CDK1 inhibitor; GSK-3 inhibitor; Molecular modeling; Microwave-assisted chemistry; Quinazolinones 1. Introduction Protein kinases have a fundamental role in signal transduc- tion pathways, and aberrant kinase activity has been observed in many diseases. In recent years, kinase inhibition has become a major area for therapeutic intervention and a variety of kinase inhibitor pharmacophores has been described. Most kinase inhibitor molecules currently developed are targeted at the ATP-binding site, an ubiquitous domain in nature, and mimic mainly the H-bonding motif of the ATP aminopyrimi- dine ring. Among the 518 human kinases [1], two classes have been particularly explored: the cyclin-dependent kinases (CDKs) which are involved in regulating the cell division cy- cle, apoptosis, neuronal cell physiology, pain signaling, tran- scription, RNA splicing and insulin release, among other activities [2,3] and the glycogen synthase kinase-3 (GSK-3) which is a family of kinases involved in cell cycle control, in- sulin action, apoptosis, neuronal cell death and developmental regulation, among other processes [4,5]. Both families of kinases are implicated in various human diseases such as can- cers, Alzheimer’s disease, diabetes and therefore both have Abbreviations: CDK, cyclin-dependent kinase; GSK-3, glycogen synthase kinase-3; ATP, adenosine triphosphate; MEPs, molecular electrostatic poten- tials; MW, microwave; AMP-PNP, 5 0 -adenylyl-imidodiphosphate; pdb code, RCSB Protein Data Bank. * Corresponding author. Tel.: þ33 (0) 240411108; fax: þ33 (0) 240412876. ** Corresponding author. Present address: UMR CNRS 6014, Laboratoire de Chimie Pharmaceutique, UFR Me ´decine-Pharmacie, Universite ´ de Rouen, 22 Boulevard Gambetta, 76183 Rouen Cedex 1, France. Tel.: þ33 (0) 235148399; fax: þ33 (0) 235148423. E-mail addresses: cedric.loge@univ-nantes.fr (C. Loge ´), thierry.besson@ univ-rouen.fr (T. Besson). 0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2007.09.020 Available online at www.sciencedirect.com European Journal of Medicinal Chemistry 43 (2008) 1469e1477 http://www.elsevier.com/locate/ejmech