Structure of N-(3,4-Dimethoxyphenyl)pyrido[3′,2′:4,5]-thieno[3,2-d]pyrimidin-4-amine, a New Inhibitor of CLK1 and DYRK1A Kinases

The complete crystal structure of N-(3,4-dimethoxyphenyl)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine, synthesized via a Dimroth rearrangement and designed as new inhibitor of CLK1 and DYRK1A kinases, was established by a single-crystal X-ray diffraction. The crystal is orthorhombic, space group Pca21; , , ？？, °, ？？3, and , C17H14N4O2S. Solid-state data could be used to enlighten the biological mechanism of action. 1. Introduction Kinases are one of the largest families of the genome. More than 500 kinases play an important role in the regulation of various cellular processes. These enzymes are involved in all major diseases, including cancer, neurodegenerative disorders, and cardiovascular diseases. Among them, the Ser/Thr kinases CDK5, GSK3, DYRK1A, CLK1, and CK1 constitute a family showing a strong implication in various regulation processes, especially Alzheimer’s disease [1–3]. Following our search for such Ser/Thr kinases inhibitors of potential therapeutic interest, we previously identified a series of novel N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amines, synthesized via a Dimroth rearrangement [4, 5]. We report herein the crystal structure of N-(3,4-dimethoxyphenyl)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine (Figure 1), which shows interesting selectivity towards CLK1 and DYRK1A kinases (IC50 = 3.4 and 2.9？μM, resp.) over the other tested kinases [4, 5]. Figure 1: Structure of N-(3,4-dimethoxyphenyl)pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidin-4-amine. The present crystal structure determination will not only help us to understand the detailed three-dimensional arrangement of the compound, which could be useful for designing new derivatives, but also contribute to the structural database in which there are very few structures containing the benzo[b]thieno[3,2-d]pyrimidine skeleton [6, 7]. Moreover, solid-state data could be used to clarify the mechanism of action implicating this new CLK1 and DYRK1A kinases inhibitor. 2. Experimental N-(3,4-Dimethoxyphenyl)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine was synthesized as previously described by Loidreau et al. [4]. Colourless crystals of title compound suitable for X-ray analysis were obtained by slow evaporation from a dichloromethane-methanol solution 4？:？1 (v/v) at room temperature. 3. Refinement A single crystal of the title compound with dimensions 0.10 × 0.10 × 0.01？mm was chosen for X-ray diffraction study. The data were collected on a Rigaku R-axis rapid diffractometer equipped with microfocus rotating anode using the monochromatic Cu-Kα radiation (λ = 1.5418？？) and a curved image