Synthesis of 2-alkyl- and 2-arylthiazolo[5,4-c]isoquinolines and in silico prediction of their biological activities and toxicity

A practical method for the synthesis of 2-alkyl- and 2-arylthiazolo[5,4-c]isoquinoline derivatives starting from simple commercially available reagents is presented. The recently reported La(OTf)3 catalysed reaction of dithiooxamide with 2-halobenzaldehydes to afford 2-arylthiazolo[5,4-c]isoquinolines is now extended to the synthesis of 2-alkylthiazolo[5,4-c]isoquinolines and "mixed" 2-arylthiazolo[5,4-c]isoquinolines. The new compounds can be prepared under the previously reported experimental conditions but using a 1:1 mixture of a 2-halobenzaldehyde and an aliphatic or (hetero)aromatic aldehyde. The new approach also allows the access to 2-alkyl-5-arylthiazolo[5,4-d]thiazoles that are hitherto unknown structures. The single-crystal X-ray diffraction structures of three thiazolo[5,4-c]isoquinolines and of two non-symmetrical thiazolo[5,4-d]thiazoles are presented. The photophysical properties of the new thiazolo[5,4-c]isoquinoline derivatives, and their potential biological activities and toxicological risks, are discussed. Some of the new compounds show interesting bioactivity scores as kinase inhibitors.