Novel acidic ionic liquid catalyst based on C8-modified caffeine for high-performance sustainable synthesis of pyridodipyrimidines and a study on their carbonic anhydrase inhibitory activity.

In this study, we designed and synthesized a novel acidic ionic liquid based on a C8-modified caffeine scaffold via ion pair formation between the 8-piperazinyl-caffeine derivative and trichloroacetic acid, yielding [8-PC]TCA. The prepared acidic ionic liquid was then used as an efficient catalyst in multicomponent reactions (MCRs) to synthesize pyrido[2,3-d:5,6-d']dipyrimidine derivatives in H2O/EtOH mixture at 80 °C. The catalyst structure was confirmed by FT-IR, 1H NMR spectroscopy and melting point analysis. The catalytic performance was confirmed by high yield (87-98%) of products obtained from the reaction of various benzaldehyde derivatives, barbituric acid and 6-aminouracile. Notably, the excellent atom economy (90.4-91.8%) highlights the high chemical efficiency of this protocol and its full alignment with green chemistry principles. To further explore the potential biological interactions of the synthesized derivatives, molecular docking studies were performed against carbonic anhydrase (PDB ID: 1H9N). The in silico results revealed favorable binding interactions and physicochemical properties consistent with Lipinski's rule of five, suggesting their promise for subsequent biological evaluations. Overall, this work introduces a green and efficient catalytic route to pyridopyrimidine derivatives while offering initial computational insights into their potential as bioactive agents.