A green fabrication of pharmacologically relevant fused pyrimidines using recyclable caffeine–H3PO4 catalyst: insight into antibacterial and cytotoxic efficacy

Abstract

An eco-friendly and high-yielding one-pot protocol has been developed for the synthesis of pyrimido[4,5-d]pyrimidine derivatives utilizing caffeine–H₃PO₄ as a recyclable, metal-free acidic catalyst under ethanolic conditions. This green approach delivers the desired fused heterocycles in notable yields within short reaction times, avoiding the use of harsh reagents and tedious purification steps. The catalyst was systematically characterized by FT-IR, NMR, XRD, SEM, EDX, TGA, DTG, DTA and DSC analyses, confirming its stability, robustness, and catalytic proficiency. Notably, caffeine–H₃PO₄ exhibited excellent recyclability across multiple runs with negligible reduction in activity. Eco-metric assessment further substantiated the environmentally benign nature of the process. Preliminary biological screening demonstrated significant cytotoxic potential, while computational studies including molecular docking, pharmacokinetic, and ADMET analyses supported the experimental outcomes and indicated favorable drug-like attributes. In summary, this work presents a green and practical synthetic route to biologically important pyrimido[4,5-d]pyrimidine frameworks, showcasing caffeine–H₃PO₄ as an effective and eco-compatible catalyst in modern heterocyclic chemistry.