Investigating the chemistry of newly synthesized acetamide linker based purines/pyrimidine derivatives towards DNA receptor site using in silico and in vitro studies.

DNA receptor site remain a crucial class of anticancer agents for many researchers. Literature revealed extensive data explaining different involving such data to control anticancer behavior. However, the structural limitations and adverse effects of existing drugs, such as doxorubicin, necessitate the development of novel agents. To address these challenges, a series of 25 linker-based purine/pyrimidine derivatives were designed and after screening through ADMET properties, compounds (4-9) were synthesized (Compounds 1-3 were taken from Literature), and well-characterized. Further, docking analysis was carried out for compounds (1-9) towards various DNA receptor sites, which were compared with doxorubicin. The most efficient compounds 1 and 5 were taken to explore DNA binding and anticancer potential. These compounds feature strategically modified linker regions to enhance stability within the DNA duplex. Computational studies, including molecular docking and MD simulations, extensively explored the structural interactions of these compounds with DNA. Compounds 1 and 5 exhibit stable interactions with linker, particularly acetamide in compound 1 is playing a key role in binding affinity and groove fitting. Notably, compound 1 maintained strong and stable interaction with both DNA strands compared to compound 5 and doxorubicin, suggesting its potential as efficient ligands. Further, FT-IR confirmed intercalation in compound 1 with carbonyl frequency reduction, while its low IC₅₀ of 42.17 µM highlighted strong anticancer potential. Overall, this study presents a structurally refined approach to DNA receptor site, offering valuable insights for designing next-generation anticancer agents with optimized therapeutic potential.