Diaryl Diimidazopyrimidine Derivatives as Potent Inhibitors of <i>Influenza A</i> Virus: Synthesis, Evaluation and Docking Studies

In this report, we present a new series of diaryl diimidazopyrimidine derivatives 3a-m, that have been synthesized and assessed for their in vitro antiviral activity. The derivatives were prepared through a one-step reaction involving commercially available 2,4-diamino-6-chloropyrimidine and various phenacyl bromides 2a-m, leading to the formation of the desired diaryl diimidazo- pyrimidines 3a-m with good yields. In vitro evaluations against the Influenza A H1N1 strain identified compounds 3m (SI = 73) and 3b (SI = 23) as the most potent candidates. Additionally, antimicrobial screening indicated that compounds 3d and 3j, which contain methyl and methoxy substitutions, exhibited moderate activity against Streptococcus mutans, Salmonella typhi, and Candida albicans. Molecular Docking studies of the promising compounds 3b and 3m demonstrated significant binding interactions with the M1 matrix protein (PDB ID: 5CQE) in comparison to M2 proton channel of Influenza A (PDB: 6US9), suggesting that these derivatives may be effectively targeting the M1 protein. Additionally, molecular dynamics (MD) simulations were conducted to evaluate the stability, dynamic behaviour, and binding affinity of the most potent compounds 3b and 3m. The in vitro antiviral studies, molecular docking and MD simulations data highlight the promising pharmacological potential of these analogues, paving the way for further structural optimization and development as potential antiviral agents.