Clarification of the Mechanism of Antioxidant Activity of Selected Vanillin‐Based Pyrido‐Dipyrimidines and Their Antibacterial Activity According to Bacillus subtilis —In Silico Approach
Svetlana Jeremić, Žiko Milanović, Jelena Đorović, Marko R. Antonijević, Nenad Janković · Chemistry & Biodiversity · 2025
ABSTRACT The antioxidant and inhibitory potential of two pyrido‐pyrimidine derivatives, synthesized via a condensation reaction between appropriate pyridine and pyrimidine precursors, whose highly conjugated heterocyclic systems promise biological activity, was evaluated. Theoretical p K a predictions indicated that, under physiological pH (∼7.4), the trianionic and tetranionic species dominate. Density functional theory (DFT) calculations revealed that these deprotonated forms exhibit significantly enhanced antioxidant activity compared to their neutral counterparts, especially in less polar environments. Molecular docking and molecular dynamics simulations were employed to assess the inhibitory potential against l ‐lactate dehydrogenase, where the tetranionic form of compound A and the trianionic form of compound B demonstrated the strongest interactions. Furthermore, ADMET profiling showed that while both compounds possess low oral bioavailability and moderate distribution, they are characterized by rapid metabolism, relatively slow elimination, low cardiotoxic and mutagenic risks, but notable hepatotoxic and neurotoxic potential. These findings highlight the importance of considering ionic species in antioxidant evaluation and support further structural optimization to improve pharmacokinetic profiles.