TiO₂ nanocatalyzed synthesis of dihydropyrido[2,3-d]pyrimidine derivatives: A theoretical insight into their antidepressant potential

Depression is a common and debilitating neuropsychiatric disorder that necessitates the exploration of novel and effective therapeutic strategies. In this study, a green and efficient synthetic method was developed for the preparation of dihydropyrido [2,3-d]pyrimidine derivatives using TiO₂ nanoparticles as a reusable nanocatalyst under mild conditions. The multicomponent reaction approach employed offers high atom economy, environmental friendliness, and operational simplicity. After structural characterization, the electronic properties, frontier molecular orbitals, and reactivity indices of the synthesized compounds were investigated using density functional theory (DFT). Moreover, molecular docking simulations were performed to predict the binding affinities of the derivatives toward central nervous system (CNS) targets associated with antidepressant activity. A comparative computational analysis with the standard antidepressant Paroxetine indicated similar electronic profiles and potential interactions with the target proteins. Although these results are promising, it is important to note that the predicted antidepressant potential is based solely on in silico data and requires further experimental validation. This integrated computational and synthetic approach provides valuable insights for the early-stage design of novel antidepressant candidates. • Green synthesis of dihydropyrido[2,3- d ]pyrimidine derivatives was achieved using TiO₂ nanoparticles as an efficient and reusable nanocatalyst under mild conditions. • Multicomponent reaction strategy ensured high atom economy, eco-friendliness, and operational simplicity in the synthetic process. • DFT calculations provided detailed insights into the electronic properties, frontier molecular orbitals, and global reactivity descriptors of the synthesized compounds. • Molecular docking studies revealed promising binding affinities of the compounds toward key CNS targets, supporting their potential antidepressant activity. • Comparative analysis with Paroxetine showed similar electronic and reactivity profiles, suggesting the new derivatives as strong candidates for antidepressant drug development.