Friedländer reactions for annulated pyrido[2,3-d]pyrimidines: Synthesis, structure characterization, anticancer and computational studies

The current work aimed to synthesize and characterize some pyrido[2,3-d]pyrimidines through Friedlander condensation of 6-amino-5-formyluracil (1) with various active methylene nucleophiles. The density functional theory (DFT) using B3LYP/6–311++G(d,p) basis set was employed to established the chemical characteristics of the prepared compounds. The molecular structural parameters and global reactivity descriptors were calculated to predict the chemical reactivity and kinetic stability of the synthesized compounds. Also, the molecular electrostatic potential (MEP) surface and Fukui functions were calculated at the same computational level. The theoretical FT-IR vibrational frequencies were analyzed and correlated with the experimental results. Gauge Independent Atomic Orbital (GIAO) approach was utilized to compute the 1H and 13C NMR spectra and the chemical shift values were correlated with experimental results. The first hyperpolarizability (βtot) values were calculated to examine the nonlinear optical (NLO) characteristics of the current compounds. The experimental and theoretical UV–visible spectra were examined using a variety of solvents and TD-DFT approach. Moreover, the in-silico absorption, distribution, metabolism, and excretion (ADME) analysis were performed to determine the drug-likeness properties of the current molecules. The in vitro anticancer activity of the studied compounds was evaluated against HepG-2 cell lines; presenting moderate to high activities compared with the standard controls. Finally, the present candidates were docked with aromatase enzymatic protein (PDB id: 31G7) receptors to elucidate their binding affinities and the key interactions; providing additional insights into their inhibitory mechanisms.