Synthesis of quinazoline derivatives with new phenolic moieties: in vitro and in silico evaluations as alternative polyphenol oxidase inhibitors

Several novel quinazoline derivatives bearing phenolic hydroxyl moiety (2–7) have been produced with good yields and screened for biological activities. All the title compounds were characterized using spectroscopic techniques such as ¹H NMR, ¹³C NMR, FTIR, and HRMS. Then, the anti-browning effects of synthesized quinazoline derivatives were investigated in vitro. The IC₅₀ values for molecules 2–7 were calculated as 0.085, 1.145, 0.106, 6.86, 0.52, 7.07 µM, respectively. K_i constants, which are inhibitory-enzyme binding constants, were calculated by using Lineweaver–Burk graphs as 0.16 ± 0.0620, 0.906 ± 0.3029, 0.055 ± 0.0171, 9.363 ± 2.5809, 0.773 ± 0.3204, 7.863 ± 1.9107 µM, respectively. In computer-aided analysis, to gain insights electrochemical properties, synthesized compounds were analysed theoretically by density functional theory. Molecular docking studies and MD simulations were performed to identify possible inhibitor-enzyme binding interactions. According to obtained results, all the compounds formed hydrogen bonds with Asn 112 and Asn 414, and showed π-cation interaction with Phe2 70, gatekeeper residue in target protein. Supporting the nm level inhibition, MD simulations indicate that protein-inhibitor complex maintain the stability and have high number of hydrogen bond formation during the simulation.