Synthesis and in silico study of 2,4-diphenylquinolines as potential KDM4B protein inhibitors

Abstract

Histone methylation/demethylation is carried out by the a-KG-dependent KDM4 family of proteins, among which KDM4B is implicated in the development and progression of prostate cancer, so it is important to explore new chemical systems that inhibit this oncogenic process. A new series of functionalized 2,4-diphenylquinolines was prepared through the reaction between arylamines, substituted benzaldehydes, and phenylacetylene in the presence of acid catalysts under microwave radiation conditions. Optimizing reaction conditions, we found that molecular iodine in glacial acetic acid promoted smoothly the cycloaddition-aromatization process, obtaining the designed 2,4-diphenylquinoline derivatives in good yields (40–65%). Their in silico study on the KDM4B protein was performed using Autodock 4.2. Among these, compounds 14f, 14h, 14a, and 14e exhibited a high KDM4B protein binding affinity, revealing five shared interaction zones of which three are hydrophobic interaction, two are hydrogen bridge-type interaction zones, determinant zones in the inhibition process of the KDM4B proteins The results of molecular docking were corroborated through a 30 ns molecular dynamics simulation, demonstrating that the quinoline compounds exhibit higher stability than the reference drug (ML-324).