Synthesis, Pharmacophores, and Mechanism Study of Pyridin-2(1H)-one Derivatives as Regulators of Translation Initiation Factor 3A

Twenty‐seven 1,5‐disubstituted‐pyridin‐2(1H)‐one derivatives were synthesized and evaluated for their anti‐cancer and anti‐fibrosis activity by A549 and NIH3T3 cell viability assays, respectively. To study the selectivity between the cancer and fibrosis cell lines, pharmacophore models (F1–F4) were built in advance for compounds with pyridin‐2(1H)‐one scaffold, which revealed the relationship between the occupation of the aromatic sub‐site F4 and potent anti‐cancer activity. The relationship between structure and anti‐cancer activity for all target compounds is also reported herein: 1‐Phenyl‐5‐((m‐tolylamino)methyl)pyridine‐2(1H)‐one (22) displayed both potency and selectivity (IC50 = 0.13 mM) toward the A549 cell line through the inhibition of translation initiation, especially by eIF3a suppression, and can be treated as a lead for the design of novel eIF3a regulators and anti‐lung cancer agents. A series of pyridin‐2(1H)‐one derivatives were synthesized. Elucidation of their pharmacophores and mechanism of action suggested that structures with F4 occupation displayed more selective anti‐cancer than anti‐fibrosis activity and that they interrupt the initiation phase of translation by acting on the eukaryotic translation initiation factor 3, subunit A.