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Synthesis, anticancer screening, and in silico ADME prediction of novel 2‐pyridones as Pim inhibitors
Author(s) -
Ismail Magda M. F.,
Farrag Amel M.,
AbouElEla Dalal
Publication year - 2020
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.4064
Subject(s) - chemistry , adme , stereochemistry , in silico , cytotoxicity , acetamide , polar surface area , lipinski's rule of five , cell cycle , pyridine , docking (animal) , selectivity , lead compound , combinatorial chemistry , hydrogen bond , cell culture , cell cycle checkpoint , molecular model , in vitro , apoptosis , biochemistry , molecule , medicinal chemistry , organic chemistry , medicine , genetics , nursing , biology , gene , catalysis
Abstract A novel series of 26 substituted N ‐(2‐ethylphenyl)‐2‐oxo‐pyridine‐3‐carbonitriles have been designed and synthesized via one‐pot synthesis of various aromatic aldehydes, different aromatic acetophenones, and 2‐cyano‐ N ‐(2‐ethylphenyl)acetamide 1 . Moreover, cytotoxicity of the target compounds was evaluated by NCI, which selected 14 compounds for one‐dose screening. Among them, compound 21 was selected for five‐dose screening, which confirmed its potency against most of cancer cell lines. This compound elicited selectivity profile against human cell line WI‐38. Cell cycle analysis was carried out, revealed that compound 21 is an apoptosis inducer causing cell cycle arrest at G2/M. Further exploration on the mode of action by evaluating its effect against Pim‐1, Pim‐2, and Pim‐3 demonstrated its inhibitory effect on Pim‐1 and Pim‐3 rather than Pim‐2. Molecular docking showed that compound 21 binds with high affinity to the active site of Pim‐1 enzyme through three hydrogen bonds and two arene‐H bonds.