Novel secondary pyridinyl amides: Synthesis, in vitro antiproliferative screenings, and molecular docking studies.

• Nine novel pyridinyl amide derivatives. • Amide location and spacer role critical for activity. • Compound 3 demonstrated good antiproliferative activity against K562 and HepG2 cells. • Molecular docking reveals targeted mechanism of action with bcr/abl tyrosine, EGFR, HER2. • Notable cancer cell selectivity over normal cells and low cytotoxicity towards HDFa. A novel series of secondary pyridinyl amides, reinforced with the methylsulfonyl pharmacophore unit, was designed and synthesized. Further, we determined the antiproliferative activities of these compounds through experimental assays and analyzed their interactions with Breakpoint Cluster Region/Abelson (bcr/abl), Epidermal Growth Factor Receptor (EGFR), and Human Epidermal Growth Factor Receptor 2 (HER2) tyrosine kinases using molecular autodocking techniques. We grouped these amides into three categories, classified by the type of spacer that binds the pyridine ring to the amide nitrogen atom. Additionally, within each group, we strategically positioned the amide moiety at the ortho, meta , or para position on the pyridyl ring. Among the studied amides, compound 3 exhibited the best overall antiproliferative activity against human immortalized myelogenous leukemia (K562) (IC 50 = 26 µM), human leukemia monocytic cell line (THP-1) (IC 50 = 81 µM), and human hepatocellular carcinoma (HepG2) (IC 50 = 210 µM). Molecular docking studies revealed that compound 3 binds effectively to bcr/abl, EGFR, and HER2 tyrosine kinases, demonstrating strong interactions with crucial active site amino acids, indicative of its targeted antiproliferative mechanism. All investigated compounds showed either very minor or no cytotoxicity against human dermal fibroblast adult cells. [Display omitted] [ABSTRACT FROM AUTHOR]