In Vitro and In Silico Study of 5-(Piperazin-1-Ylsulfonyl)-1,3-Oxazole-4-Carbonitriles Against Neuroblastoma

Neuroblastoma, a leading cause of pediatric cancer mortality, requires efficient and selective therapeutics. We synthesized and characterized a series of sulfonated 5-piperazine-containing 1,3-oxazole-4-carbonitrile derivatives via sulfonylation protocols and evaluated their in vitro cytotoxicity against human hepatocellular carcinoma (HepG2, Huh7), breast (MCF7, MDA-MB-231), cervical (HeLa), melanoma (M21), and two neuroblastoma (Kelly, SHSY5Y) cell lines, alongside non-malignant HEK293 cells. Three compounds (7a, 7b, and 8aa) demonstrated efficient and selective cytotoxicity toward MYCN-amplified (Kelly) and MYCN-non-amplified (SHSY5Y) neuroblastoma cells, with 7b being the most active (IC₅₀ = 1.9 µM in Kelly cells) and showing minimal toxicity in HEK293 (IC₅₀ > 10 µM). In Kelly cells, 7b matched doxorubicin while showing lower off-target toxicity and low-micromolar activity in solid tumors. The hit compounds were shown to be not readily biodegradable under OECD 301D test. In silico docking revealed high-affinity binding to the ATP-binding site of Aurora A kinase in the Aurora A/N-MYC complex (ΔG = –10.8 to –10.9 kcal/mol). Compound 7b exhibited broad cytotoxicity across all tested cancers (IC₅₀ = 1.5–4.0 µM). ADMET profiling of 7a, 7b, and 8aa indicated favorable pharmacokinetic and toxicity parameters compared with doxorubicin. These findings identify sulfonylated oxazole-4-carbonitriles as neuroblastoma therapeutics with potential use against proliferating malignancies.