Design and synthesis of novel 3,5-diphenyl pyrazolines acting as potent EGFR inhibitors with off-target antileukemic effect.

Aim: Searching for novel epidermal growth factor receptor (EGFR) inhibitors, 1-substituted 3,5-diphenyl pyrazolines 4a-i, 5a-i, 6a, and 6b bearing the terminal piperidine or morpholine moieties commonly observed in clinically approved EGFR inhibitors were synthesized as novel anti-cancer agents acting via EGFR inhibition.

Materials & methods: A series of 3,5-diphenyl pyrazolines was synthesized and screened for in vitro anti-cancer activity against 60 NCI cell lines.

Results: Pyrazolines 5d and 6a revealed broad-spectrum cytotoxic activities and potent EGFR inhibition with IC₅₀ values of 2.30 µM and 1.47 µM, respectively, in comparison to Vandetanib (IC₅₀ = 0.5 µM) and Gefitinib (IC₅₀ = 0.04 µM). Interestingly, compound 6a demonstrated a promising cytotoxic activity against the leukemia cell line (HL-60) and safety toward the normal cell line HSF. Additionally, compound 6a up-regulated proapoptotic markers and down-regulated Bcl-2 as an antiapoptotic marker in HL-60 cells. Docking simulations explained the EGFR inhibitory actions of 5d and 6a compared to Gefitinib. According to predictive models of oral bioavailability and drug-likeness, pyrazolines 5d and 6a are expected to be bioavailable and drug-like compounds.

Conclusion: Pyrazolines 5d and 6a are novel EGFR inhibitors with a broad-spectrum anti-cancer activity, and 6a has off-target antileukemic effect.