Design, modification and 3D QSAR studies of novel naphthalin-containing pyrazoline derivatives with/without thiourea skeleton as anticancer agents.

Abstract Two series of novel naphthalin-containing pyrazoline derivatives C1 – C14 and D1–D14 have been synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. Compound D14 displayed the most potent activity against EGFR and A549 cell line (IC 50  = 0.05 μM and GI 50  = 0.11 μM), being comparable with the positive control Erlotinib (IC 50  = 0.03 μM and GI 50  = 0.03 μM) and more potent than our previous compounds C0–A (IC 50  = 5.31 μM and GI 50  = 33.47 μM) and C0–B (IC 50  = 0.09 μM and GI 50  = 0.34 μM). Meanwhile, compound C14 displayed the most potent activity against HER-2 and MCF-7 cell line (IC 50  = 0.88 μM and GI 50  = 0.35 μM), being a little less potent than Erlotinib (IC 50  = 0.16 μM and GI 50  = 0.08 μM) but far more potent than C0–A (IC 50  = 6.58 μM and GI 50  = 27.62 μM) and C0–B (IC 50  = 2.77 μM and GI 50  = 3.79 μM). The docking simulation was performed to analyze the probable binding models and the QSAR models were built for reasonable design of EGFR/HER-2 inhibitors at present and in future. The structural modification of introducing naphthalin moiety reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity. Moreover, the replacement of thiourea skeleton by using benzene ring resulted in the slight diversity of the two series towards specific targets.