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Inhibition of β-tubulin polymerization has been set as promising therapeutic strategy for cancer therapy. Accordingly, a new set of triaryl-tethered acetohydrazide-acryloyl derivatives were designed and synthesized. The antiproliferative influence was evaluated against liver Huh-7 cell line using MTT colorimetric method with Doxorubicin as a positive control. Compounds 3b, 4f, 4i, and 4j showed excellent cytotoxic activity against Huh-7 cell line. Among the investigated compounds, 2-(naphthalene-2-yloxy)acetohydrazide having 2-(4-methyl)-3-(3,4,5-trimethoxybenzamido)acryloyl moiety (compound 4i) was the most active one with an IC₅₀ value of 2.46 µM. In addition, all compounds were further evaluated in vitro for their β-tubulin polymerization inhibition activity. Results found that compound 4i showed high activity against β-tubulin polymerization with an IC₅₀ value of 2.29 µM, surpassing the activity of the reference Podophyllotoxin (IC₅₀ = 4.45 µM). Further studies revealed the ability of the promising compound 4i to induce apoptosis and halt the cellular cycle at G2/M phase. Furthermore, the apoptosis-inducing activity of naphthalene-tethered acryloyl moiety 4i was correlated to the downregulation of Bcl-2 as well as elevation of both Bax and caspase 9 as concluded from RT-PCR immunoassay measurements. Finally, molecular docking studies were also performed to explain the displayed inhibitory activities.