Design, Synthesis, and Biological Evaluation of <i>p</i> ‐Nitrobenzene Derivatives as Colchicine‐Binding Site Tubulin Inhibitors

Abstract Tubulin plays a pivotal role in various cellular functions, making it an important target for cancer treatment. Compared to paclitaxel and vincristine, which have received approval for clinical use, colchicine‐binding site inhibitors exhibit reduced susceptibility to drug resistance. However, challenges such as toxicity, insufficient efficacy, and unsatisfactory pharmacokinetic properties impede their clinical application. In this study, we designed and synthesized a series of novel p ‐nitrobenzene derivatives as inhibitors targeting the colchicine‐binding site, utilizing IMB5046 as the lead compound. The results indicated that the antitumor activity of compound A14 (IC 50 = 0.14 µM) was comparable to that of IMB5046 (IC 50 = 0.17 µM). In addition, compound A14 could effectively reduce tubulin density and induce G2/M phase arrest. The results of molecular docking indicated that compound A14 could bind to the colchicine‐binding site of tubulin by hydrogen bonds and hydrophobic interactions. The physicochemical and pharmacokinetic properties of compound A14 were predicted, revealing that it exhibits characteristics remarkably similar to those of IMB5046. The active compound A14 identified in this study exhibits potent anti‐tumor activity, suggesting its potential as a tubulin inhibitor. This research provides a reference for the discovery of novel colchicine‐binding site inhibitors.