Discovery of benzimidazole derivatives as LDHA inhibitors with antitumor activity.

LDHA is aberrantly overexpressed in various malignancies and drives enhanced glycolytic flux. Although LDHA inhibitors have shown promising antitumor activity in preclinical studies, no such targeted antitumor drugs have been approved for clinical use at present. In this study, we designed and synthesized a series of benzimidazole derivatives bearing benzoate substituents. We evaluated their antitumor activity in vitro and in vivo, along with their LDHA inhibitory potency. Compounds 8h and 8d emerged as the primary candidates. Both exhibited LDHA inhibition activity. They inhibited proliferation of MDA-MB-231 cells (IC₅₀ = 1.43 ± 0.91 μM and 2.58 ± 1.64 μM, respectively) effectively and inhibited cell migration. Furthermore, both compounds induced apoptosis, caused cell cycle arrest, reduced lactate production, and promoted reactive oxygen species generation. Compound 8h showed superior activity compared to 8d. In an MDA-MB-231 xenograft model, 8h significantly inhibited tumor growth. These findings indicate that compound 8h possesses promising antitumor activity and represents a potential LDHA-targeted antitumor agent warranting further investigation.