Lead Optimization-Based Rational Design, Synthesis, and Anticancer Evaluation of Novel 1H-Indazole-4-carboxamide Derivatives

Malignant tumors remain a leading cause of global mortality, necessitating the urgent development of innovative antineoplastic agents. Herein, a series of novel 1H-indazole-4-carboxamide derivatives were rationally designed and synthesized through a lead optimization strategy to investigate their structure–activity relationships. Among the synthesized library, compound 8b featuring a para-fluoro substituent exhibited the most potent cytotoxicity against human esophageal squamous cell carcinoma (KYSE-150) cells with an IC50 value of 1.93±0.77 μM. Mechanistic studies demonstrated that compound 8b triggers G2/M phase cell cycle arrest, suppresses cellular migration and colony formation, and induces apoptosis via the intrinsic mitochondrial pathway. Furthermore, 8b displayed favorable drug likeness, adhering to Lipinski’s Rule of Five, and showed a promising safety profile in acute toxicity assessments. These findings establish 8b as a viable lead candidate for the development of targeted therapies against esophageal squamous cell carcinoma.