Novel Carbamate-Based o-aminobenzamide Derivatives as Potent Antigastric Carcinoma Agents via Disrupting NAD⁺ Salvage Synthesis

Blocking NAD⁺ biosynthesis presents an appealing strategy for antitumor therapies. This study developed a series of o-aminobenzamide derivatives with substantial antitumor efficacy against gastric cancer. Notably, compound 9a demonstrated exceptional antitumor activity against undifferentiated gastric cancer HGC27 cells (IC₅₀ = 0.049 μM), and significant inhibitory effects on cellular proliferation, self-renewal, invasion, and migration. Mechanistic investigations revealed that 9a could damage mitochondria, arrest the cell cycle, promote apoptosis, and alter cellular metabolism. Furthermore, the rate-limiting enzyme NAMPT in the NAD⁺ salvage synthetic pathway was identified as a primary target of 9a. By inhibiting NAMPT, 9a reduced intracellular levels of NAD⁺ and ATP, while NMN, a natural product of NAMPT, counteracts its antimetabolic and cytotoxic effects. Overall, this study highlights 9a as a promising NAMPT inhibitor with significant activity against undifferentiated gastric cancer, laying the groundwork for developing novel antigastric cancer agents through inhibiting NAD⁺ biosynthesis.