NAMPT-targeted para-ureidobenzylamine derivatives: Design, synthesis, and antitumor evaluation in gastrointestinal cancers.

Gastrointestinal cancers remain a major clinical challenge, underscoring the need for innovative therapeutic strategies. Given the elevated NAMPT expression in these malignancies, we designed and synthesized a series of 29 small-molecule NAMPT inhibitors derived from lead compound 9a. Among them, Q24 exhibited the strongest activity, showing nanomolar inhibition of NAMPT and subnanomolar antiproliferative effects against HGC-27 cells. Molecular docking and molecular dynamics simulation supported its strong binding to NAMPT. A comprehensive set of in vitro studies demonstrated that Q24 consistently surpassed 9a in suppressing proliferation and migration, disrupting energy metabolism, arresting the cell cycle, and inducing apoptosis. Q24 also displayed favorable oral pharmacokinetic properties and good systemic tolerability. In xenograft models, Q24 significantly inhibited tumor growth, achieving a tumor growth inhibition rate of 68.9% without notable histopathological abnormalities. These findings establish NAMPT as a promising therapeutic target and identify Q24 as a compelling lead for the development of anticancer drugs.