1,8-Naphthalimide Heterocycles as Skeleton Structures Targeting Cancer: Insights into Synthesis, Bioactivity, SAR, and Future Directions

Abstract

1,8-Naphthalimide-based heterocyclic compounds have emerged as an important class of anticancer agents owing to their strong DNA-intercalating ability, topoisomerase inhibition, and capacity to modulate multiple cellular pathways. This review aims to provide a comprehensive overview of recent developments (2018-present) in the design, synthesis, and biological evaluation of heterocycle-modified 1,8-naphthalimide derivatives as potential anticancer agents. Particular emphasis is placed on structural modifications involving benzothiazole, imidazole, triazole, piperazine, polyamine, carborane, and other N-substituted frameworks that significantly influence cytotoxic activity, cellular uptake, and pharmacokinetic properties. Structure–activity relationship (SAR) analyses highlight how variations in heterocyclic scaffolds, linker architecture, and substitution patterns modulate DNA binding, topoisomerase inhibition, and apoptosis induction. Key mechanistic insights reveal that these derivatives exert anticancer effects through multiple pathways, including reactive oxygen species generation, cell cycle arrest, autophagy, and ferroptosis. Despite promising biological activities, several challenges remain, including limited selectivity, suboptimal pharmacokinetics, and potential off-target toxicity. By integrating recent synthetic strategies, biological findings, and SAR trends, this review provides a focused perspective on current progress and identifies future directions for the rational design of next-generation naphthalimide-based anticancer therapeutics.