Synthetic Strategies of Heterocycle‐Linked Sulfonamide Hybrids as Emerging Anticancer Agents: An Update

Abstract

Sulfonamide‐containing heterocycles constitute a versatile and synthetically accessible class of scaffolds in contemporary anticancer drug discovery. In recent years, substantial progress has been made in developing efficient synthetic methodologies that enable the construction and late‐stage diversification of sulfonamide‐based hybrid architectures. This review provides a comprehensive overview of advances reported over the past five years in the synthesis of heterocycle‐integrated sulfonamide derivatives. Particular emphasis is placed on strategic bond‐forming approaches, modular scaffold assembly, and late‐stage sulfonylation protocols that facilitate structural diversification and rapid library generation. The discussion is organized according to the nature of the heterocyclic core, encompassing oxygen‐containing systems (e.g., coumarins, flavones, naphthoquinones, and oxadiazoles), nitrogen‐rich frameworks (including benzimidazoles, quinazolines, quinolines, triazines, and imidazole‐pyridine hybrids), nitrogen–sulfur fused scaffolds (such as benzothiazoles, thiadiazoles, and thienopyrimidines) and chalcone‐based sulfonamide hybrids, which represent an important class of molecularly hybridized anticancer scaffolds. Key synthetic strategies‐ranging from classical annulation methods and nucleophilic aromatic substitution to carbodiimide‐mediated coupling, Curtius rearrangement, click chemistry, and late‐stage N ‐sulfonylation are critically analyzed with respect to efficiency, scope, and synthetic practicality. Collectively, these advances highlight the growing strategic importance of sulfonamide‐linked heterocyclic hybrids as promising platforms for anticancer drug development.