Multicomponent mannich-type approaches to the synthesis of functionalized piperazine-based bioactive scaffolds

Piperazine is a nitrogen-containing heterocycle widely present in pharmacologically active compounds. Multicomponent strategies, particularly Mannich-type reactions, have proven highly effective for introducing molecular complexity and functional diversity into piperazine frameworks. Various noteworthy activities exhibited by piperazine-based Mannich bases include anti-cancer, antioxidant, analgesic, antiviral, antifungal, anti-inflammatory, and antibacterial properties. Herein, we have compiled literature reports from 2020 to 2025 that systematically explore synthetic advancements for piperazine-based bioactive scaffolds via Mannich-type approaches. The synthetic approaches encompass the three-component Mannich-type condensation, multicomponent reaction variations, and green or catalytic methods. Emphasis is placed on their role in enhancing scaffold diversity and drug discovery within sustainable chemistry.