Abstract
Interest in piperazine scaffolds continues to rise due to their broad relevance across anti-infective, anticancer, and neuroactive research. This review examines reports published from 2014 to 2024 and organizes current developments by therapeutic class, structural modification strategy, and computational assessment. Substitution patterns involving aryl, heterocyclic, and hybrid groups show consistent effects on target affinity, selectivity, and pharmacokinetic properties. Several series demonstrate strong activity in early biological evaluation, supported by docking and pharmacodynamic trends that highlight recurring structural motifs. Synthetic approaches, including N-functionalization, reductive routes, cross-coupling, CH activation, microwave-assisted reactions, and flow-based methods, provide diverse access to optimized derivatives. Combined interpretation of synthetic, biological, and computational results outlines reproducible structure-property relationships that guide piperazine-focused design. Future progress is expected to arise from hybrid scaffold engineering, improved strategies for central nervous system delivery, and the integration of predictive machine-learning methods into lead refinement.