Zheng_2025_Phytomedicine_141_156662

BACKGROUND: Natural products have emerged as a critical focus in modern scientific research due to their structural diversity and therapeutic potential. Among these are natural organic cations-a distinct class of nitrogen- and oxygen-containing compounds. Despite their pharmacological relevance, the literature lacks a systematic synthesis of structure-activity relationships for natural organic cations (NOC). This gap hinders the rational development of NOC-based therapies as sustainable alternatives to synthetic compounds. METHODS: Literature was searched and collected using databases, including PubMed, Science Direct, and Web of Science. The search terms used included "natural organic cation", "alkaloid", "anthocyanin", "structure-activity relationship", "charge interaction", "Pi-cation interaction", "biological activity", "antimicrobial", "antioxidant", "anticancer", "neuroprotection", "anti-inflammatory", "berberine", "coptisine", "palmatine", "cyanidin", "delphinidin", "pelargonidin", "free radical scavenging", "gut microbiota metabolism", "NF-kappaB pathway", "G-quadruplex DNA", "isoquinoline alkaloid", "protoberberine", "benzophenanthridine", "planar conjugated system", "charge delocalization", "methylenedioxy group", and several combinations of these words. RESULTS: The bioactivity of NOC is underestimated. This review uncovers the structure-activity relationships of NOC. Firstly, planar conjugated systems and substituents control target binding: N in alkaloids enhances DNA/protein affinity, while O in anthocyanins enables free radical scavenging and enzyme inhibition. Secondly, cationic species outperform neutral analogs in antimicrobial potency, antioxidant capacity, and target selectivity. NOC bind to biomolecules via Pi-cation/Pi-Pi stacking and electrostatic binding. Charge localization in conjugated systems enhances stability and bioactivity. CONCLUSION: This review consolidates evidence that NOC represent promising candidates for replacing synthetic compounds in therapies for cancer, neurodegeneration, metabolic disorders, etc. Key findings highlight the superiority of cationic species in target engagement and bioactivity, driven by planar conjugated systems and substituent effects. However, clinical translation requires addressing gaps in bioavailability and long-term safety. Future research must prioritize structural optimization and mechanistic validation. By bridging these gaps, NOC could advance as sustainable, low-toxicity agents in precision medicine and functional nutrition.