Supramolecular Synthon Strategy via Organic Salt Formation for Developing Topical Gel From Rhein: Synthesis, Gelation, Crystal Structures, and Antibacterial Properties Against MRSA

Rhein is reported to have numerous advantages in biological applications. The extreme hydrophobicity of Rhein hinders its clinical transformation into better alternatives like hydrogels. Converting a drug molecule into a supramolecular topical gel for direct application to a target site (e.g., wounds, allergic inflammation, or skin cancer) is key to developing a vehicle-free drug delivery (VFDD) system. This approach offers clear advantages over conventional drug delivery systems, which rely on a vehicle to transport and deliver the drug. However, designing a gelator-converting a drug molecule into a gel-forming entity-is a challenging task. In this study, we utilized a well-documented gelation-inducing supramolecular synthon, the primary ammonium monocarboxylate (PAM) synthon, developed by our team. We transformed Rhein into 11 PAM salts by reacting it with alkyl amines. Remarkably, all PAM salts exhibited gelation in an aqueous solvent (DMSO/water). Single-crystal structures of five PAM salts revealed a strong correlation with their gelation behavior. One salt, RHC6, demonstrated excellent cell viability with normal cell lines and effective antibacterial activity against Gram-positive and Gram-negative bacteria, including clinically isolated methicillin-resistant Staphylococcus aureus (MRSA). Its material properties, such as rheoreversibility and patch-forming ability, position the RHC6 gel as a promising candidate for antimicrobial VFDD applications.