Designing anti-bacterial supramolecular gels from primary ammonium dicarboxylate (PAD) salts for self-delivery applications

Abstract

Primary ammonium dicarboxylate (PAD) salts often display 2D columnar hydrogen bonded networks known as the PAD supramolecular synthon in the context of crystal engineering. The PAD synthon is known to play an effective role in supramolecular gelation. Vehicle-free drug delivery (VFDD) vis-à-vis conventional drug delivery (CDD), is advantageous as it does not require any vehicle to deliver the drug. In here, we disclose the development of an anti-bacterial VFDD system based on PAD salts. Synthesis, structure and supramolecular gelation behaviour of 20 PAD salts derived from 5 dicarboxylic acids – (CH₂)_n–(COOH)₂ (n = 4, 7, 10, 12 and 14) – and 4 therapeutic amines – amantadine (AMN), tyramine (TRM), tryptamine (TRP) and mafenide (MAF) – are reported. Interestingly, 40% of the PAD salts were able to gel methyl salicylate (MS) – an important ingredient in many commercially available topical ointments. The gels were characterized by rheology and TEM. The underlying supramolecular interactions were analysed using single crystal X-ray diffraction (SXRD) studies carried out on as many as 9 salts. The gelator salt, C₁₄·2MAF, containing anti-bacterial drug MAF as the amine part, showed excellent anti-bacterial behaviour against E. coli. Detailed biological studies suggested that the C₁₄·2MAF anti-bacterial property is caused by bacterial cell membrane disruption and ROS generation. Gradual release of C₁₄·2MAF from a MS-gel bed and sheer thinning of the gel phase, clearly indicated that the C₁₄·2MAF MS gel has potential use as a supramolecular topical gel for anti-bacterial treatment.