Supramolecular Synthon-Driven Design, Synthesis, and Single-Crystal Structures of a Series of Diacylhydrazines as Potential Supramolecular GelatorsExploring the Gel Matrix for Drug Delivery

Abstract

Supramolecular assembly of small molecules occasionally leads to viscoelastic materials like supramolecular gels that are important for various applications in material science including drug delivery. However, the a priori design of such soft materials remains an elusive goal. Understanding of the supramolecular synthon and its importance in the context of crystal engineering proved to be handy in occasional prediction of gelation. Herein, we report the supramolecular synthon-driven design, synthesis, and single-crystal structures of a series of diacylhydrazines as potential supramolecular gelators. Conjugation of various arylcarboxylic acids including a few non-steroidal-anti-inflammatory drugs (NSAIDs), namely, naproxen (NAP), ibuprofen (IBU), and flurbiprofen (FLB), with hydrazine afforded seven diacylhydrazine molecules, all of which were found to be gelators of various solvents. The gels were routinely characterized by dynamic rheology and electron microscopy. While hydrogen-bonded self-assembly involving the N−N fused amide moieties in these molecules as revealed by single-crystal structures appeared to have played a pivotal role in gelation, one such gelator NAP_Hydz showed the capability of loading drugs like sulfasalazine or SUL (NSAID) and doxorubicin or DOX (anti-cancer) onto the corresponding supramolecular gel matrix. In vitro studies revealed that the drug-loaded xerogels, i.e., NAP_Hydz@SUL (xerogel) and NAP_Hydz@DOX (xerogel), were effective in reducing inflammation in inflamed normal cells RAW 264.7 and killing melanoma cells (B16−F10), respectively. The rheoreversibility, injectability, and shape sustainability of the supramolecular gels of NAP_Hydz suggested a plausible drug delivery application via the topical route.