Synthesis of biocompatible novel multi-tailed indole-based resorcinarene for effective delivery of quercetin against multidrug-resistant S. aureus.

Resorcine-based macrocycles have received significant attention in drug delivery applications owing to their tunable functional groups, well-defined cavities, and inherent self-assembly behavior, considering essential for encapsulation and controlled release of loaded drug candidates. However, existing resorcinarene derivatives face certain limitations in drug loading, physiologic stability, and compatibility with structurally complex natural therapeutics, necessitating the development of novel macrocyclic architectures with improved stability and compatibility for hydrophobic drugs. To address this gap, the current research synthesized a novel resorcinarene-based macrocycle, referred to as Indole Macrocycle (IM), to improve the therapeutic potential of quercetin (QTN). The synthesized IM was characterized utilizing Mass, 1H- and 13C-NMR, and FT-IR spectroscopy. Biocompatibility studies indicated high cell viability of NIH-3T3 cells at 30 µM (95.72 ± 0.4% at 24 h and 94.10 ± 0.3% at 48 h) and low hemolytic activity (9.32% ± 1.65% at 1000 µg/mL). The critical micelle concentration (CMC) of IM was determined to be 0.022 mM. QTN-loaded IM vesicles exhibited a spherical morphology with a size of 248.7 ± 7.17 nm, zeta potential of - 15.8 ± 0.8 mV, PDI of 0.258 ± 0.05, and encapsulation efficiency of 74 ± 2.57%, while demonstrating a controlled drug release profile, with maximum release of 69% ± 1.8% over 48 h. Antibacterial evaluation against multidrug-resistant S. aureus strains (NCTC 13143 and NCTC 13277) revealed a significantly reduced MIC of 170 ± 8.23 µg/mL compared to 488 ± 9.53 µg/mL for free QTN. The results were further confirmed through AFM analysis, demonstrating significant bacterial membrane disruption following treatment. These findings revealed that QTN-loaded IM vesicles are a promising system for improving drug delivery and combating MDR bacterial infections.