Water-soluble acylhydrazone macrocycles as potent reversal agents for cisatracurium-induced neuromuscular blockade

Cisatracurium is a widely used non-depolarizing neuromuscular blocking agent during anesthesia; however, residual neuromuscular blockade post-surgery can lead to severe respiratory complications, highlighting the urgent need for effective reversal agents. In this study, we designed and synthesized a highly water-soluble acylhydrazone macrocycle featuring an electron-rich cavity as an efficient supramolecular reversal agent for cisatracurium. The macrocycle binds cisatracurium through electrostatic and hydrophobic interactions, exhibiting a binding constant of up to 10⁵ M^-1. Cytotoxicity assays confirmed its excellent biocompatibility, and in vivo studies in cisatracurium-anesthetized mice demonstrated that the macrocycle effectively reverses cisatracurium-induced neuromuscular blockade. This work provides a new strategy for developing water-soluble acylhydrazone macrocycles as potential supramolecular reversal agents for neuromuscular blockers.