Design and Evaluation of Novel Ginger 6-Shogaol-Inspired Phospholipase C Inhibitors to Enhance β-Agonist-Induced Relaxation in Human Airway Smooth Muscle

Over 300 million people suffer from asthma, with many experiencing poor symptom control despite current medications. This highlights the need for novel therapeutics. Phospholipase Cβ (PLCβ), which contributes to bronchoconstriction, is a promising drug target. We previously identified 6-shogaol (<b>6S</b>) derivatives containing a dec-1,4-dien-3-one backbone as promising PLCβ inhibitors in cell-based assays. However, they failed to relax airways in mouse lung tissues. To improve efficacy, we synthesized 15 novel <b>6S</b> derivatives. Most derivatives inhibited PLCβ activity and modulated downstream effectors, including inositol phosphates, diacylglycerol, intracellular calcium, and pMLC₂₀. Notably, derivatives <b>8a</b> and <b>8c</b> exhibited enhanced inhibition in human airway smooth muscle cells without cytotoxicity. Structure-activity analysis revealed that a <i>para</i>-phenol-conjugated dec-1,4-dien-3-one core with additional <i>meta</i>-free hydroxyl groups in the phenol moiety of <b>6S</b> derivatives significantly enhanced PLCβ inhibition. Importantly, these two derivatives also significantly potentiated β-agonist-induced relaxation in human tracheal tissue, highlighting their therapeutic potential as innovative asthma treatments.