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 (6S) 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 6S derivatives. Most derivatives inhibited PLCβ activity and
modulated downstream effectors, including inositol phosphates, diacylglycerol,
intracellular calcium, and pMLC20. Notably, derivatives 8a and 8c exhibited enhanced inhibition in human
airway smooth muscle cells without cytotoxicity. Structure–activity
analysis revealed that a para-phenol-conjugated dec-1,4-dien-3-one
core with additional meta-free hydroxyl groups in
the phenol moiety of 6S 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.