Solvent-Free Mechanochemical Synthesis, Antispasmodic Activity, and Integrated In Silico Mechanistic Analysis of a...

The structural hybridization of bioactive quinones is a promising strategy for generating pharmacologically active compounds through sustainable synthetic approaches. This study aimed to synthesize and evaluate a dapsone-derived phenylaminojuglone as a potential intestinal smooth muscle relaxant. Juglone (AJ) was functionalized with dapsone (D) via a solvent-free mechanochemical aza-Michael reaction using silica gel as a mild acid catalyst. The resulting compound (AJ-D) was characterized and evaluated in isolated rat ileum preparations. Pharmacological studies were complemented by molecular docking, density functional theory (DFT) calculations, and in silico ADMET predictions. AJ-D was obtained with complete regioselectivity at the C-3 position and required shorter reaction times than conventional solution-based methods. The compound exhibited significant spasmolytic and antispasmodic effects under basal conditions and against acetylcholine- and KCl-induced contractions. Its relaxant activity was not significantly affected by muscarinic receptor blockade or K⁺ channel inhibition, whereas verapamil reduced its potency. Calcium reintroduction experiments suggested the involvement of extracellular Ca²⁺ influx pathways. Docking studies suggested favorable interactions with the Ca_V1.2 L-type calcium channel, whereas DFT and ADMET analyses indicated suitable electronic and drug-like properties. AJ-D is a promising juglone-derived scaffold with antispasmodic activity, likely associated with the modulation of extracellular calcium influx pathways involved in intestinal smooth muscle contraction.