Antispasmodic Activity of Green-Synthesized Phenylaminojuglones: In Vitro and In Silico Studies

Asunción-Alvarez D.; Ybañez-Julca R.O.; Paredes-Doroteo G.Y.; Quispe-Díaz I.M.; Mantilla-Rodríguez E.; Enriquez-Lara C.; Vásquez-Corales E.; Buc Calderon P.; Catalán M.A.; Gutiérrez-Alvarado W.O.; Benites J. · ACS Omega (2026) · DOI: 10.1021/acsomega.5c11293

Resumen

Phenylaminojuglones were synthesized under solvent-free conditions via silica gel-mediated aza-Michael addition between juglone and substituted anilines, namely, aniline, 4-methoxyaniline, and 3,4,5-trimethoxyaniline. Among the synthesized derivatives, phenylaminojuglone (AJ-2) exhibited the most potent spasmolytic activity on rat ileal smooth muscle. Molecular docking studies revealed that AJ-2 exhibits potential binding affinities with multiple targets implicated in smooth muscle contraction, including muscarinic receptors, β-adrenergic receptors, nitric oxide synthase, guanylate cyclase, and the CaV1.2 calcium channel. Absorption, distribution, metabolism, excretion, and toxicity predictions indicated that AJ-2, AJ-8, and AJ-11 comply with Lipinski’s rule of five and do not present major predicted toxicity liabilities, supporting their pharmacological viability. Functional assays demonstrated that AJ-2 significantly inhibited both pharmacomechanical (ACh-induced) and electromechanical (KCl-induced) contractions. Mechanistic studies suggested that its relaxant effects might be mediated by the activation of β-adrenergic receptors, the NO–sGC–cGMP signaling pathway, and the opening of KV and KCa channels. AJ-2 also inhibited extracellular Ca2+ influx, as shown by its interaction with verapamil and attenuation of CaCl2-induced contractions. These findings support AJ-2 as a promising multifunctional spasmolytic agent derived from green chemistry principles and highlight the pharmacological relevance of phenylaminojuglones as novel modulators of the intestinal smooth muscle tone.

Instituciones: Universidad Nacional de Trujillo; Universidad Nacional de la Amazonía Peruana; Universidad Católica Los Ángeles de Chimbote