Discovery of structurally diverse diazatricyclododecenes as lysosomotropic autophagy inhibitors

Abstract

Lysosomotropic autophagy inhibitors were identified from a structurally diverse library of diazatricycloundecanes. Structure activity relationship (SAR) studies on the three side chain substituents (R¹-R³) of diazatricycloundecane identified compound 1e as the most potent inducer of LC3-II protein accumulation. Mechanistic analysis revealed that compound 1e functions as a lysosomotropic agent, increasing lysosomal pH and inhibiting autophagy through lysosomal dysfunction. Furthermore, compound 1e was less cytotoxic compared to previously reported lysosomotropic agents and exhibited excellent drug-like physicochemical properties, surpassing those of classical lysosomotropic agents such as chloroquine and hydroxychloroquine.