HetCA/STOCSY‐Guided Dereplication of Artemisia arborescens Reveals Furofuran Lignans with Antileishmanial Effects

Natural products represent an important source of bioactive compounds; however, their complexity often challenges conventional discovery approaches. In this study, an ethyl acetate extract of Artemisia arborescens (Vaill.) L. was investigated prior to any isolation using an integrated statistical spectroscopy–driven dereplication strategy combining the HeteroCovariance Approach (HetCA), Statistical Total Correlation Spectroscopy (STOCSY), ¹ H NMR, and LC‐HRMS/MS. HetCA illustrated candidate features correlated with antileishmanial activity, predominantly associated with furofuran lignans. STOCSY facilitated metabolite annotation and distinction of structurally similar metabolites, enabling the identification of a novel lignan and a previously unreported compound in A. arborescens . Targeted isolation verified STOCSY‐guided annotations, while biological evaluation of the pure metabolites revealed that compounds 1 – 3 exhibit moderate activity against Leishmania promastigotes, despite originating from a crude extract exhibiting negligible antileishmanial activity under the initial screening conditions. These findings demonstrate that HetCA can reveal bioactive compounds independently of extract‐level activity and highlight its potential as a robust tool for broadening natural product drug discovery beyond conventional bioactivity‐guided approaches.