Reactivity-based screening (RBS) was used to screen fungal crude extracts for the presence of new azaphilic natural products. A probe composed of a nucleophilic primary amine and an isotopic mass tag was designed for its reactivity towards azaphilic compounds. Addition of the probe to crude extracts of fungal complexes, together with analytical tools for dereplication such as haloseeker and molecular networking, allowed easy detection of azaphilic compounds. The exploitation of this RBS protocol led to the isolation and structural characterization of new azaphilones.