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The biocontrol fungus Trichoderma harzianum, from both marine and terrestrial environments, has attracted considerable attention. T. harzianum has a tremendous potential to produce a variety of bioactive secondary metabolites (SMs), which are an important source of new herbicides and antibiotics. This review prioritizes the SMs of T. harzianum from 1988 to June 2022, and their relevant biological activities. Marine-derived SMs, especially terpenoids, polyketides, and macrolides compounds, occupy a significant proportion of natural products from T. harzianum, deserving more of our attention.

Twelve new and four known alkaloids including five different structural scaffolds were isolated from the sponge Stylissa massa collected in the South China Sea. Compound 1 is the first identified precursor metabolite of the classic 5/7/5 tricyclic skeleton with unesterified guanidine and carboxyl groups, compounds 2–5 and 13–15 belong to the spongiacidin-type pyrrole imidazole alkaloids (PIAs). Z- and E-configurations of the spongiacidin-type PIAs often appeared concomitantly and were distinguished by the chemical shift analysis of 13C NMR spectra. The structures of all twelve new compounds were determined by NMR, MS, and ECD analysis combined with single-crystal data of compounds 1, 5, and 10. In the aldose reductase (ALR2) inhibitory assay, six 5/7/5 tricyclic compounds (2–5, 13–15) displayed significant activities. Compounds 13 and 14, as the representative members of spongiacidin-PIAs, demonstrated their ALR2-targeted activities in SPR experiments with KD values of 12.5 and 6.9 µM, respectively.