Pyridones and macrocyclic pyrrolidones from marine fungal PKS-NRPS hybrids: biosynthetic origin, bioactivities, and synthetic advances.

Covering: 2002-2025Marine fungi have emerged as a prolific source of structurally unprecedented and biologically potent secondary metabolites, and hybrid polyketide synthase-non-ribosomal peptide synthase (PKS-NRPS) enzymes mainly from marine fungi like symbiotic Aspergillus and deep-sea Penicillium, represent an exceptionally fertile source of such complex natural products. Among the diverse products of these mega-enzymes, pyridones and macrocyclic pyrrolidone constitute a unique class of natural products with significant therapeutic potential. This review provides a comprehensive overview on this family of natural products, covering their global distribution and biosynthetic enzymology, chemical ecology, and biosynthesis. The bioactivities of these compounds, ranging from potent anticancer and antibacterial to immunosuppressive and anti-inflammatory effects, are discussed. Furthermore, this review summarises the synthetic strategies developed to access these complex chemical scaffolds. This review provides a roadmap for future genome-guided discovery and the rational design of novel therapeutics inspired by these privileged marine natural products.