Natural Product-Based Fungicides: Design, Synthesis, and Antifungal Activity of Rhein Derivatives Against Phytopathogenic Fungi

With the long-term use of certain types of traditional chemical fungicides, phytopathogen resistance and environmental pollution have made the application of these fungicides face unprecedented challenges. Therefore, using the low toxicity and structural diversity of natural product analogs to develop alternatives has become an important tactic to improve control efficiency and reduce pathogen resistance, as well as environmental risks. In this study, thirty-eight rhein derivatives were synthesized after our continuous efforts aiming to discover new anthraquinone-based antifungal agents. Their structures were characterized by 1H-NMR, 13C-NMR and high-resolution mass spectrometry. The antifungal activities of rhein derivatives were first evaluated against four phytopathogenic fungi. The bioassay results indicated that most derivatives exhibited good antifungal activity against Rhizoctonia solani at 0.5 mM in vitro. Compounds 3e, 3j, 4a, 9d and 10f showed potent activities against R. solani, with inhibition rates over 50% at a low concentration of 0.2 mM in vitro. In particular, compound 10a strongly inhibited the growth of Sclerotinia sclerotiorum, Fusarium graminearum and P. capsica, with EC50 values of 0.079 mM, 0.082 mM and 0.134 mM, respectively, which are comparable to the commercial biofungicide phenazine-1-carboxylic acid (PCA). An in vivo study showed that 10a presented excellent curative and protective activities (92.1% and 91.1%, 0.2 mM) against wheat powdery mildew. The phytotoxicity results indicated that rhein amino acid derivatives could significantly eliminate phytotoxicity to rice and rape and could be safely used in these two crops. The resistance development assay indicated that these rhein derivatives could effectively avoid the risk of resistance development in these two strains of fungi, R. solani and S. sclerotiorum. In conclusion, rhein derivatives can be used for the development of potential agricultural fungicides.