Design, synthesis and antifungal evaluation of novel nopol derivatives as potent laccase inhibitors

Abstract

BACKGROUND To explore further potential natural product‐based antifungal agents, a series of novel nopol‐based carboxamide and hydrazide derivatives containing a natural pinene structure were designed, synthesized, and evaluated for their inhibitory activities against seven phytopathogenic fungi and oomycetes. RESULTS The bioassay results indicated that some compounds exhibited good inhibitory activities against Gibberella zeae, Sclerotinia sclerotiorum, and Phytophthora capsici. Among them, compound 3h displayed excellent in vitro activities against G. zeae, with EC50 values of 1.09 mg L−1, which was comparable with the commercial fungicides bixafen and carbendazim (median effective concentration [EC50] = 1.21 and 0.89 mg L−1, respectively). Notably, in vivo bioassay results suggested that compound 3h also showed prominent protective and curative effects (95.6% and 94.2%) at 200 mg L−1 against G. zeae. The scanning electron microscopy study indicated that compound 3h could destroy the morphological integrity of G. zeae hyphae. The in vitro enzyme inhibitory bioassay revealed that compound 3h exhibited potent inhibitory activity against laccase with median inhibitory concentration (IC50) values of 4.93 μm, superior to positive control cysteine (IC50 = 35.50 μm), and its binding modes with laccase were elucidated by molecular docking study. In addition, the fluorescent imaging of the dansylamide‐labeled derivatives 8 on wheat leaf epidermal cells and the hyphae of G. zeae revealed that this class of hydrazide derivatives could readily permeate into wheat leaves and reached the laccase target in fungal cells. CONCLUSION Some nopol‐based hydrazide derivatives exhibited excellent anti‐G. zeae activity and laccase inhibitory activity, which merits further development as a new fungicide candidate for controlling Fusarium head blight. © 2023 Society of Chemical Industry.

Synthesis and Antifungal Activity of Novel L‐Menthol Hydrazide Derivatives as Potential Laccase Inhibitors

“…Different concentrations compound 3 b (10.14 μmol/L, 5.07 μmol/L, 2.54 μmol/L, 1.23 μmol/L and 0.63 μmol/L), cysteine (82.54 μmol/L, 41.27 μmol/L, 20.63 μmol/L, 10.32 μmol/L and 5.16 μmol/L) and PMDD‐5Y (reported laccase inhibitor, 209.18 μmol/L, 104.59 μmol/L, 52.29 μmol/L, 26.15 μmol/L and 13.07 μmol/L) was tested for their laccase inhibitory activities. Specific test steps were consistent with our previous work [18] …”

“…The laccase inhibitory assay results and the docking study suggested that the target compounds could be potential laccase inhibitors [17] . Our group also designed and synthesized a novel series of nopol derivatives, and some derivatives exhibited potent antifungal and laccase inhibitory activities [18] . Although the research on laccase inhibitors is still in the preliminary stage, the discovery of this novel type of antifungal agents may offer a new approach for overcoming the emerging resistance of fungal pathogens to traditional antifungal agents [19]…”

“…[17] Our group also designed and synthesized a novel series of nopol derivatives, and some derivatives exhibited potent antifungal and laccase inhibitory activities. [18] Although the research on laccase inhibitors is still in the preliminary stage, the discovery of this novel type of antifungal agents may offer a new approach for overcoming the emerging resistance of fungal pathogens to traditional antifungal agents. [19] Natural products have been considered as an important source of lead compounds or design inspirations in the discovery of new drugs and agrochemicals in recent decades.…”

Design, Synthesis, and Biological Evaluation of Novel Camphor-Based Hydrazide and Sulfonamide Derivatives as Laccase Inhibitors against Plant Pathogenic Fungi/Oomycetes

“…Some active compounds exhibited prominent antifungal and laccase inhibitory activities. 23 Natural products (NPs) have been considered as a huge treasury of lead compounds as well as inspirations for designing novel fungicides. 24 As an important renewable natural monoterpene, camphor can be isolated from Cinnamomum camphora, while the synthetic analogue can be produced from turpentine.…”

“…In addition, our group also reported novel nopol-based amide/hydrazide derivatives. Some active compounds exhibited prominent antifungal and laccase inhibitory activities …”