Discovery of Natural Sesquiterpene Lactone 1-O-Acetylbritannilactone Analogues Bearing Oxadiazole, Triazole, or Imidazole Scaffolds for the Development of New Fungicidal Candidates

Abstract

In recent decades, natural products have been considered important resources for developing of new agrochemicals because of their novel architectures and multibioactivities. Consequently, herein, 1-O-acetylbritannilactone (ABL), a natural sesquiterpene lactone from Inula britannica L., was used as a lead for further modification to discover fungicidal candidates. Six series of ABL-based derivatives containing an oxadiazole, triazole, or imidazole moiety were designed and synthesized, and their antifungal activities were also evaluated in vitro and in vivo. Bioassay results revealed that compounds 8d, 8h, and 8j (EC50 = 61.4, 30.9, and 12.4 μg/mL, respectively) exhibited more pronounced inhibitory activity against Fusarium oxysporum than their precursor ABL (EC50 > 500 μg/mL) and positive control hymexazol (EC50 = 77.2 μg/mL). Derivatives 8d and 11j (EC50 = 19.6 and 41.5 μg/mL, respectively) exhibited more potent antifungal activity toward Cytospora mandshurica than ABL (EC50 = 68.3 μg/mL). Compound 10 exhibited excellent and broad-spectrum antifungal activity against seven phytopathogenic fungal mycelia. Particularly, the inhibitory activity of compound 10 against the mycelium of Botrytis cinerea was more than 10.8- and 2.3-fold those of ABL and hymexazol, respectively. Meanwhile, derivative 10 (IC50 = 47.7 μg/mL) displayed more pronounced inhibitory activity against the spore of B. cinerea than ABL (IC50 > 500 μg/mL) and difenoconazole (IC50 = 80.8 μg/mL). Additionally, the in vivo control efficacy of compound 10 against B. cinerea was further studied using infected tomatoes (protective effect = 58.4%; therapeutic effect = 48.7%). The preliminary structure–activity relationship analysis suggested that the introduction of the 1,3,4-oxadiazole moiety (especially the 1,3,4-oxadiazole heterocycle containing the 4-chlorophenyl, 2-furyl, or 2-pyridinyl group) on the skeleton of ABL was more likely to produce potential antifungal compounds. These findings pave the way for further design and development of ABL-based derivatives as potential antifungal agents.

Dibenzylideneacetone Overcomes Botrytis cinerea Infection in Cherry Tomatoes by Inhibiting Chitinase Activity

“…Furthermore, current research reveals that regardless of the inhibitor type, be it organic small molecules, peptides, or proteins, as well as the different target sites (histone deacetylase, succinate dehydrogenase, pyruvate kinase), inhibitors consistently exhibit a more pronounced inhibitory effect on spore germination rather than mycelium growth in B. cinerea . The results of this study are entirely consistent with the literature, suggesting that the observed variations in inhibition effects are not directly associated with the Chitinase target of the DBA inhibitor.…”

Antifungal Activity and Putative Mechanism of HWY-289, a Semisynthetic Protoberberine Derivative, against Botrytis cinerea

“…Following incubation at 26 °C for 4 days, the mycelium discs were measured, and the therapeutic effects were calculated. The formulas were calculated as Therapeutic .25em effect false( % false) = normalC − normalT normalC − 1 × 100 where C represents the diameter of B. cinerea growth on blank control and T represents the diameter of B.…”

“…In vivo, the activity of HWY-289 against B. cinerea was assayed by a previously reported method with minor modifications . We tested ripe, healthy, similarly shaped tomatoes from a local supermarket.…”

“…In vivo, the activity of HWY-289 against B. cinerea was assayed by a previously reported method with minor modifications. 28 We tested ripe, healthy, similarly shaped tomatoes from a local supermarket. The surfaces of the tomatoes were disinfected with 2% (v/v) sodium hypochlorite and 75% ethanol for 2 min, respectively, and rinsed three times with sterile distilled water.…”

“…Following incubation at 26 °C for 4 days, the mycelium discs were measured, and the therapeutic effects were calculated. The formulas were calculated as 28 Therapeutic effect(%) C T C 1 100 = ×…”