Discovery of Novel 3,4-Dichloroisothiazole-Containing Coumarins as Fungicidal Leads

Abstract

Natural products are one of the resources for discovering novel fungicidal leads. As a natural fungicide, osthole was used as a coumarin-based lead compound for the development of novel fungicides. Here, a series of 3,4-dichloroisothiazolecontaining 7-hydroxycoumarins were rationally designed, synthesized, and characterized by introducing a bioactive substructure, 3,4-dichloroisothiazole, into the coumarin skeleton. In vitro bioassay indicated that compound 7g displayed good activity against Rhizoctonia solani, Physalospora piricola, Sclerotinia sclerotiorum, and Botrytis cinerea. Its median effective concentration (EC 50 ) value against each of these fungi fell between 0.88 and 2.50 μg/mL, which was much lower than that of osthole against the corresponding pathogen (between 7.38 and 74.59 μg/mL). In vivo screening validated that 7k exhibited 100%, 60%, and 20% efficacy against R. solani Kuḧn at 200, 100, and 50 μg/mL, respectively. RNA sequence analysis implied that growth inhibition of R. solani by 7k might result from potential disruptions of fungal membrane formation and intracellular metabolism. Furthermore, a field experiment with cucumber plants indicated that 7b showed 62.73% and 74.03% efficacy against Pseudoperonospora cubensis (Berk. & Curt.) Rostov. at rates of 12.5 g a.i./ha and 25 g a.i./ha, respectively, which showed no significant difference between 7b and osthole at 30 g a.i./ha. Our studies suggested that 7b, 7g, and 7k might be used as fungicidal leads for further optimization.

Exploration of Fungicidal Activity and Mode of Action of Ferimzone Analogs

“…Purification of the crude product by flash chromatography on silica gel with a mixture of ethyl acetate/petroleum ether (bp 60–90 °C) (1:200–1:100, v/v) afforded the corresponding methyl ketone (compounds 2a – d ). The spectral data are consistent with reported data in the literature. , …”

“…RNA extraction was conducted according to our previous method. 36 RNA was extracted from R. solani mycelia that had been treated/untreated with 1.17 μg/ mL of 5q at the logarithmic growth phase. R. solani RNA samples were sent to Majorbio (Shanghai, China) to analyze their transcriptome.…”

“…34,35 Lv et al designed a series of 3,4-dichloroisothiazole-containing 7hydroxycoumarins, and in vitro studies indicated that compound 7g displayed good activity against B. cinerea with 0.88 μg/mL. 36 To discover new scaffolds with similar curative and protective fungicidal activities and explore their fungicidal mode of action, ferimzone, a fungicide with chemical spaces for further modifications and an unknown mode of action as labeled in FRAC, was chosen as a lead compound (Figure 1). Inspired by the previous studies described above, we modified the phenyl and pyrimidinyl rings of ferimzone via introducing bioactive heterocycles in order to find more potent fungicidal leads.…”

Novel [1,2,4]-Triazolo[3,4-b]-[1,3,4]thiadizoles as Potent Pyruvate Kinase Inhibitors for Fungal Control

“…solani ( R. s ), and Sclerotinia sclerotiorum ( S. s ) was assessed in vitro at a concentration of 50 μg/mL using the mycelium growth-inhibition method. The median effective concentration (EC 50 ) of the active target compounds was assessed according to the reported method with some modifications. , Generally, a mother solution of the test compound (25,000 μg/mL) was prepared with N , N -dimethylformamide (DMF) as a solvent, and then a test solution (500 μg/mL) was made by adding 100 μL of mother solution to 4900 μL of sterile water with 0.1% Tween 80. Finally, the culture with 50 μg/mL of the test compound was prepared by mixing 4 mL of the test solution with 36 mL of potato dextrose agar (PDA).…”

Discovery of Novel Triazolothiadiazines as Fungicidal Leads Targeting Pyruvate Kinase

“…The fungicidal activities of compounds 6 against Alternaria solani ( A. s ), Botrytis cinereal ( B. c ), Cercospora arachidicola ( C. a ), Gibberella zeae ( G. z ), Physalospora piricola ( P. p ), R. solani ( R. s ), and Sclerotinia sclerotiorum ( S. s ) were assessed in vitro at a concentration of 50 μg/mL using the mycelium growth-inhibition method; the median effective concentration (EC 50 ) of the active target compounds was determined by a reported method …”