Synthesis, bioactivity and molecular docking of novel coumarin-quinolinamide containing monocyclic monoterpenes as potential SDH inhibitors

Abstract

Succinate dehydrogenase inhibitors (SDHI) are widely used in plant antifungal agents. To break the barrier of resistance, a series of new coumarin-quinolinamide SDHI derivatives containing monocyclic monoterpenes were designed and synthesized using natural camphor or natural menthol as lead compounds, and their structures were characterized by FT-IR, 1H NMR, 13C NMR and HRMS. In vitro antifungal activity test results showed that the target compounds had inhibitory activity against most plant pathogenic fungi, especially against Rhizoctonia solani and Phytophthora nicotianae var. nicotianae, which was superior to other fungi. Among them, compounds 11t and 12t showed better inhibitory effects on Rhizoctonia solani than the commercial fungicide tricyclazole, with EC50 of 16.90 mg/L and 27.09 mg/L, respectively. Based on this, the detached leaf assay was used to further explore the in vivo therapeutic and preventive effects of compounds 11t and 12t on rice sheath blight in plants. The results of the antifungal activity test in vivo showed that compound 11t was slightly better than the positive control, while compound 12t was close to the control effect of azoxystrobin. More importantly, the more bioactive compounds 11t and 12t did not affect the germination of cowpea seeds and also did not affect the growth of normal human hepatocytes and kidney cells. Molecular docking experiments showed that the introduction of the diethylamino group could promote the formation of hydrogen bonds between the hydrogen atom on the amide bond of the target compound and residue Tyr91, and compounds 11t and 12t had smaller free energy between the amino acid residue, which would enhance the antifungal activity of the compounds. These studies proved the potential value of this series of compounds for the study of novel amide-based SDHI fungicides.