Design, Synthesis, and Antifungal Activity of 4-Amino Coumarin Based Derivatives

Abstract

A series of 30 succinate dehydrogenase inhibitors (SDHIs) of 4-amino coumarin-based derivatives were designed and synthesized. According to the analysis of fungicidal activity in vitro, most of the compounds expressed broad-spectrum antifungal activity against four plant pathogenic fungi (Alternaria alternata, Alternaria solani, Fusarium oxysporum, and Botrytis cinerea) using the mycelium growth inhibition method. The results showed that compounds 3n with the group of 2-ene-3-methyl-butyl and 4e with the group of 2-bromo-1-oxo-hexyl displayed excellent activity against Alternaria alternata and Alternaria solani, with EC₅₀ values of 92~145 μg/mL. Molecular docking showed that the inhibitor 3n was completely locked into the cavity of SDH, forming a conventional hydrogen bond interacting with the amino acid residue TYR58. The present work indicates that these derivatives would serve as novel potential fungicides targeting SDH.

Keywords: 4-amino coumarin; antifungal activity; fungicide; inhibitor; molecular docking; succinate dehydrogenase.

Scheme 1

Synthesis routes of compounds 3a–3o and 4a–4o. R₁ refers to the substituent labeled (a–o). (i) Cyanoacetic acid, anhydrous ZnCl₂ and HCl gas, at room temperature, 5 h; (ⅱ) substitutes, anhydrous K₂CO₃, TBAB, acetone, reflux; (ⅲ) substitutes, thionyl chloride, acetone, reflux.

Figure 1

In vitro inhibition of mycelial growth of A. Alternata and A. Salani by compounds 3n and 4n. (A) 3n at 200 μg/mL for A. Alternata; (B) 4n at 200 μg/mL for A. Alternata; (C) 3n at 200 μg/mL for A. Salani; (D) 4n at 200 μg/mL for A. Salani.

Figure 1

In vitro inhibition of mycelial growth of A. Alternata and A. Salani by compounds 3n and 4n. (A) 3n at 200 μg/mL for A. Alternata; (B) 4n at 200 μg/mL for A. Alternata; (C) 3n at 200 μg/mL for A. Salani; (D) 4n at 200 μg/mL for A. Salani.

Figure 2

Binding mode and the interaction of inhibitor 3n docking with SDH (PDB code: 1YQ3).