Synthesis and Antifungal Activity of 1,2,4-Oxadiazole Derivatives

Abstract

1,2,4-Oxadiazole derivatives containing anisic acid or cinnamic acid were designed and synthesized, which were expected to be an effective Succinate dehydrogenase (SDH) inhibitor, and their structures were characterized by ¹H NMR, ¹³C NMR, and ESI-MS. The antifungal activity of the compounds against plant pathogenic fungi was screened by the mycelial growth inhibition test in vitro. Compounds 4f and 4q showed significant antifungal activities against Rhizoctonia solani (R. solani), Fusarium graminearum (F. graminearum), Exserohilum turcicum (E. turcicum), Botrytis cinerea (B. cinerea), and Colletotrichum capsica (C. capsica). The EC₅₀ values of 4q were 38.88 μg/mL, 149.26 μg/mL, 228.99 μg/mL, and 41.67 μg/mL against R. solani, F. graminearum, E. turcicum, and C. capsica, respectively, and the EC₅₀ values of 4f were 12.68 μg/mL, 29.97 μg/mL, 29.14 μg/mL, and 8.81 μg/mL, respectively. Compound 4f was better than commercial carbendazim against Exserohilum turcicum. Compounds 4f and 4q showed an antifungal effect on C. capsica of capsicum in vivo. Molecular docking simulation showed that 4f and 4q interacted with the target protein through the hydrogen bond and hydrophobic interaction, in which 4q can form hydrogen bonds with TRP173 and ILE27 of SDH, and 4f had hydrogen bonds with TYR58, TRP173, and SER39. This also explains the possible mechanism of action between the inhibitor and target protein.

Keywords: 1,2,4-oxadiazole derivatives; antifungal activity; biological evaluation; molecular docking.

Scheme 1

Synthetic routes and chemical structures of the target compounds.

Figure 1

(A) Cytotoxicity of the target compounds on MCF-7 at 100 μM. (B) Cytotoxicity of the target compounds on MCF-7 at 0~100 μM (cytotoxicity of target compounds toward cells were determined by MTT assay, and data are presented as mean ± SD for three independent tests).

Figure 2

Antifungal activity test with mycelia growth inhibitory rate methods at 50 μg/mL.

Figure 3

Effect of compounds on E. turcicum. Blank (A), 4f (25 μg/mL) (B), 4q (50 μg/mL) (C), and carbendazim (12.5 μg/mL) (D). Effect of compounds on C. capsica. Blank (E) and 4f (25 μg/mL) (F).

Figure 4

Protective and curative activity of compounds against C. capsica.

Figure 5

Three-dimensional docking of compounds with the active pocket of protein 2fbw (A,B). Two-dimensional ligand hydrophobic interaction (C,D) of compounds with amino acid residues. Hydrogen bond interaction of compounds with amino acid residues (E,F).