Combinatorial Synthesis of Indole Derivatives as Anti-oomycetes Agents

Developing high-efficiency and low-risk small-molecule green fungicide is the key to effective control of the plant pathogenic oomycetes. Indole is an important raw material for drug synthesis. Due to its unique structural skeleton, indole, and its derivatives have exhibited a wide range of biological activities. However, a study on the synthesis of novel indole derivatives as fungicidal agents against Phytophthora capsici has not yet been reported.

The important intermediates 2a-c and 3a-c were synthesized in high yields by Vilsmeier- Haack and Knoevenagel reactions with indole as the lead compound. Furthermore, different substituted benzenesulfonyl groups were introduced into the NH position of the indole ring, and twelve indole derivatives (I-a-l) were prepared. Their structures were well characterized by ¹H NMR, HRMS, and melting point.

The results showed that 2-[(N-(4-nitrobenzenesulfonyl)-indole-3)-methylene]-diethyl malonate (I-d) and 2-[(N-(4-nitrobenzenesulfonyl)-5-cyanoindole-3)-methylene]-diethyl malonate (I-l) showed more anti-oomycete activity against P. capsici than the commercialized fungicide zoxamide, with corresponding EC₅₀ values of 26.53, 23.48 and 28.16 mg/L, respectively, and the protective effect of the compounds against P. capsici in vivo further confirmed the above results.

The preliminary structure-activity relationship showed that the formyl group modification at the C-3 position of the indole ring was acceptable, and the different anti-oomycete activities of R¹ and R² were significantly different, with R¹ being 5-CN > H > 6-Me, and R² being 4-NO₂ > 3-NO₂, H > 4-Me.