Exploration of Fungicidal Activity and Mode of Action of Ferimzone Analogs

• Published in: Journal of agricultural and food chemistry Vol. 71; no. 8; pp. 3705 - 3718
• Main Authors: Zhang, Yue, Li, Jing, Liu, Xiaoyu, Gao, Wei, Song, Shuoshuo, Rong, Yaping, Tan, Linyu, Glukhareva, Tatiana V., Bakulev, Vasiliy A., Fan, Zhijin
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.03.2023; Amer Chemical Soc
• Subjects: Agricultural and Environmental Chemistry; Agriculture; Agriculture, Multidisciplinary; Antifungal Agents - chemistry; Chemistry; Chemistry, Applied; Food Science & Technology; Fungicides, Industrial - chemistry; Life Sciences & Biomedicine; Pesticides - pharmacology; Physical Sciences; Rhizoctonia; Science & Technology; Structure-Activity Relationship; ferimzone; mode of action; scaffold hopping; fungicidal activity; POTENT; CRYSTAL-STRUCTURE; GENES; BACTERIAL; IDENTIFICATION; DISEASE RESISTANCE
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.2c08504

Lead discovery and molecular target identification are important for developing novel pesticides. Scaffold hopping, an effective approach of modern medicinal and agrochemical chemistry for a rational design of target molecules, is aiming to design novel molecules with similar structures and similar/better biological performance. Herein, 24 new ferimzone derivatives were designed and synthesized by a scaffold-hopping strategy. In vitro bioassays indicated that compound 5o showed similar potency to ferimzone against Cercospora arachidicola and 2-fold higher potency than ferimzone against Alternaria solani. Compounds 5q, 6a, and 6d displayed fungicidal activity with EC50 values ranging from 1.17 to 3.84 μg/mL against Rhizoctonia solani, and compounds 5q and 6a displayed 1.6–1.8-fold higher activity than ferimzone against Fusarium graminearum. The in vivo bioassays at 200 μg/mL indicated that compound 5q was more potent than ferimzone against Pyricularia oryzae (90% vs 70% efficacy, respectively). Density functional theory (DFT) calculations elucidated the structure–energy relationship. Although the mode of action of ferimzone is still unclear, studies suggested that compound 5q significantly inhibited the growth and reproduction of R. solani, and its energy metabolism pathways (e.g., starch, sucrose, lipids, and glutathione) were seriously downregulated after a 5q treatment.