Exploration of Fungicidal Activity and Mode of Action of Ferimzone Analogs

Abstract

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.

CoMFA Directed Molecular Design for Significantly Improving Fungicidal Activity of Novel [1,2,4]-Triazolo-[3,4-b][1,3,4]-thiadizoles

“…Seven differentially expressed genes (all down-regulated) significantly enriched in KEGG pathway were selected for real-time fluorescent quantitative PCR (qRT-PCR) analyses according to reference to the reported methods for validation. , The mycelium pretreatment protocol was consistent with the treatment protocol of the transcriptome test. The cDNA was transcribed with the reverse transcriptase kit (catalogue no.…”

“…7,23−26 Commercial pesticides such as coumoxystrobin, pyraoxystrobin, pyrimidifen, diflumetorim, and flufenerim are examples from IDM strategy. 27,28 PFVS is realized through biophysical screening via analyzing interactions between a target protein and its ligand. 29 A successful example via the PFVS strategy is the discovery of flubeneteram, a novel fungicide targeting SDH.…”

“…Typical agrochemicals from natural products include derivatives of strobilurins, coumarins, psoralen, pyrethrin, neopeltolide, nicotine, luotonin A, and rotenone − The principle of IDM is to fully consider cost of raw materials and intermediates, sustainability, facile industrialization, and freedom to operate in order to create novel bioactive molecules. Several rounds of “design–synthesis–test–analysis” are usually needed to reach targets with novel structures and reasonable biological performance. ,− Commercial pesticides such as coumoxystrobin, pyraoxystrobin, pyrimidifen, diflumetorim, and flufenerim are examples from IDM strategy. , PFVS is realized through biophysical screening via analyzing interactions between a target protein and its ligand . A successful example via the PFVS strategy is the discovery of flubeneteram, a novel fungicide targeting SDH. , CADD is carried out by a combination of bioinformatics and computer technology, which can be structure-based drug design (SBDD) and ligand-based drug design (LBDD). − SBDD considers the mode of binding between a receptor and its ligand by homology modeling and molecular docking to understand their interactions.…”

Design, Synthesis, and Herbicidal Activity of Pyrazole Amide Derivatives as Potential Transketolase Inhibitors

“…Heterocyclic compounds, especially nitrogen-containing heterocyclic compounds, are highly effective structural groups in pesticides with a broad spectrum of bioactivity. ,− For example, pyrazole is a common five-membered heterocyclic compound, and pyrazole derivatives have good biological activities in insecticides, herbicides, medicine, etc. − Some commercial herbicides contained a pyrazole ring (Figure ), such as cypyrafluone, tripyrasulfone, bipyrazone, and cypyrafluone. Additionally, pyridine derivatives have been used as pesticide agrochemicals, including the herbicide nicosulfuron, the fungicide boscalid, etc.…”

3D-QSAR Combination with Molecular Dynamics Simulations to Effectively Design the Active Ryanodine Receptor Agonists against Spodoptera frugiperda

“…New targets and leads are two important aspects in novel pesticide discovery, and the discovery of new targets is more challenging. In the field of fungicides, pyruvate kinase was discovered as a potent target after 8 years. − In the field of insecticides, insect transient receptor potential channels (TRPV) and K + /Cl – cotransporter (KCC) were discovered as a target of pymetrozine and pyrifluquinazon, respectively. , In the field of herbicides, dihydroorotate dehydrogenase (DHODH) was reported as a new herbicide target of tetflupyrolimet, which was commercialized by FMC through an interfering synthesis of pyrimidine. In the field of antiviral agents, some targets have been discovered, and several mechanisms were found to be used in the discovery of novel leads. , Therefore, the discovery of novel leads and/or pesticide candidates with known molecular targets without cross-resistance has been considered as an effective measure …”