Bioisosterism and Scaffold Hopping in Modern Nematicide Research

Abstract

The application of agrochemicals is critical to global food safety. Nowadays, environmentally friendly green agrochemicals are the trend in field crop protection. The research and development of nematicides absorbed more attention as a typical representation of agrochemicals. This review describes the origin of recently commercialized nematicides, the application of bioisosterism and scaffold hopping in the discovery and optimization of agrochemicals, especially nematicides, and novel bioisosteric design strategies for the identification of fluensulfone analogues. Pesticide repurposing, high-throughput screening, computer-aided drug design, and incorporation of known pharmacophoric fragments have been the most successful approach for the discovery of new nematicides. As outlined, the strategies of bioisosteric replacements and scaffold hopping have been very successful approaches in the search for new nematicides for sustainable crop protection. In the exploration of novel fluensulfone analogues with nematicidal activity, bioisosteric replacement of sulfone by amide, chain extension by insertion of a methylene group, and reversal of the amide group have proven to be successful approaches and yielded new and highly active fluensulfone analogues. These attempts might result in compounds with an optimal balance of steric, hydrophobic, electronic, and hydrogen-bonding properties and contribute to deal with the complex problem during the research and development of new nematicides. Further ideas are also put forward to provide new approaches for the molecular design of nematicides.

Structure-Based Virtual Screening of Natural Products and Optimization for the Design and Synthesis of Novel CeCht1 Inhibitors as Nematicide Candidates

“…It was speculated that the presence of methoxy increased oral toxicity in rats. Consequently, the chemotype of benzo[d] [1,3]dioxole-5-carboxylate compounds could become nematicide candidates for future field applications in agriculture.…”

“…Several compounds a1 (62.9%), a12 (84.1%), a19 (15.9%), a22 (0%), and b3 (45.3%) with different inhibitory activities against CeCht1 were chosen for comparative analysis. As shown in Figure 7, with the premise of occupying three binding subsites −1 to +2, the benzo[d] [1,3]dioxole moiety (part A) remained in the S1 region at the −1 subsite, retaining the π−π stacking interaction with Trp394 and a hydrogen bond with Tyr247. Compounds a1, a21, and a22 all interacted similarly to a12, namely, stacking with Trp394 and hydrogen bonding with Tyr247, whereas b3 only stacked with Trp394.…”

“…A 5% NaOH solution was slowly added under an ice bath. The solid was filtered, washed with water, and dried to afford methyl benzo[d] [1,3] To a solution of precursor 2 (1.0 g, 5.55 mmol) in acetic acid (10 mL), a solution of 65% HNO 3 (8 mL, 111 mmol) was slowly added at 0 °C (ice bath). The mixture was kept at 0 °C for 1 h and then increased to room temperature for 1 h. Ice water (50 mL) was added to the mixture.…”

“…The mixture was kept at 0 °C for 1 h and then increased to room temperature for 1 h. Ice water (50 mL) was added to the mixture. The solid was filtered, washed with water, and dried to yield methyl 6-nitrobenzo[d] [1,3]dioxole-5-carboxylate 3 (1.07 g, 86%). 1 H NMR (500 MHz, CDCl 3 ): δ 7.32 (s, 1H), 6.98 (s, 1H), 6.11 (s, 2H), 3.83 (s, 3H).…”

“…A mixture of precursor 3 (1.0 g, 4.44 mmol), powder metallic iron (1.24 g, 22.2 mmol), and ammonium chloride (142 mg, 2.66 mmol) in ethanol/water (2:1, 75 mL) was refluxed for 1 h. The reaction mixture was filtered through Celite while hot, and the filtrate was concentrated under reduced pressure and purified via column chromatography to obtain methyl 6-aminobenzo[d] [1,3]dioxole-5carboxylate 4 (0.63 g, 72%). 1 H NMR (500 MHz, CDCl 3 ): δ 7.25 (s, 1H), 6.16 (s, 1H), 5.89 (s, 2H), 5.74 (brs, 2H), 3.82 (s, 3H).…”