Novel Acaricidal Silico-Containing Pyrazolyl Acrylonitrile Derivatives Identified through Rational Carbon–Silicon Bioisosteric Replacement Strategy

Abstract

The identification of novel pyrazolyl acrylonitrile acaricides with improved properties is of great value for the control of phytophagous mites. A series of innovative silicon-containing pyrazolyl acrylonitriles were rationally designed by applying a bioisosteric carbon−silicon replacement strategy and prepared based on novel synthetic methodology. As a result of our research, we discovered compound A25 which possesses outstanding acaricidal activity. With an LC 50 value of 0.062 mg/L, compound A25 was found to be 2.3-fold and 1.9-fold more potent than the commercial acaricides cyenopyrafen and cyetpyrafen, respectively. Enzymatic inhibitory assay indicated that the active principle M1 of compound A25 possesses an IC 50 value of 2.32 μM against Tetranychus cinnabarinus SDH, which was about twofold superior compared to the active metabolites of cyenopyrafen (IC 50 = 4.72 μM). Molecular docking study showed that the active metabolites 2 and 3 and their corresponding silicon counterparts form H-bonds and cation−π interaction with the residues of Trp165, Tyr433, and Arg279.

Design, Synthesis, and Biological Activity of Silicon-Containing Carboxamide Fungicides

“…Carbon–silicon bioisosteric replacement is a powerful research strategy to favorably modulate the potency, selectivity and bioavailability as well as the physicochemical and drug-like or pesticidal properties. − Silicon is the second most abundant element on Earth, easily available and possesses unique chemical properties allowing diverse, sometimes specific, chemical reactions due to its unique d -orbitals enabling coordination. , Moreover, silicon and silicon-containing groups are suited for classical C/Si switch strategies − and nonclassical replacement, like the replacement of some heteroatoms (O, N) and groups (amide, , vinyl , ). These replacements have proven to deliver surprising results that go beyond the expected additional benefit and offer a tool to explore unexpected effects for the evaluation of issues.…”

“…For example (Figure ), the introduction of silicon into Haloperidol, a first-generation antipsychotic drug acting on dopamine D 2 receptors, alters the metabolic pathway of Haloperidol, − avoiding the synthesis of a neurotoxic metabolite (Pyridinium) and reducing the toxicity of haloperidol. In silicon-containing analogs of Camptothecin (topoisomerase I inhibitor used for the treatment of gastrointestinal tumors), BNP-1350 and DB-67, currently undergoing clinical trials, the introduction of silane groups enhanced the efficacy by improving their lipophilicity and increasing the permeability across the blood-brain barrier. , Furthermore, four silicon-containing pesticides namely Flusilazole, Silafluofen, Simeconazole and Silthiopham have already been discovered and introduced to the market more than two decades ago. − More recently, A25 , a silicon-containing analog of the complex II acaricide Cyenopyrafen (Figure ), has been discovered by our group and has demonstrated that the introduction of silicon not only improves efficacy (Tetranychus cinnabarinus: LC 50 of A25 = 0.062 mg/L vs LC 50 of Cyenopyrafen = 0.14 mg/L), but also reduces fish toxicity (Danio rerio: LC 50 of A25 = 0.71 mg/L vs LC 50 of Cyenopyrafen = 0.41 mg/L).…”

“…21,22 Furthermore, four silicon-containing pesticides namely Flusilazole, Silafluofen, Simeconazole and Silthiopham have already been discovered and introduced to the market more than two decades ago. 23−28 More recently, A25, a silicon-containing analog of the complex II acaricide Cyenopyrafen (Figure 1), has been discovered by our group 2 and has demonstrated that the introduction of silicon not only improves efficacy (Tetranychus cinnabarinus: LC 50 of A25 = 0.062 mg/L vs LC 50 of Cyenopyrafen = 0.14 mg/L), but also reduces fish toxicity (Danio rerio: LC 50 of A25 = 0.71 mg/L vs LC 50 of Cyenopyrafen = 0.41 mg/L).…”