Synthesis and evaluation of novel xanthine‐acrylamides and xanthine‐acrylates as insecticidal agents

Abstract

BACKGROUND The design and discovery of novel pesticidal agents according to bioactive natural products is an important aspect of agrochemical innovation. New xanthine derivatives derived from natural xanthine or methylxanthines are rich resources that possess great potential to afford new active pesticidal molecules. Herein novel xanthine derivatives were designed through a strategy of combining the methylxanthine caffeine skeleton with the acrylamide or acrylate motif of cinnamic acid derivatives. RESULTS A series of novel (E)‐3‐(1,3,7‐trimethyl‐2,6‐dioxo‐2,3,6,7‐tetrahydro‐1H‐purin‐8‐yl)acrylic acid derivatives, caffeine‐(E)‐acrylamides and caffeine‐(E)‐acrylates, were synthesized and confirmed via melting points, 1H NMR, 13C NMR and high‐resolution mass spectrometry. A single crystal of compound I12 was obtained to illustrate the trans‐configuration of the vinyl double bond. Preliminary insecticidal evaluations showed that some of the compounds had favorable insecticidal potentials against Mythimna separata Walker at 200 mg L−1. Some of the compounds exhibited excellent insecticidal activity against Plutella xylostella L. at low test concentrations, e.g. I18 and I24 with LC50 values of 0.0435 and 0.0133 mg L−1, respectively, were found to be more potent than the insecticide control triflumuron. The structure–activity relationship (SAR) analysis is also given in detail. CONCLUSION Compounds I12, I18, I24 and I26 generated from the integration of natural methylxanthine (caffeine) and acrylate moieties could be novel insecticidal leading compounds for further structural optimization. The SAR analysis may bring a new inspiration to the extensive and deep investigations on new xanthine derivatives in the agrochemical area.

Synthesis, Crystal Structures, and Biological Activity Evaluation of Novel Xanthine Derivatives Containing a Pyrethroid Moiety

“…The predicted CLogP values from the ChemDraw Professional software can well demonstrate such differences: 4.813 and 4.066 ( Il vs Ik ), 4.627 and 3.654 ( Io vs Im ), and 5.039 and 4.066 ( Ir vs Iq ), respectively. This result indicates that too high hydrophobicity of such kind of compounds may be unfavorable for their activity improvement, which in turn is consistent with the activity results of xanthine acrylamides reported in our recent publication …”

“…For example, caffeine could be a natural insecticide, as reported by Nathanson in 1984 and Ceja-Navarro et al in 2015, respectively. , It can inhibit phosphodiesterase activity, increase intracellular cyclic adenosine monophosphate, and modulate the release of intracellular calcium ions as well. , Caffeine was also found to show good antioxidant activity that is beneficial to mitigate the sublethal effect in honeybees caused by imidacloprid . In our recent studies, it was found that structural modifications of the methylxanthine skeleton have resulted in the generation of some promising insecticidal and fungicidal agents, such as novel trifluorobutenylthio-/sulfonyl-containing methylxanthines, piperazine-containing caffeine derivatives, xanthine acrylamides, and xanthine acrylates . In view of these valuable results, additional investigations of the natural xanthine skeleton that is less involved in pesticide design could potentially lead to more interesting findings in xanthine chemistry.…”

“…Two suitable single crystals of compounds In (CCDC 2119329) and Iq (CCDC 2172220) for X-ray diffraction were obtained, respectively, by the recrystallization from dichloromethane. According to the reported procedures, , the molecular structures of In and Iq were solved and generated based on the collected diffraction data.…”

“…17 In our recent studies, it was found that structural modifications of the methylxanthine skeleton have resulted in the generation of some promising insecticidal and fungicidal agents, such as novel trifluorobutenylthio-/sulfonyl-containing methylxanthines, 18 piperazine-containing caffeine derivatives, 19 xanthine acrylamides, and xanthine acrylates. 20 In view of these valuable results, additional investigations of the natural xanthine skeleton that is less involved in pesticide design could potentially lead to more interesting findings in xanthine chemistry. Furthermore, as a kind of biomimetic insecticides structurally derived from the natural pyrethrins, pyrethroids such as fenpropathrin, bifenthrin, tefluthrin, and tetramethrin (Figure 1) have widely been used in agriculture and have received continuous attention for decades due to their remarkable properties including high activity, broad insecticidal spectrum, and low toxicity to mammals and birds.…”

Synthesis and pesticidal activity of new 1,3,4-oxadiazole thioether compounds containing a trifluoromethylpyrazoyl moiety

“…Heterocycles play important roles in natural products [1], medicines [2], pesticides [3], and other chemical products [4]. Pyrazole nucleus can be regarded a significant skeleton for the design of biologically active compounds in synthetic pesticides and medicines [5][6][7].…”