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15 pages, 4094 KiB

Open AccessArticle

Design, Synthesis and Bioactivity Evaluation of Heterocycle-Containing Mono- and Bisphosphonic Acid Compounds

by Xin Wu, Zili Yang, Mengwei Bu, Jiang Duan and Aidong Zhang

Molecules 2023, 28(22), 7509; https://doi.org/10.3390/molecules28227509 - 9 Nov 2023

Cited by 1 | Viewed by 833

Fosmidomycin (FOS) is a naturally occurring compound active against the 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) enzyme in the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, and using it as a template for lead structure design is an effective strategy to develop new active compounds. In [...] Read more.

Fosmidomycin (FOS) is a naturally occurring compound active against the 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) enzyme in the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, and using it as a template for lead structure design is an effective strategy to develop new active compounds. In this work, by replacing the hydroxamate unit of FOS with pyrazole, isoxazole and the related heterocycles that also have metal ion binding affinity, while retaining the monophosphonic acid in FOS or replacing it with a bisphosphonic acid group, heterocycle-containing mono- and bisphosphonic acid compounds as FOS analogs were designed. The key steps involved in the facile synthesis of these FOS analogs included the Michael addition of diethyl vinylphosphonate or tetraethyl vinylidenebisphosphonate to β-dicarbonyl compounds and the subsequent cyclic condensation with hydrazine or hydroxylamine. Two additional isoxazolinone-bearing FOS analogs were synthesized via the Michaelis–Becker reaction with diethyl phosphite as a key step. The bioactivity evaluation on model plants demonstrated that several compounds have better herbicidal activities compared to FOS, with the most active compound showing a 3.7-fold inhibitory activity on Arabidopsis thaliana, while on the roots and stalks of Brassica napus L. and Echinochloa crus-galli in a pre-emergence inhibitory activity test, the activities of this compound were found to be 3.2- and 14.3-fold and 5.4- and 9.4-fold, respectively, and in a post-emergency activity test on Amaranthus retroflexus and Echinochloa crus-galli, 2.2- and 2.0-fold inhibition activities were displayed. Despite the significant herbicidal activity, this compound exhibited a DXR inhibitory activity lower than that of FOS but comparable to that of other non-hydroxamate DXR inhibitors, and the dimethylallyl pyrophosphate rescue assay gave no statistical significance, suggesting that a different target might be involved in the inhibiting process. This work demonstrates that using bioisosteric replacement can be considered as a valuable strategy to discover new FOS analogs that may have high herbicidal activities. Full article

(This article belongs to the Special Issue Advances in Novel Pesticide Discovery)

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13 pages, 5680 KiB

Open AccessArticle

A Potential Lead for Insect Growth Regulator: Design, Synthesis, and Biological Activity Evaluation of Novel Hexacyclic Pyrazolamide Derivatives

by Bingbo Guo, Biaobiao Jiang, Chunying Wang, Xiaoyu Jin, Liuyang Wang, Zhaokai Yang, Shihui Luo, Qing Yang, Li Zhang and Xinling Yang

Molecules 2023, 28(9), 3741; https://doi.org/10.3390/molecules28093741 - 26 Apr 2023

Cited by 3 | Viewed by 1193

Abstract

Ecdysone receptor (EcR) and chitinase play a critical role in the molting stage of insect pests. Each of them is considered a promising target for the development of novel insect growth regulators (IGRs). In the present paper, a total of 24 (23 novel) [...] Read more.

Ecdysone receptor (EcR) and chitinase play a critical role in the molting stage of insect pests. Each of them is considered a promising target for the development of novel insect growth regulators (IGRs). In the present paper, a total of 24 (23 novel) hexacyclic pyrazolamide derivatives were designed and synthesized by reducing the heptacycle and inserting small flexible linkers on the basis of the previously discovered dual-target compound D-27 acting simultaneously on EcR and Ostrinia furnacalis chitinase (OfChtI). Their insecticidal activities against Plutella xylostella, Spodoptera frugiperda, and Ostrinia furnacalis larvae were evaluated. The results revealed that the insecticidal activity was not significantly enhanced when the heptacycle on the pyrazole ring was reduced to a hexacycle. However, the insertion of an additional methylene spacer between the substituted phenyl ring and the amide bond can improve the insecticidal activity. Among the derivatives, the most potent compound, 6j, exhibited promising insecticidal activities against P. xylostella and S. frugiperda. Further protein binding assays and molecular docking indicated that 6j could target both EcR and OfChtI, and is a potential lead compound for IGRs. The present work provides valuable clues for the development of new dual-target IGRs. Full article

(This article belongs to the Special Issue Advances in Novel Pesticide Discovery)

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10 pages, 2330 KiB

Open AccessArticle

Synthesis, Structural Determination, and Antifungal Activity of Novel Fluorinated Quinoline Analogs

by Xinpeng Sun, Wei Yu, Lijing Min, Liang Han, Xuewen Hua, Jianjun Shi, Nabo Sun and Xinghai Liu

Molecules 2023, 28(8), 3373; https://doi.org/10.3390/molecules28083373 - 11 Apr 2023

Cited by 2 | Viewed by 1512

Abstract

A series of new fluorinated quinoline analogs were synthesized using Tebufloquin as the lead compound, 2-fluoroaniline, ethyl 2-methylacetoacetate, and substituted benzoic acid as raw materials. Their structures were confirmed by ¹H NMR, ¹³C NMR, and HRMS. The compound 8-fluoro-2,3-dimethylquinolin-4-yl 4-(tert [...] Read more.

A series of new fluorinated quinoline analogs were synthesized using Tebufloquin as the lead compound, 2-fluoroaniline, ethyl 2-methylacetoacetate, and substituted benzoic acid as raw materials. Their structures were confirmed by ¹H NMR, ¹³C NMR, and HRMS. The compound 8-fluoro-2,3-dimethylquinolin-4-yl 4-(tert-butyl)benzoate (2b) was further determined by X-ray single-crystal diffraction. The antifungal activity was tested at 50 μg/mL, and the bioassay results showed that these quinoline derivatives had good antifungal activity. Among them, compounds 2b, 2e, 2f, 2k, and 2n exhibited good activity (>80%) against S. sclerotiorum, and compound 2g displayed good activity (80.8%) against R. solani. Full article

(This article belongs to the Special Issue Advances in Novel Pesticide Discovery)

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12 pages, 1249 KiB

Open AccessArticle

Design, Synthesis, and Biological Activities of Novel 2-Cyanoacrylate Compounds Containing Substituted Pyrazolyl or 1,2,3-Triazolyl Moiety

by Yang Wang, Yudie Chen, Ye Qian, Jia Chen, Xianchao Du, Yujun Shi, Baolin Xu, Sheng Hua and Hong Dai

Molecules 2023, 28(7), 3141; https://doi.org/10.3390/molecules28073141 - 31 Mar 2023

Viewed by 1137

Abstract

To develop novel 2-cyanoacrylate derivatives with potential bioactivity, a number of 2-cyanoacrylate compounds, including substituted pyrazole or 1,2,3-triazole ring, were designed, prepared, and structurally detected by ¹H NMR, ¹³C NMR, and elemental analysis. The biological assessment displayed that some designed compounds [...] Read more.

To develop novel 2-cyanoacrylate derivatives with potential bioactivity, a number of 2-cyanoacrylate compounds, including substituted pyrazole or 1,2,3-triazole ring, were designed, prepared, and structurally detected by ¹H NMR, ¹³C NMR, and elemental analysis. The biological assessment displayed that some designed compounds had significant herbicidal activities against Brassica juncea, Chenopodium serotinum, Rumex acetosa, Alopecurus aequalis, Polypogon fugax, and Poa annua at a dosage of 1500 g/ha. Furthermore, some derivatives still expressed satisfactory herbicidal activities against Brassica juncea, Chenopodium serotinum, and Rumex acetosa when the dosage was lowered to 150 g/ha, especially the inhibitory effects of compounds 9a, 9d, 9f, 9i, 10a, 10b, 10e, and 10n against Brassica juncea were all over 80%, compounds 9d, 9f, 9g, 9h, 9i, 10h, 10i, 10m, 10n, and 10o possessed more than 70% inhibition rates against Chenopodium serotinum, and compound 9d indicated 70% herbicidal activity against Rumex acetosa. These results provided an important basis for further design and discovery of biologically active 2-cyanoacrylate compounds. Full article

(This article belongs to the Special Issue Advances in Novel Pesticide Discovery)

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15 pages, 5102 KiB

Open AccessArticle

Design, Synthesis and Bioactivity of Novel Low Bee-Toxicity Compounds Based on Flupyrimin

by Xingxing Lu, Huan Xu, Xiaoming Zhang, Tengda Sun, Yufan Lin, Yongheng Zhang, Honghong Li, Xuesheng Li, Xinling Yang, Hongxia Duan and Yun Ling

Molecules 2022, 27(18), 6133; https://doi.org/10.3390/molecules27186133 - 19 Sep 2022

Cited by 5 | Viewed by 2103

Abstract

Neonicotinoids are important insecticides for controlling aphids in agriculture. Growing research suggested that neonicotinoid insecticides are a key factor causing the decline of global pollinator insects, such as bees. Flupyrimin (FLP) is a novel nicotinic insecticide with unique biological properties and no cross-resistance, [...] Read more.

Neonicotinoids are important insecticides for controlling aphids in agriculture. Growing research suggested that neonicotinoid insecticides are a key factor causing the decline of global pollinator insects, such as bees. Flupyrimin (FLP) is a novel nicotinic insecticide with unique biological properties and no cross-resistance, and is safe for pollinators. Using FLP as the lead compound, a series of novel compounds were designed and synthesized by replacing the amide fragment with a sulfonamideone. Their structures were confirmed by ¹H NMR, ¹³C NMR and HRMS spectra. Bioassay results showed that compound 2j had good insecticidal activity against Aphis glycines with an LC₅₀ value of 20.93 mg/L. Meanwhile, compound 2j showed significantly lower acute oral and contact toxicity to Apis mellifera. In addition, compound 2j interacted well with the protein in insect acetylcholine binding protein (AChBP). The molecular docking on honeybee nicotinic acetylcholine receptor (nAChR) indicated that the sulfonamide group of compound 2j did not form a hydrogen bond with Arg173 of the β subunit, which conforms to the reported low bee-toxicity conformation. In general, target compound 2j can be regarded as a bee-friendly insecticide candidate. Full article

(This article belongs to the Special Issue Advances in Novel Pesticide Discovery)

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16 pages, 2756 KiB

Open AccessArticle

Discovery of Novel Potential Aphid Repellents: Geranic Acid Esters Containing Substituted Aromatic Rings

by Shixiang Pan, Wenhao Li, Yaoguo Qin, Zhaokai Yang, Yan Liu, Zhuo Shi, Cheng Qu, Chen Luo and Xinling Yang

Molecules 2022, 27(18), 5949; https://doi.org/10.3390/molecules27185949 - 13 Sep 2022

Cited by 4 | Viewed by 1581

Abstract

Aphids are one of the most damaging agricultural pests. For the sake of novel eco-friendly compounds with good activity for aphid control, a series of novel geranic acid esters containing substituted aromatic rings were designed by inverting ester groups of lead compounds. All [...] Read more.

Aphids are one of the most damaging agricultural pests. For the sake of novel eco-friendly compounds with good activity for aphid control, a series of novel geranic acid esters containing substituted aromatic rings were designed by inverting ester groups of lead compounds. All compounds were characterized by HRMS, ¹H-NMR, and ¹³C-NMR. In order to identify the effect of inversion ester groups on activity, a bioassay was conducted. The results showed that the repellent activity against Acyrthosiphon pisum (A. pisum) and the binding affinity with the odorant-binding protein 9 from A. pisum (ApisOBP9) of the compounds were increased after inversion of the ester groups. Particularly, 5f showed the best repellent activity (repellency proportion: 55.6%) and binding affinity (1/Ki: 0.49 µM). Meanwhile, the structure–activity relationships revealed that the introduction of meta-substitution of the benzene ring and halogen atoms, such as Cl and Br, facilitated the biological activity. The further molecular docking results demonstrated that hydrogen bonding interactions and hydrophobic interactions were vital for the binding affinity with ApisOBP9. Additionally, all compounds were predicted to be eco-friendly and their volatile physicochemical properties have been enhanced compared to the leads. The present results provide valuable clues for the further rational design of aphids’ behavioral control agents. Full article

(This article belongs to the Special Issue Advances in Novel Pesticide Discovery)

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18 pages, 5092 KiB

Open AccessArticle

Design, Synthesis, and Bioactivities of Novel Tryptophan Derivatives Containing 2,5-Diketopiperazine and Acyl Hydrazine Moieties

by Lili Li, Rongxin Yang, Jianhua Liu, Jingjing Zhang, Hongjian Song, Yuxiu Liu and Qingmin Wang

Molecules 2022, 27(18), 5758; https://doi.org/10.3390/molecules27185758 - 6 Sep 2022

Cited by 2 | Viewed by 1522

Abstract

Based on the scaffolds widely used in drug design, a series of novel tryptophan derivatives containing 2,5-diketopiperazine and acyl hydrazine moieties have been designed, synthesized, characterized, and evaluated for their biological activities. The bioassay results showed that the target compounds possessed moderate to [...] Read more.

Based on the scaffolds widely used in drug design, a series of novel tryptophan derivatives containing 2,5-diketopiperazine and acyl hydrazine moieties have been designed, synthesized, characterized, and evaluated for their biological activities. The bioassay results showed that the target compounds possessed moderate to good antiviral activities against tobacco mosaic virus (TMV), among which compounds 4, 9, 14, 19, and 24 showed higher inactivation, curative, and protection activities in vivo than that of ribavirin (39 ± 1, 37 ± 1, 39 ± 1 at 500 mg/L) and comparable to that of ningnanmycin (58 ± 1, 55 ± 1, 57 ± 1% at 500 mg/L). Thus, these compounds are a promising candidate for anti-TMV development. Most of these compounds showed broad-spectrum fungicidal activities against 13 kinds of phytopathogenic fungi and selective fungicidal activities against Alternaria solani, Phytophthora capsica, and Sclerotinia sclerotiorum. Additionally, some of these compounds exhibited larvicidal activities against Tetranychus cinnabarinus, Plutella xylostella, Culex pipiens pallens, Mythimna separata, Helicoverpa armigera, and Pyrausta nubilalis. Full article

(This article belongs to the Special Issue Advances in Novel Pesticide Discovery)

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14 pages, 2220 KiB

Open AccessArticle

Design, Synthesis and Structure-Activity Relationship of Novel Pinacolone Sulfonamide Derivatives against Botrytis cinerea as Potent Antifungal Agents

by Chaojie Liu, Xiaofang Xiang, Ying Wan, Jia Yang, Yufei Li, Xinchen Zhang, Zhiqiu Qi, Lu He, Wei Liu and Xinghai Li

Molecules 2022, 27(17), 5468; https://doi.org/10.3390/molecules27175468 - 25 Aug 2022

Cited by 2 | Viewed by 1385

Abstract

To develop new fungicides with high efficiency, 46 novel sulfonamide derivatives were designed and synthesized by introducing pinacolone fragment into chesulfamide which was used as lead compound. All compounds were characterized by ¹H NMR, ¹³C NMR, and MS spectra, and the [...] Read more.

To develop new fungicides with high efficiency, 46 novel sulfonamide derivatives were designed and synthesized by introducing pinacolone fragment into chesulfamide which was used as lead compound. All compounds were characterized by ¹H NMR, ¹³C NMR, and MS spectra, and the structure of compound P-27 was also confirmed by X-ray single crystal diffraction. It was found that a variety of compounds present excellent inhibitory effect against Botrytis cinerea. The inhibition rates of P-29 on tomato and strawberry were 90.24% (200 mg/L) and 100% (400 mg/L) in vivo respectively, which were better than the lead compound chesulfamide (59.23% on tomato seedlings and 29.63% on strawberries). Full article

(This article belongs to the Special Issue Advances in Novel Pesticide Discovery)

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17 pages, 1012 KiB

Open AccessArticle

Discovery of Novel Cinnamide Fungicidal Leads with Optical Hydroxyl Side Chain

by Weiwei Wang, Jiazhen Jiang, Zhenhua Zhang and Mingan Wang

Molecules 2022, 27(16), 5259; https://doi.org/10.3390/molecules27165259 - 17 Aug 2022

Viewed by 1093

Abstract

In order to overcome the resistance of phytopathogens to commercial fungicides, a series of optical 2-methyl-2,3-diol-5-pentyl-based cinnamamide derivatives were rationally designed, synthesized, characterized, and evaluated for their in vitro and in vivo fungicidal activities. The bioassay results indicated that the EC₅₀ (concentration [...] Read more.

In order to overcome the resistance of phytopathogens to commercial fungicides, a series of optical 2-methyl-2,3-diol-5-pentyl-based cinnamamide derivatives were rationally designed, synthesized, characterized, and evaluated for their in vitro and in vivo fungicidal activities. The bioassay results indicated that the EC₅₀ (concentration for 50% of maximal effect) values of (R)-11f, (R)-11m, (S)-11m and (R)-11n were 0.16, 0.28, 0.41 and 0.47 µg/mL in the in vitro evaluation against Sclerotinia sclerotiorum, respectively, while compounds (R)- and (S)-11i, (R)- and (S)-11j exhibited excellent in vivo fungicidal activity against Pseudoperonspera cubensis with inhibition rates of 100% at 400 μg/mL. These findings supported the idea that optical 2-methyl-2,3-diol-5-pentyl-containing cinnamamides (R)- and (S)-11i, (R)- and (S)-11j with 2-chloro-4-trifluoromethyl aniline and 2-(4-chlorophenyl) aniline showed excellent in vivo fungicidal activity against S. sclerotiorum and P. cubensis and were promising fungicide candidates. Full article

(This article belongs to the Special Issue Advances in Novel Pesticide Discovery)

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15 pages, 2366 KiB

Open AccessArticle

Antifeedant Mechanism of Dodonaea viscosa Saponin A Isolated from the Seeds of Dodonaea viscosa

by Hang Yu, Jinliang Li, Guoxing Wu, Qingbo Tang, Xiuan Duan, Quanjun Liu, Mingxian Lan, Yuhan Zhao, Xiaojiang Hao, Xiaoping Qin and Xiao Ding

Molecules 2022, 27(14), 4464; https://doi.org/10.3390/molecules27144464 - 12 Jul 2022

Cited by 2 | Viewed by 1637

Abstract

Dodonaea viscosa is a medicinal plant which has been used to treat various diseases in humans. However, the anti-insect activity of extracts from D. viscosa has not been evaluated. Here, we found that the total saponins from D. viscosa (TSDV) had strong antifeedant [...] Read more.

Dodonaea viscosa is a medicinal plant which has been used to treat various diseases in humans. However, the anti-insect activity of extracts from D. viscosa has not been evaluated. Here, we found that the total saponins from D. viscosa (TSDV) had strong antifeedant and growth inhibition activities against 4th-instar larvae of Spodoptera litura. The median antifeeding concentration (AFC₅₀) value of TSDV on larvae was 1621.81 μg/mL. TSDV affected the detoxification enzyme system of the larvae and also exerted antifeedant activity possibly through targeting the γ-aminobutyric acid (GABA) system. The AFC₅₀ concentration, the carboxylesterase activity, glutathione S-transferases activity, and cytochrome P450 content increased to 258%, 205%, and 215%, respectively, and likewise the glutamate decarboxylase activity and GABA content to 195% and 230%, respectively, in larvae which fed on TSDV. However, D. viscosa saponin A (DVSA) showed better antifeedant activity and growth inhibition activity in larvae, compared to TSDV. DVSA also exerted their antifeedant activity possibly through targeting the GABA system and subsequently affected the detoxification enzyme system. Further, DVSA directly affected the medial sensillum and the lateral sensillum of the 4th-instar larvae. Stimulation of Spodoptera litura. with DVSA elicited clear, consistent, and robust excitatory responses in a single taste cell. Full article

(This article belongs to the Special Issue Advances in Novel Pesticide Discovery)

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