A Potential Fungicide against Pseudoperonospora Cubensis: Design, Synthesis and 3D-QSAR of New Pyrazole-5-Carboxamide Derivatives.

BACKGROUND: Downy mildew is one of the major fungi causing significant economic losses to crops. The resistance of this fungus to current fungicides is increasing and new fungicides with a unique mode of action are needed. OBJECTIVE: To find a novel pyrazole amide derivative as a potential fungicide. METHODS: A series of pyrazole-5-carboxamide derivatives containing a diaryl ether were designed and synthesized by the Intermediate derivatization method (IDM). Their fungicidal activities against Pseudoperonospora cubensis (P. cubensis, cucumber downy mildew) were evaluated in the greenhouse. RESULTS: Bioassays indicated that several compounds exhibited excellent fungicidal activity against P. cubensis in vivo. In particular, T24 (EC50 = 0.88 mg L-1) had the highest activity compared with Dimethomorph and Fluazinam and other analogues. The relationship between the activity and the structure of these derivatives was analyzed, and an accurate and reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established to determine that electrostatic and steric fields had important effects on the improvement of fungicidal activity. CONCLUSION: The novel pyrazole-5-carboxamide derivative T24 can be considered a potential fungicide for P. cubensis control.

Overexpression of three P450 genes is responsible for resistance to novel pyrimidine amines in Magnaporthe oryzae.

BACKGROUND: A series of pyrimidine amine derivatives has been synthesized by modifying the pyrimidine ring group of diflumetorim-a mitochondrial complex I inhibiting fungicide. One derivative, code number SYP-34773, is investigated in this study involving Magnaporthe oryzae, the causal agent of rice blast, which is the most devastating disease in rice. The response, resistance profile and mechanism of M. oryzae to SYP-34773 were investigated, which provides or provide?? important data for the registration and rational use of pyrimidine amines. RESULTS: SYP-34773 showed greater control efficacy than fungicide isoprothiolane in the field. The baseline sensitivity was established at a mean 50% effective concentration (EC50 ) of 0.08 µg ml-1 . Four stable SYP-34773-resistant isolates with reduced sensitivity were generated from one (S118) of ten sensitive isolates with a resistance factor of EC50 ranging from 7.00 to 15.00. Conidia production and pathogenicity were similar to that of S118, although there was a significant decrease in mycelial growth and conidial germination in resistant isolates. Positive cross-resistance was observed between SYP-34773 and diflumetorim; and the SYP-34773-resistant isolates were still sensitive to isoprothiolane, carbendazim, fluazinam, azoxystrobin, or prochloraz. RNA-Seq analyses revealed three cytochrome P450 genes were upregulated in the resistant isolate under the treatment with SYP-34773, as confirmed by quantitative real-time PCR. The SYP-34773 content was significantly reduced in the resistant isolate when compared with the parental isolate. CONCLUSION: The study demonstrated that SYP-34773 exhibits high activity against M. oryzae. Overexpression of three cytochrome P450 genes has an important role in the resistance of M. oryzae to novel pyrimidine amines. © 2020 Society of Chemical Industry.

Design, synthesis and herbicidal evaluation of novel uracil derivatives containing an isoxazoline moiety.

BACKGROUND: Glyphosate is the most widely used and successful herbicide discovered to date, but its utility is now threatened by the occurrence of several glyphosate-resistant weed species. Saflufenacil is a relatively new herbicide developed by BASF in 2010. It is a highly effective selective herbicide showing excellent control on broadleaf weeds (more than 90 species), significantly superior to other protoporphyrinogen oxidase (PPO) inhibitor herbicides at the level of weeds controlled. It is also effective against glyphosate-resistant Conyza canadensis if used in combination with glyphosate. A series of novel uracil-based PPO inhibitors containing an isoxazoline moiety were designed via the intermediate derivatization method, synthesized using a key saflufenacil raw material as starting material and evaluated for herbicidal activity. RESULTS: The target compounds were characterized by 1 H NMR and high-resolution electrospray mass spectra. Bioassays indicated that some title compounds can control efficiently and effectively both broadleaf weeds and grassy weeds at low doses, especially the glyphosate-resistant weeds C. canadensis and Eleusine indica. CONCLUSION: This work provides a basis for further studies of 9b for control of a wider range of weeds, particularly for glyphosate-resistant weeds.

Design, Synthesis, and Structure-Activity Relationship of Novel Spiropyrimidinamines as Fungicides against Pseudoperonospora cubensis.

Harmful fungus and the developed resistance to available fungicides seriously threaten the yield and quality of crops; thus, the search for new, highly efficient, and resistance-overcoming fungicides remains a quite urgent goal of agricultural scientists. In this study, a series of novel spiropyrimidinamine derivatives were designed and synthesized by employing the intermediate derivatization method (IDM). Their structures were identified by 1H NMR, elemental analyses, and MS spectra. The structure of compound 5 was further confirmed by X-ray diffraction. Bioassays indicated that a number of the title compounds exhibited some fungicidal activities against Pseudoperonospora cubensis. Especially, compound 5 displayed excellent activity (EC50 = 0.422 mg/L), significantly higher than those of the commercialized fungicides cyazofamid, flumorph, and diflumetorim. The structure-activity relationship was also discussed. It was concluded that compound 5 with super fungicidal potency and a novel structure is a promising agrochemical fungicide candidate for further development.

Synthesis, biological evaluation and anti-proliferative mechanism of fluorine-containing proguanil derivatives.

Proguanil, a member of biguanide family, has excellent anti-proliferative activities. Fluorine-containing compounds have been demonstrated to have super biological activities including enhanced binding interactions, metabolic stability, and reduced toxicity. In this study, based on the intermediate derivatization methods, we synthesized 13 new fluorine-containing proguanil derivatives, and found that 7a,7d and 8e had much lower IC50 than proguanil in 5 human cancerous cell lines. The results of clonogenic and scratch wound healing assays revealed that the inhibitory effects of derivatives 7a,7d and 8e on proliferation and migration of human cancer cell lines were much better than proguanil as well. Mechanistic study based on representative derivative 7a indicated that this compound up-regulates AMPK signal pathway and downregulates mTOR/4EBP1/p70S6K. In conclusion, these new fluorine-containing derivatives show potential for the development of cancer chemotherapeutic drugs.

Design, Synthesis, and Structure-Activity Relationship of New Arylpyrazole Pyrimidine Ether Derivatives as Fungicides.

To explore a novel fungicide effectively against cucumber downy mildew (CDM), a series of new arylpyrazole containing pyrimidine ether derivatives were designed and synthesized by employing the intermediate derivatization method (IDM). The structures of synthesized compounds were identified by 1H NMR, 13C NMR, elemental analyses, MS, and X-ray diffraction. Bioassays demonstrated that some of the title compounds exhibited excellent fungicidal activities against CDM. Especially, compound 7 (EC50 = 1.22 mg/L) displayed significantly higher bioactivity than that of commercial fungicides diflumetorim and flumorph and nearly equal effect to that of cyazofamid. The relationship between the structure and fungicidal activity of the synthesized compounds was discussed as well. The study showed that compound 7 was a promising fungicide candidate for further development.

Anticancer properties of novel pyrazole-containing biguanide derivatives with activating the adenosine monophosphate-activated protein kinase signaling pathway.

Biguanides, including metformin and phenformin, have emerged as promising anticancer agents. However, the high dose needed for their efficient anticancer properties restricts their clinical application. In an attempt to obtain higher active compounds than these parent compounds, pyrazole-containing biguanide derivatives were synthesized and screened for in vitro cytotoxicity against human cancer cell lines. Clonogenic assays and scratch wound healing assays demonstrated that these new derivatives profoundly inhibit cell proliferation and migration. Compounds 10b and 10d exhibited strong potency with low IC50 values in the range of 6.9-28.3 µM, far superior to phenformin and metformin. Moreover, 20 µM 10b and 10d resulted in 72.3-88.2% (p < 0.001) inhibition of colony formation and 29.3-60.7% (p < 0.05) inhibition of cell migration. Mechanistically, 10b and 10d activated adenosine monophosphate-activated protein kinase, leading to inactivation of the mammalian target of rapamycin (mTOR) signaling pathway with the regulation of 4EBP1 and p70S6K. These results suggest the value of these novel biguanide derivatives as candidates with therapeutic potential for the treatment of bladder and ovarian cancer.

Design, synthesis, and herbicidal activity of novel quaternary ammonium salt derivatives.

A series of novel quaternary ammonium salt derivatives were designed and synthesized by introducing the herbicide carboxylic acid into substituted aminoacetanilide compounds which derived from herbicides alachlor or acetochlor, using the intermediate derivatization methods in an attempt to obtain novel candidates for weed control. The herbicidal activity assays in greenhouse demonstrated that some of the title compounds exhibited good herbicidal activities against velvet leaf, youth-and-old age, barnyard grass, and foxtail. Especially, III9 gave the best activity (EC50 (ga.i/ha): YOA 34.1, VEL 33.6, FOX 15.9, BYG 36.2). The field trials indicated that III9 had better herbicidal activity than the commercial herbicide imazethapyr to control broadleaf weeds at 150ga.i/ha. The present work demonstrated that the quaternary ammonium salt derivatives can be used as potential lead compounds for discovering novel herbicides with improved activity. III9 itself is worthy of being further developed as an herbicidal candidate. Further syntheses, structure optimization studies, and field trials around III9 are in progress.

Discovery of a New Fungicide Candidate through Lead Optimization of Pyrimidinamine Derivatives and Its Activity against Cucumber Downy Mildew.

Downy mildew is one of the most highly destructive of the diseases that cause damage to fruits and vegetables. Because of the continual development of resistance, it is important to discover new fungicides with different modes of action from existing fungicides for the control of downy mildew. This study is a continuation of our previous work on the novel pyrimidinamine lead compound, 9, and includes field trials for the identification of the optimal candidate. A new compound, 1c, was obtained, which gave a lower EC50 value (0.10 mg/L) against downy mildew than lead compound 9 (0.19 mg/L) and the commercial fungicides diflumetorim, dimethomorph, and cyazofamid (1.01-23.06 mg/L). Compound 1c displayed similar broad-spectrum fungicidal activity to compound 9 but better field efficacy than compound 9, cyazofamid, and flumorph. The present work indicates that pyrimidinamine compound 1c is a candidate for further development as a commercial fungicide for the control of downy mildew.

Synthesis and biological activity of benzoylcyclohexanedione herbicide SYP-9121.

Benzoylcyclohexanedione herbicides work by inhibiting 4-hydroxyphenylpyruvate dioxygenase which was the last new target site introduced for herbicides. In an attempt to find new 4-hydroxyphenylpyruvate dioxygenase inhibitors with high efficacy and selectivity, a novel benzoylcyclohexanedione compound SYP-9121 was synthesized and studied in greenhouse and field. In the greenhouse, SYP-9121 showed broad spectrum herbicidal activity and good safety to maize. Its control of barnyard grass, crabgrass, redroot pigweed, purslane, dayflower and night shade was equivalent to that of the commercial herbicide mesotrione. Three field trials in summer maize showed that SYP-9121 could efficiently control both grass and broadleaf weeds with good selectivity. Herbicidal activity of SYP-9121 was comparable to that of mesotrione.

Design, Synthesis, and Structure-Activity Relationship of New Pyrimidinamine Derivatives Containing an Aryloxy Pyridine Moiety.

The pyrimidinamine diflumetorim is an ideal template for the discovery of agrochemical lead compounds due to its unique mode of action, novel chemical structure, and lack of reported resistance. To develop a new pyrimidinamine fungicide effective against cucumber downy mildew (CDM), a series of new pyrimidinamine derivatives containing an aryloxy pyridine moiety were designed and synthesized by employing the recently reported intermediate derivatization method (IDM). The structures of all compounds were identified by 1H NMR, elemental analyses, HRMS, and X-ray diffraction. Bioassays demonstrated that some of the title compounds exhibited excellent fungicidal activities against CDM. Compound 9 gave the best activity (EC50 = 0.19 mg/L), which is significantly better than the commercial fungicides diflumetorim, flumorph, and cyazofamid. The relationship between structure and fungicidal activity of the synthesized pyrimidinamines was explored. The study showed that compound 9 is a promising fungicide candidate for further development.

Intermediate derivatisation method in the discovery of new acaricide candidates: synthesis of N-substituted piperazine derivatives and their activity against phytophagous mites.

BACKGROUND: To discover and exploit novel acaricidal compounds, a series of novel N-substituted piperazine derivatives were designed and synthesised using a tert-butyl piperazine-1-carboxylate as the starting material by intermediate derivatisation methods, and their acaricidal activities were evaluated. RESULTS: Compounds 11 and 12 exhibited significant acaricidal activity against adults of Tetranychus cinnabarinus in greenhouse tests. Compound 12, in particular, was found to be the best potential candidate acaricide and proved to be more active than the commercial positive controls spirodiclofen and pyridaben, with an LC50 of 0.8977 mg L-1 . Results concerning acaricidal activity against larvae and eggs of T. cinnabarinus indicated that compound 12 possessed equivalent larvicidal activity to spirodiclofen and higher larvicidal activity than pyridaben. Meanwhile, compound 12 showed less ovicidal activity than pyridaben, but higher activity than spirodiclofen. Furthermore, the results of the field trial demonstrated that compound 12 could effectively control Panonychus citri and P. ulmi with long-lasting persistence and rapid action. CONCLUSIONS: The present work indicates that compound 12 could be a novel acaricide candidate for spider mite control. © 2016 Society of Chemical Industry.

Design, synthesis and structure-activity relationship of novel diphenylamine derivatives.

Diphenylamine derivatives have been reported with good fungicidal, insecticidal, acaricidal, rodenticidal and/or herbicidal activities. To find new lead compound of this kind, a series of novel diphenylamine derivatives were designed and synthesized by the approach of Intermediate Derivatization Methods. All compounds were identified by (1)H NMR and elemental analysis. Bioassays demonstrated that some compounds substituted at 2,4,6-positions or 2,4,5-positions of phenyl ring B exhibited excellent fungicidal activities. The optimal compounds P30 and P33 showed 80% and 85% control respectively against cucumber downy mildew at 12.5mgL(-1), both 100% control against rice blast at 0.3mgL(-1) and both 100% control against cucumber gray mold at 0.9mgL(-1). The relationship between structure and fungicidal activities was discussed as well.

Synthesis and evaluation of substituted 3-(pyridin-2-yl)benzenesulfonamide derivatives as potent herbicidal agents.

In an attempt to obtain novel candidate compound for weed control, a series of newly substituted 3-(pyridin-2-yl)benzenesulfonamide derivatives 2 were designed and synthesized using compound II7 as a lead compound by Intermediate Derivatization Methods and their herbicidal activities were evaluated. The herbicidal activity assay in greenhouse tests showed several compounds (2g, 2i, 2j, 2k, 2l, 2m, 2n and 2o) exhibited significant herbicidal activity for controlling velvet leaf (Abutilon theophrasti medic.) and youth-and-old age (Zinnia elegans jacq.) at 37.5ga.i./ha. In particular, 2h was found to be the most potential candidate herbicide and was proved higher activity than the lead compound II7. The result of the weed controlling spectrum test showed that 2h could effectively control dayflower (Commelina tuberosa), bur beggarticks (Bidens tripartita linn.), youth-and-old age, cassia tora (Cassiaobtusifolia L.), velvet leaf, purslane (Portulaca oleracea) and false daisy (Eclipta prostrata L.). In addition, the mixture of compound 2h and propanil could produce a synergistic effect and enhance herbicidal activity. The result of the herbicidal activity assay in field test demonstrated that 2h could effectively control dayflower and nightshade (Disambiguation) with long-lasting persistence. The present work indicates that 2h may be a novel compound candidate as a potential herbicide.

Discovery of pyridine-based agrochemicals by using Intermediate Derivatization Methods.

Pyridine-based compounds have been playing a crucial role as agrochemicals or pesticides including fungicides, insecticides/acaricides and herbicides, etc. Since most of the agrochemicals listed in the Pesticide Manual were discovered through screening programs that relied on trial-and-error testing and new agrochemical discovery is not benefiting as much from the in silico new chemical compound identification/discovery techniques used in pharmaceutical research, it has become more important to find new methods to enhance the efficiency of discovering novel lead compounds in the agrochemical field to shorten the time of research phases in order to meet changing market requirements. In this review, we selected 18 representative known agrochemicals containing a pyridine moiety and extrapolate their discovery from the perspective of Intermediate Derivatization Methods in the hope that this approach will have greater appeal to researchers engaged in the discovery of agrochemicals and/or pharmaceuticals.

Efficient Approach To Discover Novel Agrochemical Candidates: Intermediate Derivatization Method.

Intensive competition of intellectual property, easy development of agrochemical resistance, and stricter regulations of environmental concerns make the successful rate for agrochemical discovery extremely lower using traditional agrochemical discovery methods. Therefore, there is an urgent need to find a novel approach to guide agrochemical discovery with high efficiency to quickly keep pace with the changing market. On the basis of these situations, here we summarize the intermediate derivatization method (IDM) between conventional methods in agrochemicals and novel ones in pharmaceuticals. This method is relatively efficient with short time in discovery phase, reduced cost, especially good innovated structure, and better performance. In this paper, we summarize and illustrate "what is the IDM" and "why to use" and "how to use" it to accelerate the discovery of new biologically active molecules, focusing on agrochemicals. Furthermore, we display several research projects in our novel agrochemical discovery programs with improved success rate under guidance of this strategy in recent years.

Design, synthesis, and herbicidal activity of novel substituted 3-(pyridin-2-yl)benzenesulfonamide derivatives.

A series of novel substituted 3-(pyridin-2-yl)benzenesulfonamide derivatives were designed and synthesized using 2-phenylpridines as the lead compound by intermediate derivatization methods in an attempt to obtain novel compound candidates for weed control. The herbicidal activity assay in glasshouse tests showed several compounds (II6, II7, II8, II9, II10, II11, III2, III3, III4, and III5) could efficiently control velvet leaf, youth-and-old age, barnyard grass, and foxtail at the 37.5 g/ha active substance. Especially, the activities of II6, II7, III2, and III4 were proved roughly equivalent to the saflufenacil and better than 95% sulcotrione at the same concentration. The result of the herbicidal activity assay in field tests demonstrated that II7 at 60 g/ha active substance could give the same effect as bentazon at 1440 g/ha active substance to control dayflower and nightshade, meanwhile II7 showed better activity than oxyfluorfen to control arrowhead and security to rice. The present work indicates that II7 may be a novel compound candidate for potential herbicide.

Design, synthesis, and structure-activity relationship of novel aniline derivatives of chlorothalonil.

Chlorothalonil with both low cost and low toxicity is a popularly used fungicide in the agrochemical field. The presence of nucleophilic groups on this compound allows further chemical modifications to obtain novel chlorothalonil derivatives. Fluazinam, another commercially available agent with a broad fungicidal spectrum, has a scaffold of diaryl amine structure. To mimic this backbone structure, a variety of (un)substituted phenyl amines was used as nucleophilic agents to react with chlorothalonil to obtain compounds with a diphenyl amine structure. Via an elegant design, two leads, 2,4,5-trichloro-6-(2,4-dichlorophenylamino)isophthalonitrile (7) and 2,4,5-trichloro-6-(2,4,6-trichlorophenylamino)isophthalonitrile (11), with potential fungicidal activity were discovered after a preliminary bioassay screen. These two leads were further modified to obtain final products by replacing the chlorine groups in the phenyl ring in phenyl amine with other functional groups. These functional groups with various electronic properties and spatial characteristics were considered to explore the relationship between structure and fungicidal activity. The results indicate that the electron-withdrawing group NO2 on the 4 position on the right phenyl ring plays a unique role on enhancing the fungicidal activity. The compounds were identified by proton nuclear magnetic resonance and elemental analysis. Bioassays demonstrated that some of the title compounds exhibited excellent fungicidal activities against cucumber downy mildew at 25 mg/L. Compound 20 has been shown as the optimal structure with 85% control against cucumber downy mildew at 6.25 mg/L concentration. The relationship between structure and fungicidal activity is reported. The present work demonstrates that chlorothalonil derivatives can be used as possible lead compounds for developing novel fungicides.

Design, synthesis and structure-activity relationship of novel coumarin derivatives.

BACKGROUND: The lead coumarin derivative (E)-methyl 3-methoxy-2-[2-(4-methylcoumarin-7-yloxymethyl)phenyl]acrylate was discovered by using an intermediate derivatisation method. To discover new coumarin derivatives with improved activity, a series of substituted coumarins were synthesised and bioassayed. RESULTS: The compounds were identified by ¹H NMR, IR, MS and elemental analysis. Bioassays demonstrated that some of the title compounds exhibited excellent fungicidal activity against cucumber downy mildew at 25 mg L⁻¹. The relationship between structure and fungicidal activity is reported. CONCLUSION: The present work demonstrates that coumarin derivatives containing methoxyacrylate moieties can be used as possible lead compounds for developing novel fungicides.