Commercial Agrochemicals Research Articles

CF3-Cyclobutanes: Synthesis, Properties, and Evaluation as a Unique tert-Butyl Group Analogue.

Isosteric replacement of functional groups is an emerging strategy for optimizing bioactive molecules in drug discovery. tert-Butyl group is a particularly important moiety, yet its isosteric replacement with 1-trifluoromethyl-cyclobutyl group has been rather neglected. To enable the advance of this molecular fragment in drug discovery programs, we report the synthesis of over 30 small-molecule building blocks featuring the trifluoromethyl-cyclobutyl fragment, achieved by reacting sulfur tetrafluoride with cyclobutylcarboxylic acids on a gram-to-multigram scale. Furthermore, we characterized the structural properties of this group through X-ray analysis, studied its effect on acid-base transitions, and evaluated its Hammett parameters. Finally, we evaluated the replacement of tert-butyl with 1-trifluoromethyl-cyclobutyl in several bioactive compounds that represent commercial drugs and agrochemicals. Our findings indicate that while the trifluoromethyl-cyclobutyl group exhibited slightly larger steric size and moderately increased lipophilicity, it preserved the original mode of bioactivity in the examined cases and, in some cases, enhanced resistance to metabolic clearance.

Design, Synthesis, and Fungicidal Activity against Rice Sheath Blight of Novel N-Acyl-1,2,3,4-tetrahydroquinoline Derivatives.

To discover fungicides with novel targets, a series of N-acyl-1,2,3,4-tetrahydroquinoline (NATHQ) derivatives were designed and synthesized by linking the active substructure NATHQ moiety in aspernigerin with the O-benzyl oxime-ether scaffold in commercial agrochemicals. Target compound structures were identified using proton and carbon-13 nuclear magnetic resonance spectroscopies and high-resolution mass spectrometry. Preliminary bioassays indicated that at 40 mg/L, some target compounds exhibited moderate to considerable in vitro fungicidal activities against Rhizoctonia solani and Botrytis cinerea. In particular, compound 3j exhibited higher fungicidal activities both in vitro (EC50 = 0.733 mg/L) and in vivo (EC50 = 15.2 mg/L) against R. solani than the commercial fungicide prochloraz; therefore, it should be a promising fungicide candidate against rice sheath blight. Additionally, compound 3j exhibited good laccase inhibitory activity (73.2% at 200 mg/L). Molecular docking revealed that the bis-cyano-oxime-ether moiety of compound 3j exhibited an excellent binding mode with the laccase target protein and could be used as a lead compound for developing laccase inhibitors. The structural features of these NATHQ derivatives will provide inspiration for developing laccase inhibitors and discovering more effective fungicides to control agricultural diseases.

New Axially Chiral Molecular Scaffolds with Antibacterial Activities against Xanthomonas oryzae pv. oryzae for Protection of Rice.

A new class of axially chiral thiazine molecules were constructed and showed promising antibacterial activities against the plant pathogen Xanthomonas oryzae pv. oryzae (Xoo). The axial chiralities of these compounds (R- or S-atropisomer) showed clear impacts on the in vitro inhibitory activities against Xoo. An optimal molecule of this class with the (S)-axially chiral configuration was identified to exhibit inhibitory activity against Xoo with an EC50 value of 4.18 μg/mL. This inhibition efficiency is superior to that of two commercial antibacterial agrochemicals, thiodiazole-copper and bismerthiazol, as the positive controls. This hit compound also performed better than the controls in our in vivo studies. Preliminary mechanistic studies via scanning electron microscopy images showed that our hit compound at a concentration of 10 μg/mL destroyed the bacterial integrity of Xoo. Label-free quantitative proteomics analysis indicated that a total of 366 differentially expressed proteins of the rice plants were significantly influenced in the presence of our hit molecule.

BIOFERTILIZERS- A BRIEF INSIGHT

Chemical fertilizers are more commonly used for crop production nowadays, which has a negative impact on soil and environmental quality. The rising use of chemical inputs in agricultural production systems harmed the sustainability of agricultural crop production systems, raised cultivation costs, and reduced partial factor productivity, making preserving global food security and environmental quality a difficult task. Increasing usage of commercial agrochemicals over the previous century led in bioaccumulation of various pollutants in agricultural soils and surrounding water bodies. Various scientists have observed that the constant and indiscriminate use of primary nutrients (N, P, and K) has resulted in numerous micro and secondary nutrient shortage as well as a negative impact on soil health. Microorganisms can play a variety of roles in organic farming's long-term sustainability. According to the literature, using nitrogenous fertilizers under certain meteorological conditions might result in the release of nitrous oxide (N2O), which contribute to the greenhouse effect and causes environmental imbalances. As a result, biofertilizers microorganisms such as bacteria, fungi, and algae have been proposed as potential solutions for large-scale agricultural practices that are not only ecological, ecofriendly, and cost-effective, but also sustain soil structure and biodiversity. Microbes as biofertilizers are being investigated as an alternative to chemical fertilizers in the agricultural industry because of their vast potential for improving crop yield and food safety.

Suppression of Ripe Rot on 'Zesy002' Kiwifruit with Commercial Agrochemicals.

Ripe rot caused by Botryosphaeria dothidea is one of the serious diseases of postharvest kiwifruit. In order to control ripe rot on Actinidia chinensis cultivar ‘Zesy002’, several commercial agrofungicides were selected by an antifungal test on an artificial medium. Furthermore, disease suppression by the selected fungicides was evaluated on the kiwifruit by inoculation with a conidial suspension of B. dothidea. On the artificial media containing boscalid + fludioxonil was shown to be the most effective antifungal activity. However, in the bio-test pyraclostrobin + boscalid and iminoctadine-tris were the most effective agrochemicals on the fruit. On the other hand, the infection structures of B. dothidea on kiwifruit treated with pyraclostrobin + boscalid were observed with a fluorescent microscope. Most of the fungal conidia had not germinated on the kiwifruit treated with the agrochemicals whereas on the untreated fruit the fungal conidia had mostly germinated. Electron microscopy of the fine structures showed morphological changes to the conidia and branch of hyphae on the kiwifruit pre-treated with pyraclostrobin + boscalid, indicating its suppression effect on fungal growth. Based on this observation, it is suggested that ripe rot by B. dothidea may be suppressed through the inhibition of conidial germination on the kiwifruit treated with the agrochemicals.

Nuclear magnetic resonance chiral discrimination of fipronil and malathion agrochemicals: A case study

The aim of the present study was to optimize a protocol for nuclear magnetic resonance (NMR) chiral discrimination to be used to determine the enantiomers ratio of agrochemicals. For this goal, the commercial agrochemicals fipronil and malathion were employed as active targets due the distinct physicochemical properties. We used the cyclodextrins to evaluate the chiral discrimination in aqueous media and chiral solvent agents to check in organic media. The fipronil chiral discrimination was accessed by β-CD in aqueous solution, although this procedure was ineffective for malathion due the low solubility. In organic media, the NMR chiral discrimination was successful for both agrochemicals and sensitive to dilution process. The NMR experiments explore very sensitive nuclei, for instance 1 H, 19 F, and 31 P, in a simple, practical and low residue experimental protocol.

Synthesis, Antimicrobial Activity, and Molecular Docking of Benzoic Hydrazide or Amide Derivatives Containing a 1,2,3‐Triazole Group as Potential SDH Inhibitors

Main observation and conclusionThe present study was carried out in an attempt to synthesize a new class of antimicrobial agents containing a 1,2,3‐triazole motif formed by classical copper catalyzed click chemistry. Antifungal bioassay results showed that five compounds 5a, 5e, 5h, 5j, and 5k possessed a remarkable growth inhibitory activity against Botryosphaeria dothidea, Rhizoctonia solani and Gibberella zeae with EC50 values within 10.0—0.306 μg/mL. The in vitro efficacy was better than those of the commercial agrochemicals Azoxystrobin, Boscalid, and Fluxapyroxad. In vivo trials showed that compound 5l was effective for the control of rice sheath blight and wheat scab with the effects of 75% and 95%, respectively. Antifungal mechanism studies suggested that target compounds were potential succinate dehydrogenase inhibitors (SDHIs), which were proposed by the agreeable molecular docking study and restrained SDH activity (IC50 = 3.95 μg/mL, 5l). Interestingly, compounds 5r and 5s displayed good antibacterial activity against phytopathogens. In vivo screening of 5r and 5s against rice bacterial blight afforded a superior control effect (up to 51%) than those of commercial agents Bismerthiazol and Thiodiazole copper. The current studies could support some title compounds to be the lead compounds for exploring highly bioactive antimicrobial substrates, particularly the potential SDHIs.

The herbicide quinclorac as potent lipase inhibitor: Discovery via virtual screening and in vitro/in vivo validation.

Lipolysis is primarily controlled by the stepwise action of hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL) to release free fatty acids and glycerol. A high level of circulating free fatty acids is well-known to mediate insulin resistance. Thus, the need to discover lipase inhibitors against both enzyme systems remains urgent. Agrochemicals are tightly regulated chemicals and therefore are potential source of new medicinal agents. Accordingly, we implemented a computational workflow to search for new lipase inhibitory leads by virtually screening commercial agrochemicals against HSL and MGL employing binding pharmacophores and docking experiments. Ten agrochemicals were identified as potential lipase inhibitors, out of which quinclorac, a safe herbicide, achieved high-ranking score. Subsequent in vitro evaluation against rat epididymal lipase activity showed quinclorac to exhibit nanomolar anti-lipase IC50 . Subsequent in vivo testing showed quinclorac to significantly decrease blood glycerol levels after acute exposure (150mg/kg) and multiple dosing (50 or 25mg/kg) (p<0.05).

Evaluation of Commercial Agrochemicals as New Tools for Malaria Vector Control.

Malaria is a vector-borne and life-threatening disease caused by parasites that are transmitted to people through the bites of infected female Anopheles mosquitoes. The vector control insecticide market represents a small fraction of the crop protection market and is estimated to be valued at up to $500 million at the active ingredient level. Insecticide resistance towards the current WHOPES-approved products urgently requires the development of new tools to protect communities against the transmission of malaria. The evaluation of commercial products for malaria vector control is a viable and cost effective strategy to identify new malaria vector control products. Several examples of such spin-offs from crop protection insecticides are already evidencing the success of this strategy, namely pirimiphos-methyl for indoor residual sprays and spinosad, diflubenzuron, novaluron, and pyriproxifen for mosquito larvae control, a supplementary technology for control of malaria vectors. In our study the adulticidal activities of 81 insecticides representing 23 insecticidal modes of action classes, 34 fungicides from 6 fungicidal mode of action classes and 15 herbicides from 2 herbicidal modes of action classes were tested in a newly developed screening system. WHOPES approved insecticides for malaria vector control consistently caused 80-100% mortality of adult Anopheles stephensi at application rates between 0.2 and 20 mg active ingradient (AI) litre-1. Chlorfenapyr, fipronil, carbosulfan and endosulfan showed the expected good activity. Four new insecticides and three fungicides with promising activity against adult mosquitoes were identified, namely the insecticides acetamiprid, thiamethoxam, thiocyclam and metaflumizone and the fungicides diflumetorin, picoxystrobin, and fluazinam. Some of these compounds certainly deserve to be further evaluated for malaria vector control. This is the first report describing good activity of commercial fungicides against malaria vectors.

Long Chain Alcohols Produced by Trichoderma citrinoviride Have Phagodeterrent Activity against the Bird Cherry-Oat Aphid Rhopalosiphum padi.

In this study we report the effects of fungal metabolites isolated from cultures of the fungus Trichoderma citrinoviride ITEM 4484 on the feeding preference of the aphid Rhopalosiphum padi, a major pest of cereal crops. Different phagodeterrent metabolites were purified by a combination of direct and reverse phase column chromatography and thin-layer chromatography. Chemical investigations, by spectroscopic and chemical methods, led to the identification of different long chain primary alcohols (LCOHs) of the general formula R-OH, wherein R is a long, unbranched, unsubstituted, linear aliphatic group. LCOHs have been reported as components of lepidopteran pheromone blends, but their phagodeterrent effect to aphids is herein reported for the first time. The effects of LCOHs on R. padi were studied by behavioral and electrophysiological bioassays. Feeding preference tests that were carried out with winged and wingless morphs of R. padi showed that LCOHs had high phagodeterrent activity and restrained aphids from settling on treated leaves at a concentration as low as 0.15 mM (0.036 g/l). The results of different electrophysiological analyses indicated that taste receptor neurons located on the aphid tarsomeres were involved in the LCOHs perception. Behavioral assays carried out with some commercial agrochemicals, including azadirachtin A, pyrethrum and a mineral oil-based product, in combination with 1-hexadecanol, the LCOH most abundantly produced by T. citrinoviride ITEM 4484, showed that these different active principles could be applied together, resulting in a useful increase of the phagodeterrent effect. The data shown indicate that these compounds can be profitably utilized for novel applications in biotechnical control of aphid pests. Furthermore, the tested LCOHs have no chiral centers and therefore can be obtained with good yield and at low cost through chemical synthesis, as well as from natural sources.

Variation of physical properties of LDPE greenhouse films due to agrochemicals used during cultivation

During protected cultivation, the use of agrochemicals influence the degradation of the greenhouse plastic films. A research was carried out to evaluate how agrochemicals contamination and solar radiation influence the physical properties of low density polyethylene (LDPE) films. The LDPE films were manufactured on purpose adding different anti-UV stabilizer systems and were exposed to natural outdoor weathering at the experimental farm of the University of Bari (Italy; 41° 05’ N). Each film was tested as covering of two low tunnels: one was sprayed from inside with commercial agrochemicals containing iron, chlorine and sulphur while the other one was not sprayed and used as control. Radiometric tests were carried out on the new films and on film samples taken at the end of the trial. Analyses on absorption of the selected contaminants were carried out in laboratory on the samples taken at the end of the exposure in the field in order to compare the relative effectiveness of the stabilizing systems under evaluation. The experimental tests showed that the natural weathering together with the agrochemicals did not modify significantly the radiometric properties of the films in the solar and PAR wavelength range. Significant variations were recorded for the stabilised films in the LWIR wavelength range.

Variation of physical properties of LDPE greenhouse films due to agrochemicals used during cultivation

During protected cultivation, the use of agrochemicals influence the degradation of the greenhouse plastic films. A research was carried out to evaluate how agrochemicals contamination and solar radiation influence the physical properties of low density polyethylene (LDPE) films. The LDPE films were manufactured on purpose adding different anti-UV stabilizer systems and were exposed to natural outdoor weathering at the experimental farm of the University of Bari (Italy; 41° 05’ N). Each film was tested as covering of two low tunnels: one was sprayed from inside with commercial agrochemicals containing iron, chlorine and sulphur while the other one was not sprayed and used as control. Radiometric tests were carried out on the new films and on film samples taken at the end of the trial. Analyses on absorption of the selected contaminants were carried out in laboratory on the samples taken at the end of the exposure in the field in order to compare the relative effectiveness of the stabilizing systems under evaluation. The experimental tests showed that the natural weathering together with the agrochemicals did not modify significantly the radiometric properties of the films in the solar and PAR wavelength range. Significant variations were recorded for the stabilised films in the LWIR wavelength range.

Agrochemicals against Malaria, Sleeping Sickness, Leishmaniasis and Chagas Disease

In tropical regions, protozoan parasites can cause severe diseases with malaria, leishmaniasis, sleeping sickness, and Chagas disease standing in the forefront. Many of the drugs currently being used to treat these diseases have been developed more than 50 years ago and can cause severe adverse effects. Above all, resistance to existing drugs is widespread and has become a serious problem threatening the success of control measures. In order to identify new antiprotozoal agents, more than 600 commercial agrochemicals have been tested on the pathogens causing the above mentioned diseases. For all of the pathogens, compounds were identified with similar or even higher activities than the currently used drugs in applied in vitro assays. Furthermore, in vivo activity was observed for the fungicide/oomyceticide azoxystrobin, and the insecticide hydramethylnon in the Plasmodium berghei mouse model, and for the oomyceticide zoxamide in the Trypanosoma brucei rhodesiense STIB900 mouse model, respectively.

Direct analysis in real time mass spectrometry for the rapid identification of four highly hazardous pesticides in agrochemicals

Direct analysis in real time (DART) is a new ion source technique, which is conducted in the open air under ambient conditions, applied to the rapid and direct analysis of any material (gases, liquids, and solids) with minimal or no sample preparation. In order to take advantage of the capacity of DART mass spectrometry for the real-time analysis of hazardous ingredients in commercial agrochemicals, a pilot study of rapid qualitative determination of hazardous pesticides was performed. Highly hazardous pesticides were identified by DART ionization coupled to a single-quadrupole mass spectrometer (DART-MS). Acetonitrile was chosen for dissolving samples prior to the analysis. Samples were analyzed by this technique in as little as 5 s. Phorate, carbofuran, ethoprophos and fipronil were be detected directly from commercial agrochemicals. The ionization-related parameters (DART temperature, grid voltage and MS fragment) of these compounds were optimized to obtain highly response. Isotope patterns were taken into consideration for qualitative identification. Relative standard deviations (RSDs, n = 5) of 2.3-15.0% were obtained by measuring the relative abundance of selected isotopes. This study showed that DART-MS technology was able to qualitatively determine the existence of highly hazardous pesticides in commercial pesticide formulations. It is suggested that this technology should be applied for routine monitoring in the market.

タバココナジラミバイオタイプNauruに対する各種薬剤の殺虫効果

The effect of pesticides on the Nauru biotype, a common biotype of Bemisia tabaci in the Ryukyu Islands, was compared with that on the B biotype under laboratory conditions. Twenty-four commercial agrochemicals were tested on adults, third instar larvae, and eggs. Overall, the majority of the pesticides tested were effective (>70% mortality) for Nauru, but not for the B biotype. Fourteen insecticides were effective for all stages of the Nauru biotype, while only two (pyridaben and emamectine benzoate) were effective for all stages of the B biotype. The effects of synthetic pyrethroid, imidacloprid, and some acaricides were clearly greater in the Nauru biotype than in the B biotype. The results suggest that the Nauru biotype is a less important pest than the B biotype because of the greater susceptibility to insecticides of the former.

沖縄においてカンキツ類を加害するハダニ２種，トウヨウハダニとミカンハダニに対する各種農薬の殺虫効果

The acaricidal eff ect of 29 commercial agrochemicals on two pest spider mites that in fest citrus trees in Okinawa was examined under laboratory conditions. The citrus red mite, Panonychus citri, was resistant to the majority of tested agrochemicals including organophosphate insecticides, synthetic pyrethroid insecticides, and pyrazole acaricides. Some new specifi c acaricides and spiracle-blocking insecticides were eff ective against this species. The effect of some pesticides such as fenpropathrin and hexythiazox varied between local populations of P. citri. The African red mite, Eutetranychus africanus, showed susceptibility to most of the tested agrochemicals with the exceptions of fl ufenoxuron, bifenazate, and a few spiracle-blocking insecticides. The present results suggest that P. citri would be more diffi cult to control than E. africanus using agrochemicals in citrus orchards in Okinawa.

沖縄に分布するＴｅｔｒａｎｙｃｈｕｓ属ハダニ９種に対する各種農薬の殺虫効果

The insecticidal effect of 28 commercial agrochemicals on nine Tetranychus species inhabiting Okinawa was examined under laboratory conditions. The two-spotted spider mite, T. urticae (green form), was resistant to the majority of tested agrochemicals including organophosphate insecticides, synthetic pyrethroid insecticides, and pyrazole acaricides. Some new specific acaricides and spiracle-blocking insecticides were effective against this species. Synthetic pyrethroid insecticides, pyrazole acaricides, and several other chemicals were less effective against a local population of the Kanzawa spider mite, T. kanzawai, but they were effective against another population of this species. While T. okinawanus and T. piercei were susceptible to the majority of the specific acaricides, some of the non-specific insecticides were less effective against these species. The other five species (T. neocaledonicus, T. ludeni, T. pueraricola, T. parakanzawai and T. phaselus), which are not dominant on crops in Okinawa, showed susceptibility to most of the agrochemicals tested, except a few non-specific insecticides. The present results suggest that T. urticae (green form) and T. kanzawai would be more difficult to control than other Tetranychus species in Okinawa using agrochemicals, even though the frequency of occurrence of T. okinawanus and T. piercei on crops is currently higher than that of the two species.

Studies on the synthetic development for the discovery of novel heterocyclic agrochemicals

Various heterocyclic compounds have significantly contributed to current commercial agrochemicals. We focused our attention on these heterocycles as screening targets to create novel bioactive compounds. Although recent progress in agrochemical research has enabled us to discover drugs directly, we selected a chemical approach to N- and N,S-heterocyclic compounds in an expectation of new chemical classes with biological activity. In consequence, this method led to the generation of four heterocycles which had either herbicidal or fungicidal activity. These heterocycles were extended to optimized compounds, resulting in the discovery of three herbicides (2,4-diphenylpyrimidine, 2-acylimino-1,3-thiazoline and 5-trifluoromethylpyridazinone) and one fungicide (2-pyridylpyrimidine).

New Helminthosporal Analogues with Plant-Growth Regulatory Properties Synthesized via Oxyallyl Cation

Microorganisms are a rich source of bioactive molecules which serve as models for the synthesis of new commercial agrochemicals. In this work we present the synthesis of eleven new bioactive analogues of helminthosporal, a fungal secondary metabolite with plant-growth regulatory activity. The compounds were prepared via a [4+3] cycloaddition reaction between the oxyallyl carbocation generated from 2,4-dibromo-5-methylpentan-3-one and several substituted furans. The reactions yields revealed to be highly influenced by the bulkiness and electron withdrawing capacities of the substituents in the furans. The selective effect of all compounds 10a - f, 11 -14 on the radicle growth of Sorghum bicolor and Cucumis sativus were evaluated at the concentration of 10−3 M. All test compounds inhibited the sorghum roots growth (22 - 82%) and most of them stimulated the cucumber radicle growth (up to 127%).

The unique role of fluorine in the design of active ingredients for modern crop protection.

The task of inventing and developing active ingredients with useful biological activities requires a search for novel chemical substructures. This process may trigger the discovery of whole classes of chemicals of potential commercial interest. Similar biological effects can often be achieved by completely different compounds. However, compounds within a given structural family may exhibit quite different biological activities depending on their interactions with different intracellular proteins like enzymes or receptors. By varying the functional groups and structural elements of a lead compound, its interaction with the active site of the target protein, as well as its physicochemical, pharmacokinetic, and dynamic properties can be improved. In this context, the introduction of fluorine into active ingredients has become an important concept in the quest for a modern crop protection product with optimal efficacy, environmental safety, user friendliness, and economic viability. Fluorinated organic compounds represent an important and growing family of commercial agrochemicals. A number of recently developed agrochemical candidates represent novel classes of chemical compounds with new modes of action; several of these compounds contain new fluorinated substituents. However, the complex structure-activity relationships associated with biologically active molecules mean that the introduction of fluorine can lead to either an increase or a decrease in the efficacy of a compound depending on its changed mode of action, physicochemical properties, target interaction, or metabolic susceptibility and transformation. Therefore, it is still difficult to predict the sites in a molecule at which fluorine substitution will result in optimal desired effects.