Epyrifenacil, a new systemic PPO-inhibiting herbicide for broad-spectrum weed control.

Epyrifenacil is a novel PPO-inhibiting herbicide discovered and developed by Sumitomo Chemical. Epyrifenacil belongs to the pyrimidinedione chemical class and has a unique three-ring structure. It is systemically active on a broad range of weeds including grass weeds and some target-site-based PPO-inhibitor resistant broadleaf weeds. Its systemic action is mediated by a phloem movement of the active form of epyrifenacil. In addition, epyrifenacil's vapor action is sufficiently low to not cause an off-target movement to nontarget sensitive crops. It is expected that epyrifenacil will contribute to global food production in the near future. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Recent advances and structure-activity relationship studies of DPP-4 inhibitors as anti-diabetic agents.

Diabetes mellitus (DM) is one of the largest public health problems worldwide and in the last decades various therapeutic targets have been investigated. For the treatment of type-2 DM (T2DM), dipeptidyl peptidase-4 (DPP-4) is one of the well reported target and has established safety in terms of cardiovascular complexicity. Preclinical and clinical studies using DPP-4 inhibitors have demonstrated its safety and effectiveness and have lesser risk of associated hypoglycaemic effect making it suitable for elderly patients. FDA has approved a number of structurally diverse DPP-4 inhibitors for clinical use. The present manuscript aims to focus on the well reported hybrid and non-hybrid analogues and their structural activity relationship (SAR) studies. It aims to provide structural insights for this class of compounds pertaining to favourable applicability of selective DPP-4 inhibitors in the treatment of T2DM.

Synthesis and Biological Activity Evaluation of Benzoxazinone-Pyrimidinedione Hybrids as Potent Protoporphyrinogen IX Oxidase Inhibitor.

Protoporphyrinogen IX oxidase (PPO/Protox, E.C. 1.3.3.4) is recognized as one of the most important targets for herbicide discovery. In this study, we report our ongoing research efforts toward the discovery of novel PPO inhibitors. Specifically, we identified a highly potent new compound series containing a pyrimidinedione moiety and bearing a versatile building block-benzoxazinone scaffold. Systematic bioassays resulted in the discovery of compound 7af, ethyl 4-(7-fluoro-6-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoate, which exhibited broad-spectrum and excellent herbicidal activity at the dosage of 37.5 g a.i./ha through postemergence application. The inhibition constant (Ki) value of 7af to Nicotiana tabacum PPO (NtPPO) was 14 nM, while to human PPO (hPPO), it was 44.8 µM, indicating a selective factor of 3200, making it the most selective PPO inhibitor to date. Moreover, molecular simulations further demonstrated the selectivity and the binding mechanism of 7af to NtPPO and hPPO. This study not only identifies a candidate that showed excellent in vivo bioactivity and high safety toward humans but also provides a paradigm for discovering PPO inhibitors with improved performance through molecular simulation and structure-guided optimization.

Design and synthesis of novel PPO-inhibiting pyrimidinedione derivatives safed towards cotton.

Developing innovative and effective herbicides is of utmost importance since weed management has become a worldwide agricultural production concern, resulting in severe economic losses every year. In this study, a series of new pyrimidinedione compounds were developed via combination of pyrimidinediones with N-phenylacetamide moiety. The herbicidal activity test (37.5-150 g of ai/ha) indicated that most of the new derivatives exhibited excellent herbicidal activity against dicotyledonous weeds, but less against grasses. Among them, compound 34 was identified as the best postemergence herbicidal activities against six species of weeds (Amaranthus retrof lexus, AR; Abutilon theophrasti, AT; Veronica polita, VP; Echinochloa crusgalli, EC; Digitaria sanguinalis, DS; Setaria viridis, SV), which were comparable to the commercial control agent saflufenacil (≥90%). The protoporphyrinogen oxidase (PPO; EC. 1.3.3.4) activity experiment suggested that compound 34 could significantly reduce the PPO content in weeds, the relative expression levels of the PPO gene were verified by real-time quantitative polymerase chain reaction (RT-qPCR), and the results were consistent with the trend of the enzyme activity data. Molecular docking showed that compound 34 could occupy the PPO enzyme catalytic substrate pocket, which played an excellent inhibitory effect on the activity of receptor protein. Meanwhile, the tolerance of compound 34 to cotton was better than that of the commercial agent saflufenacil at 150 g of ai/ha. Thus, compound 34 exhibits the potential to be a new PPO herbicide for weed control in cotton fields. This study provided a basis for the subsequent structural modification and mechanism research of pyrimidinedione derivatives.

Synthesis and Characterization of Functionalized Chitosan Nanoparticles with Pyrimidine Derivative for Enhancing Ion Sorption and Application for Removal of Contaminants.

Modified chitosan has been widely used for heavy metals removal during the last few decades. In this research, the study was focused on the effect of modified chitosan particles after grafting with heterocyclic constituent for enhancing the sorption of Cr(VI) ions. Chitosan was functionalized by 2-thioxodihydropyrimidine-4,6(1H,5H)-dione, in which the synthesized composite considered as a nanoscale size with average 5-7 nm. This explains the fast kinetics of sorption with large surface area. The prepared sorbent was characterized by Fourier-transform infrared (FTIR), elemental analysis (EA), Brunauer-Emmett-Teller (BET surface area) theory, thermogravimetric analysis (TGA), mass spectroscopy, and scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX) analyses. The experimental part of this work involved the application of the synthesized sorbent for the removal of Cr(VI) ions from highly contaminated tannery effluents that are characterized by a high concentration toward chromate ions with other associated toxic elements, i.e., Pb(II) and Cd (II) ions, which underscore the importance of this treatment. Under the selected conditions (K2Cr2O7 salt, Co: 100 mg L-1 and pH: 4), the sorption diagram shows high Cr(VI) sorption and fast uptake kinetics. The sorption was enhanced by functionalization to 5.7 mmol Cr g-1 as well as fast uptake kinetics; 30 min is sufficient for total sorption compared with 1.97 mmol Cr g-1 and 60 min for the non-grafted sorbent. The Langmuir and Sips equations were fitted for the sorption isotherms, while the pseudo-first order rate equation (PFORE) was fitted for the uptake kinetics.

Polycyclic nitrogen heterocycles as potential thymidine phosphorylase inhibitors: synthesis, biological evaluation, and molecular docking study.

New polycyclic heterocycles were synthesised and evaluated as potential inhibitors of thymidine phosphorylase (TP). Inspired by the pharmacophoric pyrimidinedione core of the natural substrate, four series have been designed in order to interact with large empty pockets of the active site: pyrimidoquinoline-2,4-diones (series A), pyrimidinedione linked to a pyrroloquinoline-1,3-diones (series B and C), the polycyclic heterocycle has been replaced by a pyrimidopyridopyrrolidinetetraone (series D). In each series, the tricyclic nitrogen heterocyclic moiety has been synthesised by a one-pot multicomponent reaction. Compared to 7-DX used as control, 2d, 2l, 2p (series A), 28a (series D), and the open intermediate 30 showed modest to good activities. A kinetic study confirmed that the most active compounds 2d, 2p are competitive inhibitors. Molecular docking analysis confirmed the interaction of these new compounds at the active binding site of TP and highlighted a plausible specific interaction in a pocket that had not yet been explored.

Ionotropic Glutamate Receptor GluA2 in Complex with Bicyclic Pyrimidinedione-Based Compounds: When Small Compound Modifications Have Distinct Effects on Binding Interactions.

(S)-2-Amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic acid (AMPA) receptors comprise an important class of ionotropic glutamate receptors activated by glutamate in the central nervous system. These receptors have been shown to be involved in brain diseases, for example, Alzheimer's disease and epilepsy. To understand the functional role of AMPA receptors at the molecular level and their potential as targets for drugs, development of tool compounds is essential. We have previously reported the synthesis of six bicyclic pyrimidinedione-based analogues of willardiine with differences limited to the pyrimidinedione-fused five-membered rings. Despite minor molecular differences, we observed >500-fold difference in binding affinity of the compounds at full-length GluA2. Here, we report binding affinities and the binding mode of these compounds at the ligand-binding domain of GluA2 using X-ray crystallography. The structures revealed similar binding modes, with distinct differences in the interaction between GluA2 and the compounds. The methylene (2) and sulfur (3) containing compounds showed the greatest binding affinities. Changing the dihydrothiophene (3) into pyrrolidine (4), N-methyl pyrrolidine (5), or dihydrofuran (6) induced flexibility in the position of a binding-site water molecule and changes in the hydrogen-bonding network between compound, water, and GluA2. This might be essential for explaining the reduced binding affinity of these compounds. The weakest binding affinity was observed when the aliphatic oxygen containing dihydrofuran (6) was changed into an aromatic furan system (7). Molecular docking studies revealed two possible orientations of 7, whereas only one binding mode was observed for the other analogues. This could likely contribute to the weakest binding affinity of 7 at GluA2.

Synthesis and anti-H5N1 virus activity of triazole- and oxadiazole-pyrimidine hybrids and their nucleoside analogs.

New 1,2,3-triazole glycosides and 1,2,4-thioglycosides incorporating a substituted pyrimidinedione ring system were synthesized via click dipolar cycloaddition and heterocyclization of hydrazine-1-carbodithioate derivatives, respectively. The sugar hydrazine derivatives linked aminodimethyluracil were also prepared. In addition, the oxadiazoline substituted with acyclic sugar moieties linked to the pyrimidinedione as acyclic nucleoside analogs were synthesized. The antiviral activity of the synthesized compounds against avian influenza H5N1 virus was investigated and compounds 18, 13 and 19 showed good activities against the virus strains.

Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors.

A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety was found to be the optimal amide substitute and the observed activity was rationalized with the use of calculated properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compounds demonstrated moderate clearance and moderate exposure.

Interaction between saflufenacil and imazapyr+imazapic in the management of barnyardgrass and weedy rice and selectivity for irrigated rice / Interação entre saflufenacil e imazapyr+imazapic no manejo de capim-arroz e arroz-daninho e a seletividade para cultura do arroz irrigado

ABSTRACT: The use of imidazolinone-tolerant rice cultivars allows selective control of weedy rice and barnyardgrass. However, in many situations, there is a need to add herbicides from other chemical groups to increase the spectrum of weed control. In this sense, saflufenacil has the potential to be used in mixture with imidazolinone herbicides. This study aimed to evaluate the interaction effects of the imazapyr+imazapic and saflufenacil herbicides in weedy rice and barnyardgrass and to investigate their impacts on the yield of the irrigated rice cultivar Puitá INTA CL. To reach these aims, greenhouse and field experiments were carried out during two growing seasons, with herbicide treatments sprayed separately and in mixtures of saflufenacil with imazapyr+imazapic. Results showed that saflufenacil did not interfere with control of weedy rice and barnyardgrass obtained with imazapyr+imazapic. The D50 values of imazapyr+imazapic for weedy rice control were 14.5+5, 9.1+3 and 12.5+4.2 g ha-1of imazapyr+imazapic for combinations with 0, 3.06 and 6.12 g ha-1of saflufenacil, respectively. In the field experiments, all doses of imazapyr+imazapic applied isolated or in mixture with saflufenacil provided control levels barnyardgrass above 90% at 28 days after herbicides application. Furthermore, saflufenacil did not cause damage or loss in the yield of the rice crop when mixed with imazapyr+imazapic. The Puitá INTA CL rice cultivar was tolerant of the tested herbicides, whether applied alone or in mixture, reaching grain yield of 9.987 kg ha-1 when applied 42 g ha-1 of saflufenacil plus 147+49 g ha-1 of imazapyr+imazapic.

RESUMO: A utilização de cultivares de arroz tolerantes às imidazolinonas possibilita um controle seletivo de arroz-daninho. No entanto, em muitas situações existe a necessidade de adição de herbicidas de outros grupos químicos para aumentar o espectro de controle de plantas daninhas. Neste sentido, saflufenacil apresenta potencial para ser utilizado em mistura com herbicidas imidazolinonas. Este estudo teve como objetivo avaliar os efeitos da interação dos herbicidas imazapyr+imazapic e saflufenacil em arroz-daninho e capim-arroz; e averiguar os impactos sobre a produtividade do cultivar de arroz irrigado Puitá INTA CL. Para alcançar esses objetivos, foram realizados experimentos em casa de vegetação e a campo em duas estações de cultivo, com os tratamentos herbicidas aplicados separadamente e em misturas de saflufenacil com imazapyr+imazapic. Os resultados mostraram que a adição de saflufenacil não interferiu no controle de arroz-daninho e capim-arroz obtido com imazapyr+imazapic. Os valores D50 de imazapyr+imazapic para o controle de arroz-daninho foram 14,5+5; 9,1+3 e 12,5+4,2 g ha-1 de imazapyr+imazapic para combinações com 0; 3,06 e 6,12 g ha-1 de saflufenacil. No experimento de campo todas doses de imazapyr+imazapic, aplicadas isoladas ou em mistura, proveram níveis de controle de capim-arroz superiores a 90% aos 28 dias após a aplicação dos herbicidas. Além disso, saflufenacil não causou injúrias ou perda de rendimento da cultura do arroz quando misturado com imazapyr+imazapic. O cultivar Puitá INTA CL foi tolerante aos herbicidas testados, sejam aplicados isolados ou em mistura, atingindo uma produtividade de 9.987 Kg ha-1 quando aplicado 42 g ha-1 de saflufenacil mais 147+49 g ha-1 de imazapyr+imazapic.

Biochemical and physiological mode of action of tiafenacil, a new protoporphyrinogen IX oxidase-inhibiting herbicide.

We conducted biochemical and physiological experiments to investigate the mode of action of tiafenacil (Terrad'or™), a new protoporphyrinogen IX oxidase (PPO)-inhibiting pyrimidinedione herbicide. Analysis of the half-maximal inhibitory concentration (IC50) against recombinant PPO enzymes from various plant species, including amaranth (Amaranthus tuberculatus), soybean (Glycine max), arabidopsis (Arabidopsis thaliana), and rapeseed (Brassica napus), showed that tiafenacil had an IC50 of 22 to 28 nM, similar to the pyrimidinedione herbicides butafenacil and saflufenacil and the N-phenylphthalimide herbicide flumioxazin. By contrast, tiafenacil exhibited 3- to 134-fold lower IC50 values than the diphenyl ether herbicides fomesafen, oxyfluorfen, and acifluorfen. Tiafenacil is non-selective and is herbicidal to both dicots and monocots, such as the weeds velvetleaf (Abutilon theophrasti), amaranth, and barnyardgrass (Echinochloa crus-galli) as well as the crops soybean, rapeseed, rice (Oryza sativa), and maize (Zea mays) at concentrations ranging from 1 to 50 µM. Treatment of plant tissue with tiafenacil in darkness resulted in the accumulation of protoporphyrin IX. Subsequent exposure to light increased the content of malondialdehyde and significantly decreased the Fv/Fm values of chlorophyll fluorescence. The results suggest that tiafenacil is a new PPO-inhibiting pyrimidinedione herbicide.

Synthesis, Herbicidal Activity, and QSAR of Novel N-Benzothiazolyl- pyrimidine-2,4-diones as Protoporphyrinogen Oxidase Inhibitors.

Protoporphyrinogen oxidase (PPO, E.C. 1.3.3.4) is known as a key action target for several structurally diverse herbicides. As a continuation of our research work on the development of new PPO-inhibiting herbicides, a series of novel 3-(2'-halo-5'-substituted-benzothiazol-1'-yl)-1-methyl-6-(trifluoromethyl)pyrimidine-2,4-diones 9 were designed and synthesized. The bioassay results indicated that a number of the newly synthesized compounds exhibited higher inhibition activity against tobacco PPO (mtPPO) than the controls, saflufenacil and sulfentrazone. Compound 9F-5 was identified as the most potent inhibitor with a Ki value of 0.0072 µM against mtPPO, showing about 4.2-fold and 1.4-fold higher potency than sulfentrazone (Ki = 0.03 µM) and saflufenacil (Ki = 0.01 µM), respectively. An additional green house assay demonstrated that compound 9F-6 (Ki = 0.012 µM) displayed the most promising postemergence herbicidal activity with a broad spectrum even at a concentration as low as 37.5 g of active ingredient (ai)/ha. Maize exhibits relative tolerance against compound 9F-6 at the dosage of 150 g ai/ha, but it is susceptible to saflufenacil even at 75 g ai/ha. Thus, compound 9F-6 exhibits the potential to be a new herbicide for weed control in maize fields.

The rational design and development of a dual chamber vaginal/rectal microbicide gel formulation for HIV prevention.

The DuoGel™ was developed for safe and effective dual chamber administration of antiretroviral drugs to reduce the high incidence of HIV transmission during receptive vaginal and anal intercourse. The DuoGel™s containing IQP-0528, a non-nucleoside reverse transcriptase inhibitor (NNRTI), were formulated from GRAS excipients approved for vaginal and rectal administration. The DuoGel™s were evaluated based upon quantitative physicochemical and biological evaluations defined by a Target Product Profile (TPP) acceptable for vaginal and rectal application. From the two primary TPP characteristics defined to accommodate safe rectal administration three DuoGel™ formulations (IQB3000, IQB3001, and IQB3002) were developed at pH 6.00 and osmolality ⩽400mmol/kg. The DuoGel™s displayed no in vitro cellular or bacterial toxicity and no loss in viability in ectocervical and colorectal tissue. IQB3000 was removed from consideration due to reduced NNRTI delivery (∼65% reduction) and IQB3001 was removed due to increase spread resulting in leakage. IQB3002 containing IQP-0528 was defined as our lead DuoGel™ formulation, possessing potent activity against HIV-1 (EC50=10nM). Over 12month stability evaluations, IQB3002 maintained formulation stability. This study has identified a lead DuoGel™ formulation that will safely deliver IQP-0528 to prevent sexual HIV-1 transmission in the vagina and rectum.

Enthalpies of Solution of the Nucleic Acid Bases. 4. Uracil in Water.

An adiabatic solution calorimeter was used to measure enthalpies of solution in water of 7 uracil samples in a concentration range of 3 to 45 mmol · kg-1 and over a temperature range of 298 K to 325 K. Analytical data for the samples are given. Our best value for the enthalpy of solution is Δ H 0 ( ∞ , 298.15 K ) = ( 29.33 ± 1.2 ) kJ mol - 1 and for the change in heat capacity for the reaction with temperature, Δ C p 0 = ( 57 ± 13 ) J mol - 1 K - 1 No change in the enthalpy of solution with concentration was found in this range. Values were calculated for the entropy of solution, ΔS° = (68.1 ± 4.2) J · mol-1 · K-1, and for the apparent molal heat capacity at infinite dilution, C p 2 0 = ( 178 ± 15 ) J m o l - 1 K - 1 .

Enthalpies of Solution of the Nucleic Acid Bases. 2. Thymine in Water.

An adiabatic solution calorimeter was used to measure enthalpies of solution in water of 8 samples of thymine for which analytical data are reported. Our best values for the enthalpy of solution and the change in heat capacity are Δ H ∘ ( ∞ , 298.15 K ) = ( 24.32 ± 0.70 ) kJ ⋅ mol - 1 Δ C p ∘ = ( 106 ± 26 ) J ⋅ mol - 1 ⋅ K - 1 , 298 K < T < 328 K . These were used to calculate ΔS° = (53. 1 ± 3.6) J · mol-1 · K-1 for the entropy of solution, and C p 2 ∘ = ( 256 ± 26 ) J · mol-1 · K-1 for the apparent molal heat capacity at infinite dilution. No change in the enthalpy of solution with concentration was observed in the range of 5 to 35 mmol · kg-1.