Facile synthesis, crystal structure, quantum calculation, and biological evaluations of novel selenenyl sulfide compounds as potential agrochemicals.

BACKGROUND: In order to design compounds with fresh molecular skeleton to break through the limitation of available agrochemicals, a series of 36 novel selenenyl sulfide compounds were chemically synthesized, and their biological activities were fully evaluated against tobacco mosaic virus (TMV), 14 plant pathogenic fungi, three insect species and plant acetohydroxyacid synthase (AHAS). RESULTS: All the target compounds were characterized by proton nuclear magnetic resonance (1 H-NMR), carbon-13 (13 C)-NMR, selenium-77 (77 Se)-NMR, and high-resolution mass spectrometry (HRMS). The crystal structure of 10j indicated that the Se-S bond was successfully constructed. Compounds 10d, 10h, 10s, 10u, 10aa, 10ac, 10ae, 10ag, and 10ai exhibited 40%, 43%, 39%, 41%, 47%, 46%, 47%, 42%, and 39% anti-TMV activities at 500 mg L-1 , better than that of ribavirin. The median effective concentration (EC50 ) against Sclerotinia sclerotiorum of 10ac was 6.69 mg L-1 and EC50 values against Physalospora piricola and Pyricularia grisea of 10z were 12.25 mg L-1 and 15.27 mg L-1 , respectively, superior to the corresponding values of chlorothalonil. Compounds 10c and 10v demonstrated 100% larvicidal activity against Culex pipiens pallens at 5 mg L-1 , while 10a displayed 100% insecticidal activity against Mythimna separata at 200 mg L-1 . Compounds 10c, 10j, and 10o showed > 60% inhibitions against plant AHAS at 10 µmol L-1 . From the quantum calculation, highest occupied molecular orbital (HOMO) was considered as a factor that affects the anti-TMV activity. CONCLUSION: The preliminary results suggested that more efforts should be devoted to exploring the selenenyl sulfides for the discovery of new leads of antiviral agent, fungicide, insecticide or AHAS inhibitors as potential agrochemicals for crop protection. © 2023 Society of Chemical Industry.

Chemical preparation, degradation analysis, computational docking and biological activities of novel sulfonylureas with 2,5-disubstituted groups.

Based on the previous finding that a substitution at 5-position of the benzene ring is favorable to enhance the degradation rates of sulfonylurea herbicides, a total of 16 novel 2,5-disubsituted sulfonylurea compounds were chemically synthesized and fully characterized by means of 1H NMR, 13C NMR, HRMS and X-ray diffraction. By using HPLC analysis, the degradation behavior of M03, a compound belonging to this family, was studied and confirmed that chlorsulfuron itself is not a degraded product of the 2,5-disubstituted sulfonylureas. Inhibition constants against plant acetohydroxyacid synthase (AHAS) were determined for selected compounds, among which SU3 showed seven times stronger activity against the mutant W574L enzyme than chlorsulfuron. Molecular docking suggested that the substituted group at 5-position of benzene ring is likely to interact with the surrounding residues Met200 and Asp376 of AtAHAS. From the greenhouse herbicidal assay and crop safety test, SU5 and SU6 are considered as herbicide candidates to control dicotyledon weeds in corn, while SU3 is likely to be a promising candidate to control dicotyledon weed species and barnyard grass in wheat. The present research has therefore provided some new insights to understand the structure-activity relationships of herbicidal sulfonylureas with di-substitutions at benzene ring.

Chemical synthesis, biological activities, and molecular simulations of novel sulfonylurea compounds bearing ortho-alkoxy substitutions.

A series of 51 novel sulfonylurea compounds with ortho-alkoxy substituent at phenyl ring were chemically synthesized and spectroscopically characterized. The biological activities of the target compounds were evaluated using the enzyme inhibition against acetohydroxyacid synthase (AHAS; EC 2.2.1.6) from fungal or plant source, as well as cell-based antifungal assay and greenhouse pot herbicidal assay. Among the target compounds, 6e showed desirable antifungal activity against Candida albicans standard isolate sc5314 with minimum inhibition concentration (MIC) of 0.39 mg/L (0.98 µM) after 24 h, and 6a demonstrated promising pre-emergence herbicidal activity against Echinochloacrus-galli at 30 g/ha dosage. Representative compounds 6a, 6e, and 6i showed no cell cytotoxicity even at 40 mg/L concentration. Theoretical DFT calculations indicated HOMO maps should be considered to understand the structure-activity relationships. The present study has hence provided useful information for further discovery of novel antifungal agents or selective herbicides.

Discovery of ortho-Alkoxy Substituted Novel Sulfonylurea Compounds That Display Strong Herbicidal Activity against Monocotyledon Grasses.

In the present study, we have designed and synthesized a series of 42 novel sulfonylurea compounds with ortho-alkoxy substitutions at the phenyl ring and evaluated their herbicidal activities. Some target compounds showed excellent herbicidal activity against monocotyledon weed species. When applied at 7.5 g ha-1, 6-11 exhibited more potent herbicidal activity against barnyard grass (Echinochloa crus-galli) and crab grass (Digitaria sanguinalis) than commercial acetohydroxyacid synthase (AHAS; EC 2.2.1.6) inhibitors triasulfuron, penoxsulam, and nicosulfuron at both pre-emergence and postemergence conditions. 6-11 was safe for peanut for postemergence application at this ultralow dosage, suggesting that it could be considered a potential herbicide candidate for peanut fields. Although 6-11 and triasulfuron share similar chemical structures and have close Ki values for plant AHAS, a significant difference has been observed between their LUMO maps from DFT calculations, which might be a possible factor that leads to their different behaviors toward monocotyledon weed species.

Fragment-based discovery of flexible inhibitor targeting wild-type acetohydroxyacid synthase and P197L mutant.

BACKGROUND: Intensifying weed resistance has challenged the use of existing acetohydroxyacid synthase (AHAS)-inhibiting herbicides. Hence, there is currently an urgent requirement for the discovery of a new AHAS inhibitor to effectively control AHAS herbicide-resistant weed species produced by target mutation. RESULTS: To combat weed resistance caused by AHAS with P197L mutation, we built a structure library consisting of pyrimidinyl-salicylic acid derivatives. Using the pharmacophore-linked fragment virtual screening (PFVS) approach, hit compound 8 bearing 6-phenoxymethyl substituent was identified as a potential AHAS inhibitor with antiresistance effect. Subsequently, derivatives of compound 8 were synthesized and evaluated for their inhibitory activities. The study of the enzyme-based structure-activity relationship and structure-resistance relationship studies led to the discovery of a qualified candidate, 28. This compound not only significantly inhibited the activity of wild-type Arabidopsis thaliana (At) AHAS and P197L mutant, but also exhibited good antiresistance properties (RF = 0.79). Notably, compared with bispyribac at 37.5-150 g of active ingredient per hectare (g a.i. ha-1 ), compound 27 exhibited higher growth inhibition against both sensitive and resistant Descurainia sophia, CONCLUSION: The title compounds have great potential to be developed as new leads to effectively control herbicide-resistant weeds comprising AHAS with P197L mutation. Also, our study provided a positive case for discovering novel, potent and antiresistance inhibitors using a fragment-based drug design approach.

Chemical synthesis, crystal structure, versatile evaluation of their biological activities and molecular simulations of novel pyrithiobac derivatives.

Since pyrithiobac (PTB) is a successful commercial herbicide with very low toxicity against mammals, it is worth exploring its derivatives for an extensive study. Herein, a total of 35 novel compounds were chemically synthesized and single crystal of 6-6 was obtained to confirm the molecular structure of this family of compounds. The novel PTB derivatives were fully evaluated against various biological platforms. From the bioassay results, the best AHAS inhibitor 6-22 displayed weaker herbicidal activity but stronger anti-Candida activity than PTB did. For plant pathogenic fungi, 6-26 showed excellent activity at 50 mg/L dosage. Preliminary insecticidal activity and antiviral activity were also observed for some title compounds. Strikingly, 6-5 exhibited a promising inhibitory activity against SARS-CoV Mpro with IC50 of 4.471 µM and a low cellular cytotoxicity against mammalian 293 T cells. Based on the results of molecular modeling, HOMO-1 was considered to be a factor that affects AHAS inhibition and a possible binding mode of 6-5 with SARS-CoV Mpro was predicted. This is the first time that PTB derivatives have been studied as biological agents other than herbicides. The present research hence has suggested that more attentions should be paid to compounds belonging to this family to develop novel agrochemicals or medicines.

Chemical preparation, biological evaluation and 3D-QSAR of ethoxysulfuron derivatives as novel antifungal agents targeting acetohydroxyacid synthase.

Accetohydroxyacid synthase (AHAS) is the first enzyme involved in the biosynthetic pathway of branched-chain amino acids. Earlier gene mutation of Candida albicans in a mouse model suggested that this enzyme is a promising target of antifungals. Recent studies have demonstrated that some commercial AHAS-inhibiting sulfonylurea herbicides exerted desirable antifungal activity. In this study, we have designed and synthesized 68 novel ethoxysulfulron (ES) derivatives and evaluated their inhibition constants (Ki) against C. albicans AHAS and cell based minimum inhibitory concentration (MIC) values. The target compounds 5-1, 5-10, 5-22, 5-31 and 5-37 displayed stronger AHAS inhibitions than ES did. Compound 5-1 had the best Ki of 6.7 nM against fungal AHAS and MIC values of 2.5 mg/L against Candida albicans and Candica parapsilosis after 72 h. A suitable nematode model was established here and the antifungal activity of 5-1 was further evaluated in vivo. A possible binding mode was simulated via molecular docking and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationship. The current study has indicated that some ES derivatives should be considered as promising hits to develop antifungal drugs with novel biological target.

Design, Synthesis, and Herbicidal Activity of Pyrimidine-Biphenyl Hybrids as Novel Acetohydroxyacid Synthase Inhibitors.

The issue of weed resistance to acetohydroxyacid synthase (EC 2.2.1.6, AHAS) inhibitors has become one of the largest obstacles for the application of this class of herbicides. In a continuing effort to discover novel AHAS inhibitors to overcome weed resistance, a series of pyrimidine-biphenyl hybrids (4aa-bb and 5aa-ah) were designed and synthesized via a scaffold hopping strategy. Among these derivatives, compounds 4aa ( Ki = 0.09 µM) and 4bb ( Ki = 0.02 µM) displayed higher inhibitory activities against Arabidopsis thaliana AHAS than those of the controls bispyribac ( Ki = 0.54 µM) and flumetsulam ( Ki = 0.38 µM). Remarkably, compounds 4aa, 4bb, 5ah, and 5ag exhibited excellent postemergence herbicidal activity and a broad spectrum of weed control at application rates of 37.5-150 g of active ingredient (ai)/ha. Furthermore, 4aa and 4bb showed higher herbicidal activity against AHAS inhibitor-resistant Descurainia sophia, Ammannia arenaria, and the corresponding sensitive weeds than that of bispyribac at 0.94-0.235 g ai/ha. Therefore, the pyrimidine-biphenyl motif and lead compounds 4aa and 4bb have great potential for the discovery of novel AHAS inhibitors to combat AHAS-inhibiting herbicide-resistant weeds.

Discovery of New 2-[(4,6-Dimethoxy-1,3,5-triazin-2-yl)oxy]-6-(substituted phenoxy)benzoic Acids as Flexible Inhibitors of Arabidopsis thaliana Acetohydroxyacid Synthase and Its P197L Mutant.

In the search for new antiresistance acetohydroxyacid synthase (AHAS, EC 2.2.1.6) inhibitors to combat weed resistance associated with AHAS mutations, a series of 2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)oxy]-6-(substituted phenoxy)benzoic acids 11-38 were designed and synthesized via the strategy of conformational flexibility analysis. Compounds 21, 22, 26, 33, 36, and 38 with high potency against both wild-type AtAHAS and its P197L mutant were identified as promising candidates with low resistance factors (RF, defined as the ratio between the ki values toward P197L mutant and wild-type AHAS) ranging from 0.73 to 6.32. Especially, compound 22 (RF = 0.73) was further identified as the most potent antiresistance AHAS inhibitor because of its significantly reduced resistance level compared with that of tribenuron-methyl (RF = 2650) and bispyribac (RF = 4.57). Furthermore, compounds 26, 33, 36, and 38 also displayed promising herbicidal activities against sensitive and resistant (P197L) Descurainia sophia at the dosage of 75-150 g of active ingredient (ai)/ha. Notably, compounds 33 and 38 still maintained over 60% herbicidal activity toward the resistant weed even at much lower dosages (37.5 g ai/ha). Therefore, the designed scaffold has the great potential to discover new candidate compounds for the control of weed resistance associated with AHAS mutation.

Synthesis and Herbicidal Activity of Pyrido[2,3-d]pyrimidine-2,4-dione-Benzoxazinone Hybrids as Protoporphyrinogen Oxidase Inhibitors.

To search for new protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors with improved bioactivity, a series of novel pyrido[2,3-d]pyrimidine-2,4-dione-benzoxazinone hybrids, 9-13, were designed and synthesized. Several compounds with improved tobacco PPO (mtPPO)-inhibiting and promising herbicidal activities were found. Among them, the most potent compound, 3-(7-fluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-6-yl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, 11q, with a Ki value of 0.0074 µM, showed six times more activity than flumioxazin (Ki = 0.046 µM) against mtPPO. Compound 11q displayed a strong and broad spectrum of weed control at 37.5-150 g of active ingredient (ai)/ha by both post- and pre-emergence application, which was comparable to that of flumioxazin. 11q was safe to maize, soybean, peanut, and cotton at 150 g ai/ha, and selective to rice and wheat at 75 g ai/ha by pre-emergence application, indicating potential applicability in these fields.

Computational Discovery of Potent and Bioselective Protoporphyrinogen IX Oxidase Inhibitor via Fragment Deconstruction Analysis.

Tuning the binding selectivity through appropriate ways is a primary goal in the design and optimization of a lead toward agrochemical discovery. However, how to achieve rational design of selectivity is still a big challenge. Herein, we developed a novel computational fragment generation and coupling (CFGC) strategy that led to a series of highly potent and bioselective inhibitors targeting protoporphyrinogen IX oxidase. This enzyme plays a vital role in heme and chlorophyll biosynthesis, which has been proven to be associated with many drugs and agrochemicals. However, existing agrochemicals are nonbioselective, resulting in a great threat to nontargeted organisms. To the best of our knowledge, this is the first bioselective inhibitor targeting the tetrapyrrole biosynthesis pathway. In addition, the candidate showed excellent in vivo bioactivity and much better safety toward humans.

Computational design of novel inhibitors to overcome weed resistance associated with acetohydroxyacid synthase (AHAS) P197L mutant.

BACKGOUND: Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) is the first common enzyme in the biosynthetic pathway leading to the branched-chain amino acids in plants and a wide range of microorganisms. With the long-term and wide application of AHAS inhibitors, weed resistance is becoming a global problem, which leads to an urgent demand for novel inhibitors to antagonize both wild-type and resistant AHAS. RESULTS: Pyrimidinyl salicylic acid derivatives, as one of the main classes of commercial AHAS herbicides, show potential anti-resistant bioactivity to wild-type and P197L mutant. In current work, a series of novel 2-benzoyloxy-6-pyrimidinyl salicylic acid derivatives were designed through fragment-based drug discovery. Fortunately, the newly synthesized compounds showed good inhibitory activity against both wild-type and P197L mutant. Some compounds not only had a lower resistance factor value but also showed excellent inhibitory activity against wild-type AHAS and P197L mutant. Furthermore, greenhouse experiments showed compound 11m displayed almost 100% inhibition against both wild-type and high-resistant Descurainia sophia at a dosage of 150 g a.i. ha-1 . CONCLUSION: The present work indicated that the 2-benzoyloxy-6-pyrimidinyl salicylic acid motif was well worth further optimization. Also, compound 11m could be used as a potential anti-resistant AHAS herbicide, which requires further research. © 2016 Society of Chemical Industry.

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.

Synthesis and biological evaluation of nonsymmetrical aromatic disulfides as novel inhibitors of acetohydroxyacid synthase.

46 Novel nonsymmetrical aromatic disulfides containing [1,3,4]thiadiazole or [1,3,4]oxadiazole groups were synthesized and their biological activities were evaluated as inhibitors of acetohydroxyacid synthase (AHAS, EC 2.2.1.6). Besides their strong in vitro inhibition against plant AHAS, compounds 3e and 3f also display 80-100% post-emergence herbicidal activities in greenhouse bioassay at 1500g /ha dosage. The assay of exogenous branched-chain amino acids supplementation on rape root growth of 3e suggests that the herbicidal activity has relationship with AHAS inhibition.

Syntheses and herbicidal activity of new triazolopyrimidine-2-sulfonamides as acetohydroxyacid synthase inhibitor.

The triazolopyrimidine-2-sulfonanilide, discovered from preparing bioisosteres of the sulfonylurea herbicides, is an important class of acetohydroxyacid synthase (AHAS, EC 4.1.3.18) inhibitors. At least over ten triazolopyrimidine sulfonanilides have been commercialized as herbicides for the control of broadleaf weeds and grass with cereal crop selectivity. Herein, a series of triazolopyrimidine-2-sulfonanilides were designed and synthesized with the aim of discovery of new herbicides with higher activity. The assay results of the inhibition activity of the synthesized compounds against Arabidopsis thatiana AHAS indicated that some compounds showed a little higher activity against flumetsulam (FS), the first commercial triazolopyrimidine-2-sulfonanilide-type herbicide. The ki values of two promising compounds 3d and 8h are respectively, 1.61 and 1.29 microM, while that of FS is 1.85 microM. Computational simulation results indicated the ester group of compound 3d formed hydrogen bonds with the surrounding residues Arg'198 and Ser653, which accounts for its 11.5-folds higher AHAS inhibition activity than Y6610. Further green house assay showed that compound 3d has comparable herbicidal activity as FS. Even at the concentration of 37.5g.ai/ha, 3d showed excellent herbicidal activity against Galium aparine, Cerastium arvense, Chenopodium album, Amaranthus retroflexus, and Rmumex acetasa, moderate herbicidal activity against Polygonum humifusum, Cyperus iria, and Eclipta prostrate. The combination of in vitro and in vivo assay indicated that 3d could be regarded as a new potential acetohydroxyacid synthase-inhibiting herbicide candidate for further study.

Design and synthesis of N-2,6-difluorophenyl-5-methoxyl-1,2,4-triazolo[1,5-a]-pyrimidine-2-sulfonamide as acetohydroxyacid synthase inhibitor.

Triazolopyrimidine-2-sulfonamide belongs to a herbicide group called acetohydroxyacid synthase inhibitors. With the aim to discover new triazolopyrimidine sulfonanilide compounds with high herbicidal activity and faster degradation rate in soil, the methyl group of Flumetsulam (FS) was modified into a methoxy group to produce a new herbicidal compound, N-2,6-difluorophenyl-5-methoxy-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide (experimental code: Y6610). The enzymatic kinetic results indicated that compound Y6610 and FS have k(i) values of 3.31x10(-6) M and 3.60x10(-7) M against Arabidopsis thaliana AHAS, respectively. The 10-fold lower enzyme-inhibiting activity of Y6610 was explained rationally by further computational simulations and binding free energy calculations. In addition, compound Y6610 was found to display the same level in vivo post-emergent herbicidal activity as FS against some broad-leaf weeds and good safety to rice, maize, and wheat at the dosages of 75-300 gai/ha. Further determination of the half-lives in soil revealed that the half-life in soil of Y6610 is 3.9 days shorter than that of FS. The experimental results herein showed that compound Y6610 could be regarded as a new potential acetohydroxyacid synthase-inhibiting herbicide candidate for further study.