Expanding the Structural Diversity of Tubulin-Targeting Agents: Development of Highly Potent Benzimidazoles for Treating Fungal Diseases

Journal of Agricultural and Food Chemistry, Год журнала: 2024, Номер 72(28), С. 15541 - 15551

Опубликована: Июль 3, 2024

Benzimidazoles, the representative pharmacophore of fungicides, have excellent antifungal potency, but their simple structure and single site action hindered wider application in agriculture. In order to extend structural diversity tubulin-targeted benzimidazoles, novel benzimidazole derivatives were prepared by introducing attractive pyrimidine pharmacophore. 2-((6-(4-(trifluoromethyl)phenoxy)pyrimidin-4-yl)thio)-1H-benzo[d]imidazole (A25) exhibited optimal activity against Sclerotinia sclerotiorum (S. s.), affording an half-maximal effective concentration (EC50) 0.158 μg/mL, which was higher than that reference agent carbendazim (EC50 = 0.594 μg/mL). Pot experiments revealed compound A25 (200 μg/mL) had acceptable protective (84.7%) curative (78.1%), comparable with (protective activity: 90.8%; 69.9%). Molecular docking displayed multiple hydrogen bonds π–π interactions could be formed between β-tubulin, resulting a stronger bonding effect carbendazim. Fluorescence imaging intracellular microtubules can changed significantly after treatment. Overall, these remarkable profiles constructed facilitate microtubule-targeting agents.

Язык: Английский

---

Recent Advances in Design and Development of Diazole and Diazine Based Fungicides (2014–2023)

Journal of Agricultural and Food Chemistry, Год журнала: 2024, Номер 72(28), С. 15427 - 15448

Опубликована: Июль 5, 2024

With fungal diseases posing a major threat to agricultural production, the application of fungicides control related is often considered necessary ensure world's food supply. The search for new bioactive agents has long been priority in crop protection due continuous development resistance against currently used types active compounds. Heterocyclic compounds are an inseparable part core structures numerous lead compounds, these rings constitute pharmacophores significant number developed over past decade by agrochemists. Among heterocycles, nitrogen-based play essential role. To date, diazole (imidazole and pyrazole) diazine (pyrimidine, pyridazine, pyrazine) derivatives make up important series synthetic fungicides. In recent years, many reports have published on design, synthesis, study fungicidal activity scaffolds, but there was lack comprehensive classified review nitrogen-containing scaffolds. Regarding this issue, here we reviewed articles families. current review, molecules synthesized so far based size ring.

Язык: Английский

---

Discovery of Pyrazole-5-yl-amide Derivatives Containing Cinnamamide Structural Fragments as Potential Succinate Dehydrogenase Inhibitors

Journal of Agricultural and Food Chemistry, Год журнала: 2023, Номер unknown

Опубликована: Ноя. 3, 2023

To promote the development of novel agricultural succinate dehydrogenase inhibitor (SDHI) fungicides, we introduced cinnamamide and nicotinamide structural fragments into structure pyrazol-5-yl-amide by carbon chain extension scaffold hopping, respectively, synthesized a series derivatives. The results biological activity assays indicated that most target compounds exhibited varying degrees inhibitory against tested fungi. Notably, G22, G28, G34, G38, G39 excellent in vitro antifungal activities Valsa mali with EC50 values 0.48, 0.86, 0.57, 0.73, 0.87 mg/L, this result was significantly more potent than boscalid (EC50 = 2.80 mg/L) closer to specialty control drug tebuconazole 0.30 mg/L). Compounds G22 G34 also vivo protective curative effects V. at 40 mg/L. SEM TEM observations may affect normal mycelial morphology as well cellular ultrastructure. Molecular docking analysis possessed similar binding mode SDH, detailed SDH inhibition validated feasibility designed potential inhibitors. G3 were selected for theoretical calculations, terminal carboxylic acid group be key region influencing activity. Furthermore, toxicity tests on Apis mellifera l. revealed low A. populations. above demonstrated these pyrazole-5-yl-amide derivatives are promising low-risk drug-resistance SDHI fungicides.

Язык: Английский

---

Discovery of Benzothiazolylpyrazole-4-Carboxamides as Potent Succinate Dehydrogenase Inhibitors through Active Fragment Exchange and Link Approach

Journal of Agricultural and Food Chemistry, Год журнала: 2023, Номер 71(40), С. 14471 - 14482

Опубликована: Сен. 29, 2023

Succinate dehydrogenase (SDH) is an attractive target for developing green fungicides to manage agricultural pathogens in modern agriculture research. Herein, this work, we report the discovery of benzothiazolylpyrazole-4-carboxamides I-III as potent SDH inhibitors using active fragment exchange and link approach. The results fungicidal activity assays showed that some synthesized compounds exhibited excellent inhibition against tested fungi. Systematic structure-activity relationship studies led compound Ip, N-(1-((4,6-difluorobenzo[d]thiazol-2-yl)thio)propan-2-yl)-3-(difluoromethyl)-N-methoxy-1-methyl-1H-pyrazole-4-carboxamide, which higher Fusarium graminearum Schw (EC50 = 0.93 μg/mL) than commercial thifluzamide > 50 boscalid μg/mL). molecular simulation suggested hydrophobic interactions were primary driving forces between ligands SDH. Promisingly, found Ip could stimulate growth wheat seedlings Arabidopsis thaliana increase biomass treated plants. Preliminary on plant promoter mechanism indicated it nitrate reductase planta, that, turn, stimulates

Язык: Английский

---

Rational design, synthesis, and antimicrobial evaluation of novel 1,2,4-trizaole-substituted 1,3,4-oxadiazole derivatives with a dual thioether moiety

Molecular Diversity, Год журнала: 2024, Номер 29(1), С. 255 - 267

Опубликована: Апрель 30, 2024

Язык: Английский

---

Asymmetric Synthesis and Bioactivity Evaluation of Chiral Oxazoline Skeleton Molecules

Journal of Agricultural and Food Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 6, 2025

The utilization of novel organic synthesis methods is increasingly critical in the development innovative agrochemicals. In this study, we designed and synthesized a series chiral oxazoline derivatives using one-pot method. This method involved first catalyzing asymmetric aldol addition reaction oxazolinyl esters with paraformaldehyde, followed by esterification various pharmacophore-containing carboxylic acids. Unexpectedly, many target compounds exhibited promising antifungal antioomycete activities, their absolute configurations showing pronounced enantioselective activities. Notably, compound (R)-5c demonstrated significant biological activities against Valsa mali Phytophthora capsica (EC50 = 1.023 mg/L EC50 0.149 mg/L, respectively), which were markedly superior to its enantiomer (S)-5c 9.565 0.924 respectively). vivo experiments confirmed that both curative protective effects V. P. capsici. CLSM SEM analyses further indicated 5c had distinct physiological on capsici hyphae. Moreover, acute toxicity tests zebrafish (Danio rerio) revealed significantly lower compared control drugs tebuconazole dimethomorph. Consequently, study provides valuable insights for analogues as potential

Язык: Английский

---

Synthetic aspects, structural insights and pharmacological potential of pyrazole derivatives: an overview

Deleted Journal, Год журнала: 2025, Номер 7(2)

Опубликована: Фев. 13, 2025

Abstract There is an increase in infectious diseases every year. Heterocyclic compounds have been use as drugs for a long time. Amongst many heterocyclic derivatives, the containing pyrazole core has limelight because of its relative ease synthesis and excellent biological activities. Pyrazoles are aromatic consisting ring structure where two nitrogen atoms adjacent to each other contain three carbon atoms. Over years pyrazoles explored variety pharmacological applications. Herein, this review overviews information related industrially important pyrazoline scaffolds their applications, recent literature on synthesizing providing explanation activity by focusing structural relationship hence affording ideas design scaffolds. Graphical abstract

Язык: Английский

---

Discovery of Potential Antifungal Agents: Chalcone Derivatives Containing Thiourea and Piperidine Moieties

Journal of Agricultural and Food Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 16, 2025

Twenty-two chalcone derivatives containing thiourea and piperidine moieties were synthesized. The in vitro antifungal activities of these compounds against nine fungi evaluated. results demonstrated that a majority exhibited exceptional activities. Especially, K2 displayed the most potent fungicidal activity Phytophthora capsici (P. capsici), with half-effective concentration (EC50) 5.96 μg/mL, surpassing control drug azoxystrobin (Az, 25.2 μg/mL). vivo experiments conducted on pepper leaves fruits. It significant protective efficacy P. (95.3%) at 200 which surpassed Az (79.0%). Morphological investigations utilizing scanning electron microscopy (SEM) fluorescence (FM) unveiled disruptive impact mycelium. Moreover, mechanistic studies have capacity to disrupt integrity cellular membrane pathogenic fungi, influence lipid peroxidation processes within membrane, induce content release. These experimental findings provided new idea for effectively preventing plant fungal diseases developing novel green chemical pesticide products.

Язык: Английский

---

Synthesis and Activity of Novel Pyrazole/Pyrrole Carboxamides Containing a Dinitrogen Six-Membered Heterocyclic as Succinate Dehydrogenase and Ergosterol Biosynthesis Inhibitors against Colletotrichum camelliae

Journal of Agricultural and Food Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 23, 2025

Pyrazole carboxamide derivatives were initially extensively studied as succinate dehydrogenase inhibitors (SDHIs). In the present study, a series of pyrazole/pyrrole carboxamides containing dinitrogen six-membered heterocyclic designed based on our reported active skeletons with dual mode action. Bioactivity results showed that target compound Q18 demonstrated superior antifungal efficacy against Colletotrichum camelliae (C. camelliae) an EC50 value 6.0 mg/L. The in vivo protective activity was 74.7% at 100 Scanning electron microscopy and transmission could disrupt surface morphology mycelia cause lipid peroxidation cell membrane, which further verified by determination relative conductivity malondialdehyde contents. Combined ergosterol content, docking between SDH CYP51, IC50 for (9.7 mg/L), it is concluded potential SDHI biosynthesis inhibitor. Thus, study provides fresh insight into amides.

Язык: Английский

---

Design, synthesis, antimicrobial activity, and mechanism of novel 3‐(2,4‐dichlorophenyl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazole derivatives

Pest Management Science, Год журнала: 2024, Номер 80(10), С. 5388 - 5399

Опубликована: Июль 3, 2024

Abstract BACKGROUND Plant pathogens cause substantial crop losses annually, posing a grave threat to global food security. Fungicides have usually been used for their control, but the rapid development of pesticide resistance renders many ineffective, therefore search novel and efficient green pesticides prevent control plant diseases has become top priority in planting. RESULTS The results bioassay studies indicated that most target compounds showed certain antimicrobial activity vitro . In particular, compound X7 high inhibitory against Xanthomonas oryzae pv. ( Xoo ), with an EC 50 value 27.47 μg mL −1 , surpassing conventional agents such as thiazole zinc (41.55 ) thiodiazole copper (53.39 ). Further on molecular docking had strong binding affinity 2FBW. morphological change observed by scanning electron microscopy surface appears wrinkled cracked under treatment total 2662 proteins were identified label‐free proteomic analysis. Three experiments elucidated mechanism whereby induced considerable changes physiological biochemical properties which turn affected reproduction growth bacteria. CONCLUSION This work represents pivotal advancement, offering important reference research therapeutics combating pathogens. © 2024 Society Chemical Industry.

Язык: Английский

---