1,2,4-Triazole benzamide derivative TPB against Gaeumannomyces graminis var. tritici as a novel dual-target fungicide inhibiting ergosterol synthesis and adenine nucleotide transferase function.

BACKGROUND: Isopropyl 4-(2-chloro-6-(1H-1,2,4-triazol-1-yl)benzamido)benzoate (TPB) was a 1,2,4-triazole benzoyl arylamine derivative with excellent antifungal activity, especially against Gaeumannomyces graminis var. tritici (Ggt). Its mechanism of action was investigated by transmission electron microscopy (TEM) observation, assays of sterol composition, cell membrane permeability, intracellular ATP and mitochondrial membrane potential, and mPTP permeability, ROS measurement, RNA sequencing (RNA-seq) analysis. RESULTS: TPB interfered with ergosterol synthesis, reducing ergosterol content, increasing toxic intermediates, and finally causing biomembrane disruption such as increasing cell membrane permeability and content leakage, and destruction of organelle membranes such as coarse endoplasmic reticulum and vacuole. Moreover, TPB destroyed the function of adenine nucleotide transferase (ANT), leading to ATP transport obstruction in mitochondria, inhibiting mPTP opening, inducing intracellular ROS accumulation and mitochondrial membrane potential loss, finally resulting in mitochondrial damage including mitochondria swelled, mitochondrial membrane dissolved, and cristae destroyed and reduced. RNA-seq analyses showed that TPB increased the expression of ERG11, ERG24, ERG6, ERG5, ERG3 and ERG2 genes in ergosterol synthesis pathway, interfered with the expression of genes (NDUFS5, ATPeV0E, NCA2 and Pam17) related to mitochondrial structure, and inhibited the expression of genes (WrbA and GST) related to anti-oxidative stress. CONCLUSIONS: TPB exhibited excellent antifungal activity against Ggt by inhibiting ergosterol synthesis and destroying ANT function. So, TPB was a novel compound with dual-target mechanism of action and can be considered a promising novel fungicide for the control of wheat Take-all. The results provided new guides for the structural design of active compounds and powerful tools for pathogen resistance management. © 2023 Society of Chemical Industry.

Structure-Activity Studies of N-Heterocyclic Benzoyl Arylamine Derivatives Led to a Highly Fungicidal Candidate against Gaeumannomyces graminis var. tritici and Four Fusarium Wheat Pathogens.

Wheat root diseases can seriously reduce yields and quality of wheat. 1,2,4-Triazole benzoyl arylamine derivatives previously showed good activities against some wheat root fungal pathogens. To further systematically disclose the structure-activity relationship, a series of benzoyl arylamines were designed and prepared. Their structures were characterized and fungicidal activities against Gaeumannomyces graminis var. tritici and Fusarium graminearum were evaluated. The results indicated that the structure of the N-heterocyclic group and the substituted group and their position on the benzamide scaffold had an important influence on the activities, as predicted. Finally, compound 18f was found to show excellent activities against G. graminis var. tritici, F. graminearum, Fusarium culmorum, Fusarium pseudograminearum, and Fusarium moniliforme with half-maximum effective concentrations of 0.002, 0.093, 0.011, 0.881, and 0.287 µg/mL, respectively. These results proposed that compound 18f deserved serious consideration as a novel fungicide candidate for the control of wheat root diseases.

Synthesis of 1, 2, 4-triazole benzoyl arylamine derivatives and their high antifungal activities.

Two series of novel 1, 2, 4-triazole benzoyl arylamine derivatives were prepared and screened for their activities against three pathogens of Gaeumannomyces graminis var.tritici, Sclerotinia sclerotiorum and Fusarium graminearum using the mycelium growth inhibition method in vitro. The results indicated that most of the synthesized derivatives displayed antifungal activities. Compounds 6c-d and 6f-g exhibited lower EC50s against all the three pathogens. Among of them, the compound 6g displayed the most potent antifungal activities with EC50 values of 0.01, 0.19 and 0.12 µg mL-1 respectively. The structure and activity relationship showed that election-withdrawing group at pata-position of aniline was favorable for high activities, and the preferred groups were alkoxy carbonyls. These results proposed that the compound 6g can be a lead compound for development of novel fungicide.

An Effective Graph Clustering Method to Identify Cancer Driver Modules.

Identifying the molecular modules that drive cancer progression can greatly deepen the understanding of cancer mechanisms and provide useful information for targeted therapies. Most methods currently addressing this issue primarily use mutual exclusivity without making full use of the extra layer of module property. In this paper, we propose MCLCluster to identity cancer driver modules, which use somatic mutation data, Cancer Cell Fraction (CCF) data, gene functional interaction network and protein-protein interaction (PPI) network to derive the module property on mutual exclusivity, connectivity in PPI network and functionally similarity of genes. We have taken three effective measures to ensure the effectiveness of our algorithm. First, we use CCF data to choose stronger signals and more confident mutations. Second, the weighted gene functional interaction network is used to quantify the gene functional similarity in PPI. The third, graph clustering method based on Markov is exploited to extract the candidate module. MCLCluster is tested in the two TCGA datasets (GBM and BRCA), and identifies several well-known oncogenes driver modules and some modules with functionally associated driver genes. Besides, we compare it with Multi-Dendrix, FSME Cluster and RME in simulated dataset with background noise and passenger rate, MCLCluster outperforming all of these methods.

Senile Lemierre syndrome complicated with descending necrotizing mediastinitis: A case report.

RATIONALE: Senile patients with LS complicated with DNM are rarely seen in clinical practice, and extensive cervical incision and drainage plus administration of effective antibiotics are the basis for treatment. Currently, the treatment controversy mainly has focused on whether mediastinal incision and drainage is necessary for patients with type I DNM, and whether anticoagulation therapy is required for jugular venous emboli and distant metastatic emboli induced by LS. PATIENT CONCERNS: A female, 76 years old, developed pain of tonsil on right side 5 days ago, and felt that the pain aggravated complicated with dysphagia and swelling pain of neck on both sides since then. DIAGNOSES: She was diagnosed with LS complicated with type I DNM. INTERVENTIONS: Tazobactam and Piperacillin 4.5 q8h and Ornidazole 100 ml q6h ivgtt were administered empirically,and secondary extensive cervical incision and drainage was performed under general anesthesia, after which low molecular weight heparin 4250 U q12h SC was administered. G test was performed 3 days later, which showed (1,3)-ß-D-glucan >1000 pg/ml. Bridging anticoagulation therapy, low molecular weight heparin 4250 U q12h SC, and Warfarin 2.5 mg qd po were given one week later. Low molecular weight heparin SC was discontinued and only Warfarin po was administered after treatment of bridging therapy for 3 days. OUTCOMES: CT of head and neck was reexamined on post-admission d24 and revealed that neck infection was improved on both sides, jugular vein distension on right side was restored to normal, abscess and pneumatosis of superior mediastinum were improved, distension of pulmonary artery on both sides was normalized, WBC was 9.94×109/L, neutrophil count was 4.43×109/L, CRP level was 9.8mg/L, D-D level was 0.81mg/L, PCT level was 0.800ng/mL and G test suggested (1,3)-ß-D-glucan pf 27.1 pg/mL. LESSONS: Concomitant use of anticoagulants on the basis of repeated cervical incision and drainage + administration of effective antibiotics can obtain excellent therapeutic efficacy in the treatment of patient with LS complicated with type I DNM.

Treatment of cryotherapy and orthotopic transplantation following chondromyxoid fibroma of zygomatic bone: A case report.

INTRODUCTION: Chondromyxoid fibrotherma (CMF) is a rare benign cartilage tumor that occurs more frequently in young males at the age of 20 to 30. It occurs more frequently on long bones, but rarely involves craniofacial bones. CASE PRESENTATION: This study mainly introduced a 30-year-old male with CMF of zygomatic bone. Single tumor excochleation was conducted initially. However, CMF reoccurred, and then the following steps were adopted: firstly, the tumor was extensively excised; secondly, in vitro tumor excochleation was conducted; thirdly, the excised tumor bone was placed in liquid nitrogen for 3 cycles of cryoablation; finally, the orthotopic transplantation was performed to reconstruct the zygomatic appearance, with satisfactory follow-up efficacy obtained. CONCLUSIONS: Orthotopic transplantation after tumorectomy and cryopreservation of tumor bone in liquid nitrogen could lead to excellent therapeutic efficacy and deserves to be widely applied in clinical practice in the treatment of a male patient with CMF of zygomatic bone, because it not only radically eliminates the tumor and kills tumor cells, but also provides bony skeleton for the growth of new bone, thus greatly promoting postoperative aesthetic degree and reducing the occurrence rates of complications.

Palladium-catalyzed three-component arylcyanation of internal alkynes with aryl bromides and K4[Fe(CN)6].

The one-pot, palladium-catalyzed, three-component coupling of aryl bromides, internal alkynes, and environmentally friendly K4[Fe(CN)6] provides an efficient and direct method for the preparation of beta-arylalkenylnitriles.