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ABSTRACT Botrytis cinerea causes gray mold on thousands of plants, leading to huge losses in production. Anilinopyrimidine (AP) fungicides have been applied to control B. cinerea since the 1990s. Although resistance to AP fungicides was detected soon after their application, the mechanism of AP resistance remains to be elucidated. In this study, a sexual cross between resistant and sensitive isolates was performed, and the genomes of parental isolates and progenies were sequenced to identify resistance-related single nucleotide polymorphisms (SNPs). After screening and verification, mutation E407K in the Bcmdl1 gene was identified and confirmed to confer resistance to AP fungicides in B. cinerea. Bcmdl1 was predicted to encode a mitochondrial protein that belonged to a half-type ATP-binding cassette (ABC) transporter. Although Bcmdl1 was a transporter, it did not mediate resistance to multiple fungicides but mediated resistance specifically to AP fungicides. On the other hand, reductions in conidial germination and virulence were observed in Bcmdl1 knockout transformants compared to the parental isolate and complemented transformants, illustrating the biological functions of Bcmdl1. Subcellular localization analysis indicated that Bcmdl1 was localized in mitochondria. Interestingly, the production of ATP was reduced after cyprodinil treatment in Bcmdl1 knockout transformants, suggesting that Bcmdl1 was involved in ATP synthesis. Since Mdl1 could interact with ATP synthase in yeast, we hypothesize that Bcmdl1 forms a complex with ATP synthase, which AP fungicides might target, thereby interfering with the metabolism of energy. IMPORTANCE Gray mold, caused by B. cinerea, causes huge losses in the production of many fruits and vegetables. AP fungicides have been largely adopted to control this disease since the 1990s, and the development of resistance to AP fungicides initiates new problems for disease control. Due to the unknown mode of action, information on the mechanism of AP resistance is also limited. Recently, mutations in mitochondrial genes were reported to be related to AP resistance. However, the mitochondrial process of these genes remains to be elucidated. In this study, we identified several AP resistance-related mutations by quantitative trait locus sequencing (QTL-seq) and confirmed that mutation E407K in Bcmdl1 conferred AP resistance. We further characterized the expression patterns, biological functions, subcellular localization, and mitochondrial processes of the Bcmdl1 gene. This study deepens our understanding of the mechanism of resistance to and mode of action of AP fungicides.

In this study, 162 Penicillium isolates, i.e., 31 P. expansum isolates and 131 isolates from 13 other Penicillium spp. referred to as "non-expansum" were collected from apples and pears from multiple packinghouses in Washington State and Oregon. The sensitivity of the isolates to the postharvest fungicides pyrimethanil (PYR) and fludioxonil (FDL) was assessed in vitro. The mean EC 50 value for PYR was 0.75 μg/mL in P. expansum compared to 1.63, 3.47, 6.95, 7.06 and 32.21 μg/mL in P. solitum , P. palitans , P. commune , P. roqueforti and P. carneum , respectively. For FDL, the mean EC 50 value was 0.04 μg/mL in P. expansum compared to >0.80, 1.00, 10.40, 13.99, and 158.10 μg/mL in P. commune , P. palitans , P. roqueforti , P. solitum , and P. paneum , respectively. Overall, > 40 % of isolates from five "non-expansum" species showed dual resistance to PYR and FDL versus 9.6 % in P. expansum. The recommended rates of PYR and FDL failed to control isolates of six Penicillium spp. on detached apples after five months at 1.5 °C. Sequencing of the Mdl1, NikA, and Os1 genes from different isolates of eight species revealed a high polymorphism in the Mdl1 and NikA of several "non-expansum" species. Three and two concurrent mutations, in addition to a G409R and S959, were detected in the Mdl1 and NikA, respectively, that potentially confer resistance to PYR and FDL. The high level of resistance and the control failure observed on fruits highlight the potential risk posed by several "non-expansum" Penicillium species to pome fruit packers. [Display omitted] • 162 isolates of 14 Penicillium spp. causing blue mold of pome fruit were tested. • High levels of resistance to fludioxonil and pyrimethanil in "non-expansum" species. • "Non-expansum" Penicillium spp. exhibit more dual resistance than P. expansum. • Higher polymorphism in the Mdl1 and NikA genes of "non-expansum" species. • Point mutations in Mdl1 and NikA may confer resistance to the two fungicides. [ABSTRACT FROM AUTHOR]

The paper presents a methodology for the preparation of samples of oilseeds, lettuce leaves, apple fruits for the study of xenobiotics by chromatographic control of the following chemical groups of pesticides: benzimidazole derivatives, anilinopyrimidine derivatives, bipyridyl derivatives. The following processes are considered: homogenisation of the sample, purification of the extract by solid-phase or liquid-liquid extraction methods, obtaining of plant extract, and obtaining of analytes extract. For fine-grained homogenised samples of sunflower seeds, the optimal raw material-extractant ratio is 1:20, for paste-like homogenised samples of apple fruit – 1:10, and for liquid samples of homogenised lettuce – 1:5. Analysis of the distribution of xenobiotics parameter in the octane/water system (log Pow), reference data on dielectric constant and dipole moment of solvents allowed identifying extractants capable of dissolving and removing xenobiotics from raw materials. It has been found that a mixture of acetonitrile and methanol (4:1) should be used for the extraction of benzimidazole derivatives and anilinopyrimidine derivatives, bipyridyl derivatives are best extracted with methanolic trifluoroacetic acid (9.5:0.5). The content of xenobiotics in extracts obtained from samples artificially enriched with xenobiotics was quantitatively analysed. Xenobiotics were removed from samples of crop products containing traces of fat. The most difficult process of sample preparation is the process of extracting sunflower seeds. The content of xenobiotics in extracts obtained from samples artificially enriched with analytes is affected by the temperature at which the process takes place and the duration of extraction. Based on the chemical composition of the sample matrix and the list of analytes, the conditions of the variable component of the methodology are proposed: obtaining plant extracts under the action of selective solvents, homogenised raw material-solvent with constant stirring of the extraction system at a speed of 180-200 rpm, or when exposed to ultrasonic vibrations at a frequency of 37 kHz from 4 °C to 25 °C for 5-25 minutes. Control of the qualitative and quantitative composition of the studied plant extracts and extracts of analytes was studied by methods of high-performance liquid and gas chromatography (liquid and gas) with mass-selective detectors

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Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines.

The synthesis of a series of ribose-modified anilinopyrimidine derivatives was efficiently achieved by utilizing DBU or tBuOLi-promoted coupling of ribosyl alcohols with 2,4,5-trichloropyrimidine as key step. Preliminary biological evaluation of this type of compounds as new EGFR tyrosine kinase inhibitors for combating EGFR L858R/T790M mutant associated with drug resistance in the treatment of non-small cell lung cancer revealed that 3-N-acryloyl-5-O-anilinopyrimidine ribose derivative 1a possessed potent and specific inhibitory activity against EGFR L858R/T790M over WT EGFR. Based upon molecular docking studies of the binding mode between compound 1a and EGFR, the distance between the Michael receptor and the pyrimidine scaffold is considered as an important factor for the inhibitory potency and future design of selective EGFR tyrosine kinase inhibitors against EGFR L858R/T790M mutants.

Crop protection anilinopyrimidine (AP) fungicides were introduced more than 20 years ago for the control of a range of diseases caused by ascomycete plant pathogens, and in particular for the control of gray mold caused by Botrytis cinerea. Although early mode of action studies suggested an inhibition of methionine biosynthesis, the molecular target of this class of fungicides was never fully clarified. Despite AP-specific resistance having been described in B. cinerea field isolates and in multiple other targeted species, the underlying resistance mechanisms were unknown. It was therefore expected that the genetic characterization of resistance mechanisms would permit the identification of the molecular target of these fungicides. In order to explore the widest range of possible resistance mechanisms, AP-resistant B. cinerea UV laboratory mutants were generated and the mutations conferring resistance were determined by combining whole-genome sequencing and reverse genetics. Genetic mapping from a cross between a resistant field isolate and a sensitive reference isolate was used in parallel and led to the identification of an additional molecular determinant not found from the characterized UV mutant collection. Together, these two approaches enabled the characterization of an unrivaled diversity of resistance mechanisms. In total, we report the elucidation of resistance-conferring mutations within nine individual genes, two of which are responsible for almost all instances of AP resistance in the field. All identified resistance-conferring genes encode proteins that are involved in mitochondrial processes, suggesting that APs primarily target the mitochondria. The functions of these genes and their possible interactions are discussed in the context of the potential mode of action for this important class of fungicides.

Crop protection anilinopyrimidine (AP) fungicides were introduced more than 20 years ago for the control of a range of diseases caused by ascomycete plant pathogens, and in particular for the control of gray mold caused by Botrytis cinerea. Although early mode of action studies suggested an inhibition of methionine biosynthesis, the molecular target of this class of fungicides was never fully clarified. Despite AP-specific resistance having been described in B. cinerea field isolates and in multiple other targeted species, the underlying resistance mechanisms were unknown. It was therefore expected that the genetic characterization of resistance mechanisms would permit the identification of the molecular target of these fungicides. In order to explore the widest range of possible resistance mechanisms, AP-resistant B. cinerea UV laboratory mutants were generated and the mutations conferring resistance were determined by combining whole-genome sequencing and reverse genetics. Genetic mapping from a cross between a resistant field isolate and a sensitive reference isolate was used in parallel and led to the identification of an additional molecular determinant not found from the characterized UV mutant collection. Together, these two approaches enabled the characterization of an unrivaled diversity of resistance mechanisms. In total, we report the elucidation of resistance-conferring mutations within nine individual genes, two of which are responsible for almost all instances of AP resistance in the field. All identified resistance-conferring genes encode proteins that are involved in mitochondrial processes, suggesting that APs primarily target the mitochondria. The functions of these genes and their possible interactions are discussed in the context of the potential mode of action for this important class of fungicides. [ABSTRACT FROM AUTHOR]

A series of thirty two anilinopyrimidines derived from WZ4002 has been synthesized and evaluated for percentage inhibition of six different EGFR kinases using LanthaScreen binding assay method (EGFR d746 – 750) or Z’LYTE assay method (EGFR-WT, EGFR d746 – 750, EGFR T790M, EGFR T790M L858R, EGFR C797S and EGFR T790M L858R C797S). Ortho -hydroxyacetamide 10 exhibited complete inhibition of all the six kinases at 10 µM. Against the triple mutant, EGFR T790M C797S L858R, compounds 9 – 12 exhibited complete inhibition at 10 µM and nearly complete inhibition at 1 µM. The target compounds were also evaluated using the MTT assay to determine their cytotoxic activity against human non-small cell lung cancer cells (PC9, PC9GR and H460) and mouse leukemic cells (Ba/F3 WT and Ba/F3T 3151). Overall, 7 , 9 – 12 , 30 and 31 were found to be the most potent compounds across all five cell lines. [ABSTRACT FROM AUTHOR]

The effect of the fungicide pyrimethanil (0.7 mg L) on biofilm development and alder leaf litter decomposition in aquatic ecosystems was assessed in outdoor lentic mesocosms immediately and 274 days after pyrimethanil application. Pyrimethanil decreased ergosterol concentrations (an indicator of fungal biomass) and the abundance and richness of the macroinvertebrate community associated with decomposing leaves. However, because neither fungi nor macroinvertebrates were main factors contributing to decomposition in this particular system, organic matter processing rates were not affected. After 274 days, pyrimethanil concentration in the water column was ≤0.004 mg L but richness, biomass and composition of the invertebrate community associated with decomposing leaf-litter still showed the effect. The comparison of ergosterol (a molecule existing on both algae and fungal cell membranes), with chlorophyll (an indicator of algal biomass) associated with biofilm suggests that pyrimethanil may decrease fungal biomass and alter the relative abundance of algae and fungi on biofilm developing in control- and treated-mesocosms. [ABSTRACT FROM AUTHOR]

Cyprodinil is among the most common agrochemical residues found in highly perishable fruits, such as strawberries. In the present study, high-affinity monoclonal antibodies to this anilinopyrimidine fungicide were raised for the first time with the aim to produce valuable immunochemical analytical assays. Cyprodinil bioconjugates and the generated novel monoclonal antibodies were employed for sensitive competitive immunoassay development in two different formats. The limits of detection of the optimized assays were 20 and 30 ng L −1 for the indirect and direct assay, respectively. Influence over assay parameters of different physicochemical factors was studied. Strawberry samples were extracted following the recommended QuEChERS procedure for pesticide residues in food, and analyzed by the optimized immunoassays. Recoveries and coefficients of variation from fortified samples were within standard values. In addition, the obtained immunochemical results with naturally contaminated samples were statistically comparable, according to Deming regression analysis, to those of a reference chromatographic method. [ABSTRACT FROM AUTHOR]

In accordance with Article 6 of Regulation (EC) No 396/2005, France, hereafter referred to as the evaluating Member State (EMS), received an application from Syngenta France SAS to modify the existing maximum residue level (MRL) for the active substance cyprodinil in celery. In order to accommodate for the intended uses of cyprodinil, France proposed to raise the existing MRL from the value of 5 mg/kg to 7 mg/kg. France drafted an evaluation report in accordance with Article 8 of Regulation (EC) No 396/2005, which was submitted to the European Commission and forwarded to EFSA. According to EFSA the submitted data support a MRL proposal of 5 mg/kg for the proposed outdoor uses on celery and therefore, that there is no need to change the current MRL value of 5 mg/kg set under Regulation (EC) No 396/2005. The intended indoor use on celery was not adequately supported by residue data and therefore no MRL proposal could be made to accommodate the intended indoor use. Adequate analytical enforcement methods are available to control the residues of cyprodinil in celery. Based on the risk assessment results, EFSA concludes that the proposed use of cyprodinil on celery will not result in a consumer exposure exceeding the toxicological reference values and therefore is unlikely to pose a consumer health risk. [ABSTRACT FROM AUTHOR]

Abstract: Novel compounds 12a–i were synthesized and biologically evaluated. Several ones exhibited stronger inhibitory activity than gefitinib against EGFR L858R/T790M and antiproliferative effects on H1975 and HCC827 cells. The 3-aminopropamide in compounds like 12h could be converted to the active acrylamide in the presence of arginine. Importantly, 12h showed improved stability relative to compound 1 whose structure is same to 12h excepting an acrylamide moiety. Interestingly, 12i, a NO donating compound of 12h, showed more potent and selective inhibition than 12h on H1975 cells. Significantly, 12i produced high levels of NO in H1975 cells but not in non-tumorous 16HBE cells, and its inhibition was diminished by NO scavenger. Furthermore, 12i dose-dependently produced inhibitory effects on EGFR downstream signaling in H1975 cells. [Copyright &y& Elsevier]

According to Article 12 of Regulation (EC) No 396/2005, the European Food Safety Authority (EFSA) has reviewed the Maximum Residue Levels (MRLs) currently established at European level for the pesticide active substance cyprodinil. In order to assess the occurrence of cyprodinil residues in plants, processed commodities, rotational crops and livestock, EFSA considered the conclusions derived in the framework of Directive 91/414/EEC, the MRLs established by the Codex Alimentarius Commission as well as the European authorisations reported by Member States (incl. the supporting residues data). Based on the assessment of the available data, MRL proposals were derived and a consumer risk assessment was carried out. Although no apparent risk to consumers was identified, some information required by the regulatory framework was found to be missing. Hence, the consumer risk assessment is considered indicative only and some MRL proposals derived by EFSA still require further consideration by risk managers. [ABSTRACT FROM AUTHOR]

Abstract: To search for potent nitric oxide (NO) donating epidermal growth factor receptor (EGFR) inhibitors, a series of phenylsulfonylfuroxan-based anilinopyrimidines 10a–h were synthesized and biologically evaluated. Compounds 10f–h exhibited potent inhibitory activity against EGFR L858R/T790M and were as potent as WZ4002 in inhibition of H1975 cells harboring EGFR L858R/T790M. Additionally, 10h produced high levels of NO in H1975 cells but not in normal human cells, and its antiproliferative activity was diminished by hemoglobin, an NO scavenger. Furthermore, 10h inhibited EGFR activation and downstream signaling in H1975 cells. These results suggest that the strong antiproliferative activity of 10h could be attributed to the synergic effects of high levels of NO production and inhibition of EGFR and downstream signaling in the cancer cells. [Copyright &y& Elsevier]

Abstract: 2-Anilino-4-(benzimidazol-2-yl)-pyrimidines, synthesized by reaction of a readily available benzimidazole-substituted enaminone with suitable arylguanidines, were shown to inhibit four cancer-related protein kinases (Aurora B, PLK1, FAK, and VEGF-R2). The most potent derivative exhibited antiproliferative activity for several cancer cell lines of the NCI in vitro cell line panel in submicromolar concentrations. Both the anilinopyrimidine structure and the substitution pattern at the aniline ring appear to be important for the protein kinase inhibitory activity. [Copyright &y& Elsevier]

Early blight, caused by Alternaria solani, and brown leaf spot, caused by a number of small-spored Alternaria spp. including Alternaria alternata sensu stricto , Alternaria arborescens, and Alternaria tenuissima, are observed annually in all midwestern potato production areas. However, Alternaria spp. have developed reduced sensitivity and/or resistance to many single-site mode of action fungicides such as quinone outside inhibitor (QoI; FRAC group 11), succinate dehydrogenase inhibitor (SDHI; FRAC group 7), and anilinopyrimidine (AP; FRAC group 9). Mean in vitro sensitivity EC 50 values (effective concentration where fungal growth is inhibited by 50%) of A. alternata (n = 16) , A. arborescens (n = 3) , A. tenuissima (n = 5) , and A. solani (n = 58) in response to the AP fungicides pyrimethanil and cyprodinil and the phenylpyrrole (PP) fungicide fludioxonil were determined via mycelial growth assays. Significant fungicide by isolate interactions were observed for all Alternaria spp. evaluated in vitro, indicating reduced-sensitivity of some isolates to individual fungicides. EC 50 values for three non-baseline A. solani isolates collected in 2010, 2011 and 2013 were within the baseline for all three fungicides. A significant correlation was observed between pyrimethanil and cyprodinil EC 50 values among A. alternata isolates, but no relationship was observed with the other fungicides or in A. solani. In greenhouse evaluations, a significant loss of disease control was observed for some non-baseline A. solani isolates, and this was more pronounced in the AP fungicides, pyrimethanil and cyprodinil. No significant correlation was observed between in vitro EC 50 value and area under the dose response curve based on greenhouse assays, likely due to the limited number of isolates evaluated. Further research is needed to determine if these reductions affect control of early blight and brown leaf spot in potato under field conditions. Results from this study indicate that fludioxonil and cyprodinil are potentially good additions into fungicide rotation programs or as co-pack chemistries for control of leaf spot diseases and fungicide resistance management. • AP and PP fungicides remain effective on potato early blight/brown spot pathogens. • Cross-sensitivity between pyrimethanil and cyprodinil in baseline A. alternata. • Significant loss of disease control seen for some non-baseline A. solani isolates. • Fludioxonil and cyprodinil are good candidates for addition to a potato IPM program. [ABSTRACT FROM AUTHOR]

Among the diverse mechanisms involved in the pathophysiology of post-ischemic and post-traumatic injuries, excitotoxicity and nuclear factor-κB (NF-κB) activation through induction of IκB kinase (IKK) complex have a primary role. We investigated the effects of the selective inhibitor of the IKK2 subunit, the anilinopyrimidine derivative AS602868, on excitotoxic injury produced in rat organotypic hippocampal slices and cerebellar primary neurons. Brief exposure to N-methyl- d-aspartate (NMDA) induces astrocyte reactivity, neuron cell death and oligodendrocyte degeneration in hippocampal slices. Application of AS602868 elicited a long-lasting protection of both neurons and oligodendrocytes. Maximal effect was observed with prolonged application of the compound after NMDA exposure. Neuroprotection was also evident in primary cultures of cerebellar granule cells starting from 20 nM concentration. AS602868-elicited neuroprotection correlated with inhibition of NF-κB activity. Our results suggest that AS602868 may prove to be a valuable approach in treating neurodegeneration and demyelination associated with cerebral trauma and ischemia. [ABSTRACT FROM AUTHOR]

Penicillium expansum is the primary cause of blue mold, a major postharvest disease of apple. Fludioxonil and pyrimethanil are two newly registered postharvest fungicides for pome fruit in the United States. To evaluate the potential risk of resistance development in P. expansum to the new postharvest fungicides, one isolate of each of thiabendazole-resistant (TBZ-R) and -sensitive (TBZ-S) P. expansum was exposed to UV radiation to generate fungicide-resistant mutants. Four fludioxonil highly-resistant mutants (EC50 > 1,000 µg/ml) and four pyrimethanil-resistant mutants (EC50 > 10 µg/ml) were tested for sensitivities to thiabendazole, fludioxonil, and pyrimethanil, and fitness parameters including mycelial growth, sporulation on potato dextrose agar (PDA), sensitivity to osmotic stress, and pathogenicity and sporulation on apple fruit. The stability of resistance of the mutants was tested on PDA and apple fruit. Efficacy of the three fungicides to control blue mold incited by the mutants was evaluated on apple fruit. Six fungicide-resistant phenotypes were identified among the parental wild-type isolates and their mutants based upon their resistance levels. All four fludioxonil highly-resistant mutants were sensitive to pyrimethanil and retained the same phenotypes of resistance to TBZ as the parental isolates. All four pyrimethanil-resistant mutants had a low level of resistance to fludioxonil with a resistance factor >15. The two pyrimethanil-resistant mutants derived from a TBZ-S isolate became resistant to TBZ at 5 µg/ml. After 20 successive generations on PDA and four generations on apple fruit, the mutants retained the same phenotypes as the original generations. All mutants were pathogenic on apple fruit at both 0 and 20°C, but fludioxonil highly-resistant mutants were less virulent and produced fewer conidia on apple fruit than pyrimethanil-resistant mutants and their parental wild-type isolates. Compared with the parental isolates, all four fludioxonil highly-resistant mutants had an increased sensitivity to osmotic stress on PDA amended with NaCl, while the pyrimethanil-resistant mutants did not. Pyrimethanil was effective against blue mold caused by fludioxonil-resistant mutants at both 0 and 20°C. Pyrimethanil and fludioxonil reduced blue mold incited by pyrimethanil-resistant mutants during 12-week storage at 0°C but were not effective at 20°C. TBZ was not effective against pyrimethanil-resistant mutants derived from TBZ-S wild-type isolates at room temperature but provided some control at 0°C. The results indicate that: (i) a fitness cost was associated with fludioxonil highly resistant mutants of P. expansum in both saprophytic and pathogenic phases of the pathogen but not pyrimethanil-resistant mutants; (ii) pyrimethanil possessed a higher risk than fludioxonil in the development of resistance in P expansum; and (iii) triple resistance to the three apple-postharvest fungicides could emerge and become a practical problem if resistance to pyrimethanil develops in P. expansum populations. [ABSTRACT FROM AUTHOR]

To prolong the effective life of the newer, more active DeMethylation Inhibitor (DMI) fungicides, two-spray programmes were evaluated for their effectiveness in combining good control of rhynchosporium on winter barley with prevention of the build-up of DMI-resistant pathogen strains. Programmes were based on the DMI epoxiconazole alone or in combination or alternation with three partner fungicides with different modes of action, fenpropimorph (a morpholine), cyprodinil (an anilinopyrimidine), azoxystrobin (a QoI/strobilurin fungicide). In the majority of six field trials in Northern Ireland and South-west England (1998–2000), DMI sensitivity of Rhynchosporium secalis isolates was lower after fungicide treatment than before and the least sensitive isolates came from the plots treated with two half-rate applications of epoxiconazole alone. All fungicide programmes reduced disease compared with the untreated control. Epoxiconazole used alone gave the poorest disease control, but did increase the yield. The three partner fungicides all improved disease control and yield; two applications of half-rate epoxiconazole with half-rate azoxystrobin or cyprodinil performed best overall. With the range of pathogen sensitivities found in the present study, a DMI such as epoxiconazole remains a useful component of a control programme for R. secalis, but should be supplemented by a partner fungicide with a different mode of action such as a strobilurin or anilinopyrimidine. [Copyright &y& Elsevier]

A series of 2-anilinopyrimidines was prepared and their fungicidal activities against Botrytis cinerea Pers were examined. The activity fell sharply with any substitution on the anilinobenzene ring. Substitutions at the 5-position of the pyrimidine ring greatly reduced the activity. Substituents such as chloro, methoxy, methylamino, methyl or 1-propynyl were well tolerated at the 4- and 6-positions of the pyrimidine ring. Among these substituents, the combination of methyl and 1-propynyl groups was the most favourable. 2-Anilino-4-methyl-6-(1-propynyl)pyrimidine (KIF-3535), which showed excellent activity and no significant phytotoxicity, was finally selected for development and has been given the common name mepanipyrim. [ABSTRACT FROM AUTHOR]

Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines. [ABSTRACT FROM AUTHOR]

Background: The third-generation irreversible Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) inhibit the T790M mutation while sparing EGFRWT. However, the C797S point mutation confers resistance to existing irreversible EGFRT790M inhibitors., Objective: Novel EGFRT790M inhibitors were designed through hybridization of quinoline and anilinopyrimidine, and biologically evaluated their antiproliferative activity against Non-Small Cell Lung Cancer (NSCLC) cell lines., Methods: The target compounds 11a-h were synthesized and structurally characterized with 1H, 13C Nuclear Magnetic Resonance (NMR) spectroscopy and High-Resolution Mass Spectrometry (HRMS). Their inhibitory effects on tumor cell proliferation and EGFR kinase were biologically evaluated. Additionally, molecular docking studies were also performed on the representative typical EGFRT790M inhibitor., Results: Most of the evaluated compounds displayed moderate antiproliferative activity on H1975 cells with EGFRL858R/T790M. However, compound 11a (IC50 = 2.235 ± 0.565μM) showed stronger inhibition than gefitinib (IC50 = 8.830 ± 0.495μM) in concentration- and time-dependent manner. Moreover, compound 11a exhibited weaker inhibitory activities on cells with EGFRWT. Specifically, compound 11a strongly suppressed EGFRL858R/T790M (IC50 = 0.515 ± 0.011μM) relative to EGFRWT (IC50 = 0.913 ± 0.068μM). Furthermore, molecular docking studies demonstrated its strong binding contacts with the EGFRT790M enzyme through hydrogen bonds and other non-bonded interactions., Conclusion: Taken together, these results indicate that the hybrid of quinoline and anilinopyrimidine 11a, could be a potential inhibitor of EGFRT790M in NSCLC, which warrants further in-depth studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid analoguing of the designed molecules for structure-activity relationship (SAR) exploration. Some analogues displayed nanomolar potency against c-Met and VEGFR-2 at enzymatic level. Privileged compounds 3a, 3b, 3g, 3h, and 18a exhibited potent antiproliferative effect against c-Met addictive cell lines with IC50 values ranged from 0.33 to 1.7 μM. In addition, a cocrystal structure of c-Met in complex with 3h has been determined, which reveals the binding mode of c-Met to its inhibitor and helps to interpret the SAR of the analogues.