Synthesis and Improved Antifungal and Antiparasitic Activity of Novel Metallocene-containing Fluconazole
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ABSTRACT:
PROVIDER: PRJEB57349 | ENA |
REPOSITORIES: ENA
Dataset's files
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| ERR10658400.fastq.gz | Fastqsanger.gz | |||
| ERR10658401.fastq.gz | Fastqsanger.gz | |||
| ERR10658402.fastq.gz | Fastqsanger.gz | |||
| ERR10658403.fastq.gz | Fastqsanger.gz | |||
| ERR10658404.fastq.gz | Fastqsanger.gz |
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Project description:The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action.
| S-EPMC5803358 | biostudies-literature
Project description:Purpose: We compared the expression profile of three fluconazole resistant clinical isolates to two fluconazole sensitive clinical isolates, from the same patient, all containing mutation in the trancription factor Mrr1, to define the Mrr1 regulon in Candida lusitaniae.
2018-11-14 | GSE111421 | GEO
Project description:Design and synthesis of triazole library antifungal agents having piperazine side chains, analogues to fluconazole were documented. The synthesis highlighted utilization of the click chemistry on the basis of the active site of the cytochrome P450 14α-demethylase (CYP51). Their structures were characterized by (1)H-NMR, (13)C-NMR, MS and IR. The influences of piperazine moiety on in vitro antifungal activities of all the target compounds were evaluated against eight human pathogenic fungi.
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Project description:Transcriptional profiling of Candida albicans comparing fluconazole treated cells with fluconazole and osthole treated cells
2017-04-24 | GSE84936 | GEO
Project description:Purpose: Compare the fluconazole-induced transcriptome of isogenic wild-type and upc2A null cells. Methods: Prepare total RNA from wild-type and upc2A null cells grown under unstressed conditions or challenged with 50 microgram/ml fluconazole for 6 hours. Use standard RNA-seq to evaluate and compare the transcriptomic changes caused by fluconazole in the presence or absence of UPC2A. Results: These data established that over 100 genes were induced by fluconazole in a UPC2A-dependent manner. However, most fluconazole-induced genes (>500) did not require the presence of UPC2A. Fluconazole-induced genes included the expected genes involved in ergosterol biosynthesis but also large number of plasma membrane-localized transporters. Conclusions: These data suggest that Upc2A provided transcriptional co-regulation between membrane transporters and the lipid environment in which these proteins function. A significant portion of the fluconazole-induced transcriptome does not require the presence of Upc2A, suggesting the presence of other transcriptional circuits responsive to this pharmacologic block of ergosterol biosynthesis.
2021-09-23 | GSE182489 | GEO
Project description:BackgroundThe plant pathogenic fungus (such as Gibberella zeae, Fusarium oxysporum and Cytospora mandshurica) causes devastating disease in agriculture. The pathogenic fungus is responsible for billions of dollars in economic losses worldwide each year. In order to discover new fungicidal molecule with good fungicidal activity against G. zeae, F. oxysporum, and C. mandshurica, we sought to combine the active sub-structure of hydrazone and pyrazole amide derivatives together to design and synthesize novel pyrazole amide derivatives containing a hydrazone moiety.ResultsA series of novel pyrazole amide derivatives bearing hydrazone moiety were synthesized. Their structures were characterized by 1?H-NMR, 13?C-NMR, IR, and elemental analysis. The preliminary biological assays revealed that most of the synthesized compounds exhibit favorable antifungal activities against G. zeae. The activity of compounds 7a, 7f, 7g, 7h, 7i, 7j, 7l and 7q were 40.82%, 47.78%, 50.32%, 40.82%, 49.05%, 48.73%, 40.19% and 45.89%, respectively, and the synthesized compounds showed certain antifungal activities against F. oxysporum and C.mandshurica.ConclusionA practical synthetic route to pyrazole amide derivatives containing a hydrazone moiety were synthesized by the condensation of intermediates 5-chloro-N-(4-subsititued-2-(hydrazinecarbonyl)-6-methylphenyl)-1,3-dimethyl-1?H-pyrazole-4-carboxamide with different aldehydes or ketones in ethanol at room temperature is presented, the results of the study suggested that the pyrazole amide derivatives containing hydrazone moieties could inhibit the growth of G. zeae, F. oxysporium and C. mandshurica to a certain extent.
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Project description:Transcriptional profiling of Candida albicans comparing fluconazole treated cells with fluconazole- and berberine-treated cells, as well untreated cells with berberine treated cells
2013-11-14 | GSE43662 | GEO
Project description:BackgroundPlant fungi (e.g., Pellicularia sasakii, Gibberella zeae, Fusarium oxysporum, and Cytospora mandshurica and Phytophthora infestans) and bacteria (e.g., Ralstonia solanacearum) are extremely difficult to manage in agricultural production. The high incidence of plant mortality and the lack of effective control methods make P. sasakii and R. solanacearum two of the world's most destructive plant pathogens. Pathogenic fungi and bacteria are responsible for billions of dollars in economic losses worldwide each year. Thus, we designed an active amide structure and synthesized a series of novel amide derivatives containing a triazole moiety to discover new bioactive molecules and pesticides that can act against fungi and bacteria.ResultsA series of amide derivatives containing a triazole moiety were synthesized. All the obtained compounds were characterized through proton and carbon nuclear magnetic resonance spectroscopy, infrared spectroscopy, and elemental analysis. Preliminary antifungal activity test showed that some of the synthesized compounds exhibited moderate antifungal activity against P. sasakii, G. azeae, F. oxysporum, C. mandshurica, and P. infestans at 50 mg/L. Compound 4u displayed more potent antifungal activity against P. sasakii and G. azeae than hymexazol. Preliminary antibacterial activity results showed that some of the synthesized compounds exhibited high anti-bacterial activity against R. solanacearum at 200 mg/L. Compounds 4m and 4q displayed high antibacterial activity against R. solanacearum, with 71% and 65% inhibitory rates, respectively.ConclusionsA series of novel amide derivatives containing 1,2,4-triazole moiety were synthesized through the reaction of intermediate 3 with different acyl chlorides and anhydrous potassium carbonates in anhydrous tetrahydrofuran at 50°C, using 2,4-dichloroacetophenoneas as a starting material. The title compounds exhibited high inhibitory effects against P. sasakii, R. solanacearum, and G. azeae.
| S-EPMC3598687 | biostudies-literature
Project description:Twenty 1,4-pentadiene-3-one derivatives containing quinazolinone (W1-W20) were designed and synthesized. The bioactivity test results showed that some compounds had antifungal activities in vitro. W12 showed excellent bioactivity against Sclerotinia sclerotiorum (S. sclerotiorum) and Phomopsis sp., with EC50 values of 0.70 and 3.84 μg/mL, which are higher than those of the control drug azoxystrobin at 8.15 and 17.25 μg/mL. In vivo activity tests were carried out on oilseed rape and kiwifruit. The protective effect of W12 on oilseed rape infected with S. sclerotiorum (91.7 and 87.3%) was better than that of azoxystrobin (90.2 and 79.8%) at 100 and 50 μg/mL, respectively, and the protective effect on kiwifruit infected with Phomopsis sp. (96.2%) was better than that of azoxystrobin (94.6%) at 200 μg/mL. Scanning electron microscopy results showed the hyphae of S. sclerotiorum treated with compound W12 abnormally collapsed and shriveled, inhibiting the growth of mycelium and, thus, laying the inhibiting effect on S. sclerotiorum. The results of the mechanism research showed that the action of W12 changed the mycelial morphology of S. sclerotiorum, affected the permeability of cells, increased the leakage of cytoplasm and allowed the cell membrane to break down. This study shows that 1,4-pentadiene-3-one derivatives containing quinazolinone have good effects on plant fungi and the potential for becoming new fungicides.
| S-EPMC9916701 | biostudies-literature
Project description:In Candida albicans, the transcription factor Upc2 is central to the regulation of ergosterol biosynthesis. UPC2-activating mutations contribute to azole resistance, whereas disruption increases azole susceptibility. In the present study, we investigated the relationship of UPC2 to fluconazole susceptibility, particularly in azole-resistant strains. In addition to the reduced fluconazole MIC previously observed with UPC2 disruption, we observed a lower minimum fungicidal concentration (MFC) for a upc2Δ/Δ mutant than for its azole-susceptible parent, SC5314. Moreover, the upc2Δ/Δ mutant was unable to grow on a solid medium containing 10 µg/ml fluconazole and exhibited increased susceptibility and a clear zone of inhibition by Etest. Time-kill analysis showed higher fungistatic activity against the upc2Δ/Δ mutant than against SC5314. UPC2 disruption in strains carrying specific resistance mutations also resulted in reduced MICs and MFCs. UPC2 disruption in a highly azole resistant clinical isolate containing multiple resistance mechanisms likewise resulted in a reduced MIC and MFC. This mutant was unable to grow on a solid medium containing 10 µg/ml fluconazole and exhibited increased susceptibility and a clear zone of inhibition by Etest. Time-kill analysis showed increased fungistatic activity against the upc2Δ/Δ mutant in the resistant background. Microarray analysis showed attenuated induction by fluconazole of genes involved in sterol biosynthesis, iron transport, or iron homeostasis in the absence of UPC2. Taken together, these data demonstrate that the UPC2 transcriptional network is universally essential for azole resistance in C. albicans and represents an attractive target for enhancing azole antifungal activity.
2014-05-24 | GSE57929 | GEO