Special Issue: Treatments for Fungal Infections

Segal, Esther; Elad, D.

doi:10.3390/jof4040135

Cited by 9 publications

(9 citation statements)

References 15 publications

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“…These and related morpholines and piperidines inhibit, to various extents, the enzymes sterol C14-reductase and sterol C8-isomerase of the post-squalene part of ergosterol biosynthesis [3,4]. At physiological pH protonated, the core element for this enzyme inhibition is the morpholine/piperidine ring, which can imitate the carbocationic high-energy intermediates (HEIs) of the conversions catalysed by these two enzymes [5][6][7][8]. [9] and (II) [10] from our previous work; (D) approved azoles: voriconazole, posaconazole.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Structure–Activity Relationships of 4-Aminopiperidines as Novel Antifungal Agents Targeting Ergosterol Biosynthesis

et al. 2021

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The aliphatic heterocycles piperidine and morpholine are core structures of well-known antifungals such as fenpropidin and fenpropimorph, commonly used as agrofungicides, and the related morpholine amorolfine is approved for the treatment of dermal mycoses in humans. Inspired by these lead structures, we describe here the synthesis and biological evaluation of 4-aminopiperidines as a novel chemotype of antifungals with remarkable antifungal activity. A library of more than 30 4-aminopiperidines was synthesized, starting from N-substituted 4-piperidone derivatives by reductive amination with appropriate amines using sodium triacetoxyborohydride. Antifungal activity was determined on the model strain Yarrowia lipolytica, and some compounds showed interesting growth-inhibiting activity. These compounds were tested on 20 clinically relevant fungal isolates (Aspergillus spp., Candida spp., Mucormycetes) by standardized microbroth dilution assays. Two of the six compounds, 1-benzyl-N-dodecylpiperidin-4-amine and N-dodecyl-1-phenethylpiperidin-4-amine, were identified as promising candidates for further development based on their in vitro antifungal activity against Candida spp. and Aspergillus spp. Antifungal activity was determined for 18 Aspergillus spp. and 19 Candida spp., and their impact on ergosterol and cholesterol biosynthesis was determined. Toxicity was determined on HL-60, HUVEC, and MCF10A cells, and in the alternative in vivo model Galleria mellonella. Analysis of sterol patterns after incubation gave valuable insights into the putative molecular mechanism of action, indicating inhibition of the enzymes sterol C14-reductase and sterol C8-isomerase in fungal ergosterol biosynthesis.

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Section: Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Structure–Activity Relationships of 4-Aminopiperidines as Novel Antifungal Agents Targeting Ergosterol Biosynthesis

et al. 2021

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“…The hemolytic activity of select peptoids was determined as done previously. , Selected peptoids were prepared in twofold serial dilutions in PBS at the desired concentrations. hRBCs (9 mL) were centrifuged at 1000 rpm for 10 min, and the supernatant was removed and discarded.…”

Section: Methodsmentioning

confidence: 99%

“…5,6 Fungi are eukaryotes; therefore, agents that are active against fungal cells tend also to be active against host cells. 7 Antifungal agents such as fluconazole, flucytosine, and amphotericin B (AmpB) are currently available to treat fungal infections caused by C. neoformans, and while these can be potent against fungal infections, they are known to have worrisome mammalian cytotoxicity, with up to 50% of recipients experiencing acute renal failure when treated with AmpB. 8,9 Due to the high mammalian toxicity of AmpB, it is only administered in cases of severe systemic infections such as CM.…”

Section: ■ Introductionmentioning

confidence: 99%

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Synthesis and Characterization of Derivatives of the Antifungal Peptoid RMG8-8

2022

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Cryptococcal meningitis, caused by the fungal pathogen Cryptococcus neoformans, is a devastating disease with a mortality rate of over 80%. Due to the increasing prevalence of resistance to antifungals and the high mammalian toxicity of current treatments, the development of new antifungal therapies is vital. In an effort to improve the biological properties of a previously discovered antifungal peptoid, termed RMG8-8, an iterative structure–activity relationship study was conducted. This three-round study sought to optimize the structure of RMG8-8 by focusing on three main structural components: the lipophilic tail, aliphatic side chains, and aromatic side chains. In addition to antifungal testing against C. neoformans, cytotoxicity testing was also performed on all derivatives against human liver cells, and select promising compounds were tested for hemolytic activity against human red blood cells. A number of derivatives containing unique aliphatic or aromatic side chains had antifungal activity similar to RMG8-8 (MIC = 1.56 μg/mL), but all of these compounds were more toxic than RMG8-8. While no derivative was improved across all biological tests, modest improvements were made to the hemolytic activity with compound 9, containing isobutyl side chains in positions 2 and 5, compared to RMG8-8 (HC10 = 130 and 75 μg/mL, respectively). While this study did not yield a dramatically optimized RMG8-8 derivative, this result was not totally unexpected given the remarkable selectivity of this compound from discovery. Nonetheless, this study is an important step in the development of RMG8-8 as a viable antifungal therapeutic.

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“…Conventional antifungal treatment is based on polyene agents, flucitosine and azole agents, or more recently, on virulence factor inhibitors and immunomodulators. This has led to the production of new and improved azoles and polyene formulations, as well as a new family of drugs, the echinocandins [ 46 ].…”

Section: Selected Centaureinae (Asteraceae) Plant Materials In Phymentioning

confidence: 99%

Phytotherapy Perspectives for Treating Fungal Infections, Migraine, Sebhorreic Dermatitis and Hyperpigmentations with the Plants of the Centaureinae Subtribe (Asteraceae)

2020

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Sesquiterpene lactones, coumarins, phytoecdysones and phenolic compounds are characteristic of the species from the subtribe Centaureinae (Asteraceae). Many of the compounds isolated from plants of the Centaureinae subtribe have strong pharmacological properties. It may be suggested that these compounds’ chemical structure might be an indicator of these pharmacological properties. The aim of the study was to describe recent studies in the field of phytotherapy, focusing on compounds isolated from chosen plants of Centaureinae and the possibilities of using them to treat antifungal infections, inhibit serotonin and ease symptoms of seborrhea dermatitis and hyperpigmentation. The results of these biological studies have shown that in the future, extracts from the above-mentioned plant material may be used as active substances in new safe and effective drugs.

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Special Issue: Treatments for Fungal Infections

Abstract: Antifungal therapy is complicated compared to antibacterial treatments by the fact that fungi and their hosts are both eukaryotic organisms, resulting in fewer targets for selective activity. [...]

Cited by 9 publications

References 15 publications

Synthesis, Biological Evaluation, and Structure–Activity Relationships of 4-Aminopiperidines as Novel Antifungal Agents Targeting Ergosterol Biosynthesis

Synthesis, Biological Evaluation, and Structure–Activity Relationships of 4-Aminopiperidines as Novel Antifungal Agents Targeting Ergosterol Biosynthesis

Synthesis and Characterization of Derivatives of the Antifungal Peptoid RMG8-8

Phytotherapy Perspectives for Treating Fungal Infections, Migraine, Sebhorreic Dermatitis and Hyperpigmentations with the Plants of the Centaureinae Subtribe (Asteraceae)

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