Arylpiperidines as a new class of oxidosqualene cyclase inhibitors

Keller, Marco; Wolfgardt, Annette; Müller, Christoph; Wilcken, Rainer; Böckler, Frank; Oliaro‐Bosso, Simonetta; Ferrante, Terenzio; Balliano, Gianni; Bracher, Franz

doi:10.1016/j.ejmech.2015.12.025

Cited by 10 publications

(5 citation statements)

References 48 publications

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“…The compound was prepared according to general procedure 1 from 610 mg (3.0 mmol) 1-(2-phenylethyl)-4-piperidone, 610 mg (4.5 mmol) 1-(S)-cyclohexylethylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 797 mg (85%) of 3e as a pale yellow oil. 1 (20), 180 (85), 166 (19), 160 (45), 105 (38), 98 (48), 96 (100), 70 (82). HRMS (EI) calcd.…”

Section: N-(4-(tert-butyl)benzyl)-1-phenethylpiperidin-4-amine (3c)mentioning

confidence: 99%

“…In continuation of our research on the development of antifungals starting from simple aliphatic amines such as benzylamines, (partly) hydrogenated quinolines, and isoquinolines [9,10,17,18] (Figure 1C), we merged essential fragments from these chemotypes and evaluated the 4-aminopiperidine motif as a core structure for novel antifungals. The introduction of a second protonable nitrogen into a sterol biosynthesis inhibitor designed to imitate a carbocationic HEI had shown great benefit in our recent investigations on oxidosqualene cyclase inhibitors [19]. The nature of the residues at both nitrogen atoms of the 4-aminopiperidine core structure was inspired by arylalkylamines (e.g., fenpropidin, Figure 1A), as well as allylamine-type drugs (squalene epoxidase inhibitors) (B) approved allylamines: naftifine, terbinafine; (C) antifungal compounds (I) [9] and (II) [10] from our previous work; (D) approved azoles: voriconazole, posaconazole.…”

Section: Introductionmentioning

confidence: 99%

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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: N-(4-(tert-butyl)benzyl)-1-phenethylpiperidin-4-amine (3c)mentioning

confidence: 99%

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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“…While we understand that 3-fold selectivity is not large and distant from the goal, it can be a clue to acquire highly T. cruzi OSC-selective inhibitors. We should point out that a compound with a similar structure but lacking the dimethylamine moiety of 3 or 4 (compound 29 in ref ) was effective to human OSC but not to T. cruzi OSC.…”

Section: Resultsmentioning

confidence: 99%

NMR Biochemical Assay for Oxidosqualene Cyclase: Evaluation of Inhibitor Activities on Trypanosoma cruzi and Human Enzymes

et al. 2018

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Oxidosqualene cyclase (OSC), a membrane-associated protein, is a key enzyme of sterol biosynthesis. Here we report a novel assay for OSC, involving reaction in aqueous solution, NMR quantification in organic solvent, and factor analysis of spectra. We evaluated one known and three novel inhibitors on OSC of Trypanosoma cruzi, a parasite causative of Chagas disease, and compared their effects on human OSC for selectivity. Among them, one novel inhibitor showed a significant parasiticidal activity.

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“…2,3-Oxidosqualene (OS) and [ 14 C]-(3S)-2,3-oxidosqualene were prepared as previously described [22]. )formamido]-4-methyl-4-aza-5α-androstan-3-one} (Fig.…”

Section: Chemicalsmentioning

confidence: 99%

“…CHILD, Congenital hemidysplasia with ichthyosiform erythroderma and limb defects; DHT, dihydrotestosterone; E1, estrone; E2, estradiol; Erg27p, yeast 3-ketosteroid reductase; ERG27, gene encoding yeast 3-ketosteroid reductase; 17β-HSDs, 17β-hydroxysteroid dehydrogenases; HSD17B1, 17β-hydroxysteroid dehydrogenase type 1; HSD17B7, 17βhydroxysteroid dehydrogenase type 7; 4-MZs, 4-methylzymosterone; 4-MFs, 4-methylfecosterone; Zs, zymosterone NSDHL, NADH sterol dehydrogenase-like; OS, 2,3-oxidosqualene; OSC, oxidosqualene cyclase; P, progesterone; SC4MOL, sterol C-4 methyl oxidase-like; SRD, short-chain dehydrogenase/reductase22 …”

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confidence: 99%

Multiple catalytic activities of human 17β-hydroxysteroid dehydrogenase type 7 respond differently to inhibitors

et al. 2020

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Arylpiperidines as a new class of oxidosqualene cyclase inhibitors

Cited by 10 publications

References 48 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

NMR Biochemical Assay for Oxidosqualene Cyclase: Evaluation of Inhibitor Activities on Trypanosoma cruzi and Human Enzymes

Multiple catalytic activities of human 17β-hydroxysteroid dehydrogenase type 7 respond differently to inhibitors

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