Abstract
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.
Highlights
The antifungal activity of the resulting compounds was evaluated in an in-house microdilution assay against the non-pathogenic yeast strain Yarrowia lipolytica (Supporting Information, Table S1)
A library of more than 30 novel 4-aminopiperidines was prepared by reductive amination of 4-piperidone derivatives with a broad variety of aliphatic amines
A screening on the model yeast Yarrowia lipolytica disclosed that compounds 2b and 3b are almost equipotent to established antifungals
Summary
The mechanism of action of these antifungals is inhibition of ergosterol biosynthesis These and related morpholines and piperidines inhibit, to various extents, the enzymes sterol C14-reductase and sterol C8isomerase of the post-squalene part of ergosterol biosynthesis [3,4]. Molecules 2021, 26, 7208 of these antifungals is inhibition of ergosterol biosynthesis These and related morpholines and piperidines inhibit, to various extents, the enzymes sterol C14-reductase and sterol. 1C), we merged essential fragments chemotypes evaluated the 4-aminopiperidine motif as aas core structure for novel antifungals. 1A), as1A), wellasaswell allylamine-type drugsdrugs (squalene epoxidase inhibitors) such fenpropidin, as allylamine-type as naftifine and terbinafine (Figure 1B) on the one side, and medium to long, linear or branched alkyl chains Should be possible by systematic modification of both N-substituents
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