Chiral N-benzyl-N-methyl-1-(naphthalen-1-yl)ethanamines and their in vitro antifungal activity against Cryptococcus neoformans, Trichophyton mentagrophytes and Trichophyton rubrum

Abstract

In the search for new antifungal compounds and to explore structure activity relationships, a series of 24 chiral benzyl amine type antifungals was synthesised and characterised. In vitro testing against the human pathogen Cryptococcus neoformans revealed that several derivatives had MIC50 values similar to that of the commercial drug Butenafine. All of these contained a bulky group in the para position of the benzyl fragment. Eighteen compounds were also tested for activity against the dermatophytes Trichophyton mentagrophytes and Trichophyton rubrum. Of these (R)-N-(4-tert-butylbenzyl)-N-methyl-1-(naphthalen-1-yl)ethanamine (MIC50: 0.06 μg/mL) and a para-benzyloxy substituted derivative (MIC50: 0.125 μg/mL) possessed high activity. Testing of derivatives with a stereocentre at the benzylic carbon, revealed that (S)-stereochemistry was required for potency: a MIC50 value of 1 μg/mL was obtained for (S)-1-(4-tert-butylphenyl)-N-methyl-N-(naphthalen-1-ylmethyl)ethanamine. Preparation of the corresponding fluoromethyl compound was achieved employing lipase B from Candida antarctica as catalyst in the key step. A low antifungal activity was observed for the fluorinated derivative indicating the importance of the amine basicity for the antifungal potency of these compounds.

Dynamic Kinetic Resolution-Enabled Highly Stereoselective Nucleophilic Fluoroalkylation to Access Chiral β-Fluoro Amines

“…A number of methods for accessing β-fluoro amines have been developed, including fluoroamination of alkenes, − nucleophilic fluorination of alcohols, , and ring opening with metal fluorides. − However, these methods cannot be applied for chiral β-fluoro amines, given the fact that the potential dangers of racemic drugs have been documented (Figure b). − In 2007, Shibata and Toru developed an elegant catalytic enantioselective fluoromethylation with in situ-generated aldimines and FBSM, to yield chiral β-fluoro amines . However, the reaction time was up to 2 days at −80 °C, and enaminalizable ketimines were not compatible (Figure c-i).…”

“…To obtain the monofluoromethylated free amine, 5a could undergo deprotection of the Bus group with AlCl 3 and reductive C–S bond cleavage with aluminum amalgam to yield free amine 9a in 63% yield and 98/2 er (Figure b). Free amines can allow different modifications and provide the possibility of accessing chiral amine derivatives, especially those bioactive molecules. − …”

Butenafine and analogues: An expeditious synthesis and cytotoxicity and antifungal activities

“…This value is within the MIC range found in other studies for both dermatophytes. Thvedt and colleagues evaluated the antifungal activity of chiral benzyl- N -methyl-1-(naphthalen-1-yl)ethanamines and determined MIC values that ranged from 0.125 µg/mL to >32 µg/mL against the yeast C. neoformans and the dermatophytes T. rubrum and T. mentagrophytes [63] .…”