Effects of Chirality on the Antifungal Potency of Methylated Succinimides Obtained by Aspergillus fumigatus Biotransformations. Comparison with Racemic Ones

Abstract

Eighteen (3R) and (3R,4R)-N-phenyl-, N-phenylalkyl and N-arylsuccinimides were prepared with high enantioselectivity by biotransformation of maleimides with A. fumigatus. This environmentally friendly, clean and economical procedure was performed by the whole-cell fungal bioconversion methodology. Their corresponding eighteen racemic succinimides were prepared instead by synthetic methods. Both, the racemic and the chiral succinimides were tested simultaneously by the microbroth dilution method of CLSI against a panel of human opportunistic pathogenic fungi of clinical importance. Chiral succinimides showed higher antifungal activity than the corresponding racemic ones and the differences in activity were established by statistical methods. The bottlenecks for developing chiral drugs are how to obtain them through a low-cost procedure and with high enantiomeric excess. Results presented here accomplish both these objectives, opening an avenue for the development of asymmetric succinimides as new antifungal drugs for pharmaceutical use.

Identification and Characterization of a Welwitindolinone Alkaloid Biosynthetic Gene Cluster in the Stigonematalean Cyanobacterium Hapalosiphon welwitschii

“…Herein, we address these issues by studying the electrochemical reduction of five maleimide derivatives 1 a–e . The corresponding succinimides of the methylated derivatives ( 1 d and 1 e ) are particularly interesting because they are reported to have antifungal activity against human opportunistic pathogenic fungi, including yeasts and dermatophytes 11…”

Chemo‐ and Diastereoselectivities in the Electrochemical Reduction of Maleimides

“…The corresponding succinimides of the methylated derivatives ( 1 d and 1 e ) are particularly interesting because they are reported to have antifungal activity against human opportunistic pathogenic fungi, including yeasts and dermatophytes. [ 11 ]…”

Solid‐Phase Conversion of Four Stereoisomers into a Single Enantiomer

“…They are structurally closely related to phensuximide (imide 4 ), a drug used to treat epilepsy . Related methylated succinimides are known for their antifungal activity, of which the enantiopure ( R , R )‐configured succinimides are the most effective ones . Obtaining such succinimides in enantiopure form is therefore highly relevant.…”