Synthesis of Novel Fluorinated Febrifugine Analogs and Evaluation of Their Antifungal Activity

Described herein are the design, synthesis, and preliminary antimicrobial evaluations of fluorinated pyrrolidine analogs of the potent antiparasitic agents: febrifugine and halofuginone. Molecular modeling is used to confirm that this "isosteric" replacement of a 3-hydroxy with a 3-fluoro group might be well tolerated at the most widely reported molecular target of this compound class, prolyl-tRNA synthetase. The synthesis of the fluorinated analogs is then detailed including the separate preparation of both the trans-2,3- and cis-2,3-diastereomeric forms. These synthetic compounds are subsequently assessed for their ability to inhibit the growth of pathogenic fungi (C. albicans and F. graminearum) and representative Gram-positive and Gram-negative bacteria (Bacillus sp. CS93 and E. coli). Notably, the 3-fluoro halofuginone analog has anti-C. albicans activity at levels comparable to the natural product iturin A.