The Preparation of Novel Fluorenes Inspired by Hipposudoric Acid

Abstract

ABSTRACT The growing challenge of antimicrobial resistance has intensified the need for new antimicrobial therapeutics. Hipposudoric acid and norhipposudoric acid, pigments isolated from the skin secretions of Hippopotamus amphibius , are predicted to exhibit antimicrobial activity, but are limited by intrinsic chemical instability and synthetically demanding access. Herein, we report on the design and synthesis of a series of fluorene‐based derivatives loosely inspired by the tricyclic framework of the natural products. Preparation of sixteen novel N‐alkylated derivatives was accomplished via a series of concise one‐step amide N‐alkylation reactions. Reaction outcome was noted to be strongly dependent on electronic activation and steric accessibility of the alkyl halide electrophiles, with adjacent electron‐withdrawing groups significantly enhancing the efficiency of the N‐alkylation reaction. All synthesized compounds exhibited excellent short‐term stability under both solution‐phase and solid‐state storage conditions. Furthermore, in silico ADME evaluation predicted that the entire library complies with Lipinski's rule of five and possesses favorable predicted drug‐like properties, including acceptable predicted gastrointestinal absorption and membrane permeability profiles.