An Investigation of 5-Halogenated N-Indolylsulfonyl-2-fluorophenol Derivatives as Aldose Reductase Inhibitors

Diabetes mellitus is a group of chronic metabolic disorders characterized by persistent hyperglycemia. Aldose reductase, the first enzyme in the polyol pathway, plays a key role in the onset of long-term diabetic complications. Aldose reductase inhibition has been widely established as a potential pharmacotherapeutic approach to prevent and treat diabetes mellitus-related comorbidities. Although several promising aldose reductase inhibitors have been developed over the past few decades, they have failed in clinical trials due to unacceptable pharmacokinetic properties and severe side effects. This paper describes the design, synthesis, and pharmacological evaluation of four novel 5-halogenated N-indolylsulfonyl-2-fluorophenol derivatives (3a-d) as aldose reductase inhibitors.

The design of compounds was based on a previously published lead compound (IIc) developed by our research group to enhance its inhibitory capacity. Compounds 3a-d were screened for their ability to inhibit in vitro partially purified aldose reductase from rat lenses, and their binding modes were investigated through molecular docking.

The presence of a sulfonyl linker between indole and o-fluorophenol aromatic rings is mandatory for potent aldose reductase inhibition. The 5-substitution of the indole core with halogens resulted in a slight decrease in the inhibitory power of 3a-c compared to IIc. Among halogens, bromine was the most capable of filling the selectivity pocket through hydrophobic interactions with Thr113 and Phe115 residues.

Although our strategy to optimize the inhibitory potency of IIc via inserting halogen atoms in the indole scaffold was not fruitful, aromatic ring halogenation can be still utilized as a promising approach for designing more potent aldose reductase inhibitors.