Synthesis and Functional Evaluation of Novel Aldose Reductase Inhibitors Bearing a Spirobenzopyran Scaffold

Abstract

Background:Aldose reductase, the first enzyme of the polyol pathway, is the key determinant for the pathogenesis of long term diabetic complications. Accordingly, its inhibition represents the major therapeutic strategy to treat this kind of pathologies. Objectives:In this work we describe the synthesis and the functional evaluation of a number of spiro-oxazolidinone and spiro-morpholinone acetic acid derivatives, and their benzyloxy analogs, developed as aldose reductase inhibitors. Results:Most of them proved to inhibit the target enzyme, showing IC50 values in the micromolar/low micromolar range. SARs observed among the three different series allowed to highlight their key pharmacophoric elements, thus creating sound basis for the design of novel and more effective inhibitors. Conclusion: Although further substitution patterns are needed, the novel compounds here proposed represent a good starting point for the development of novel and effective ARIs.

Oxazolidinones as versatile scaffolds in medicinal chemistry

“…20 ) was shown to be less active against the enzyme (IC 50 3.19 μM), highlighting the importance of the spiro-oxazolidinone moiety. 166 Together, these results highlight the potential of oxazolidinones in the discovery of drugs for the treatment of metabolic syndromes.…”

Assessing the Phytochemical Profile and Potential of Traditional Herbal Infusions against Aldose Reductase through In Silico Studies and LC-MS/MS Analysis

“…As a result, AR represents an attractive therapeutic target for the prevention of and reduction in the effects of diabetic complications. Many studies have been performed targeting the discovery of novel molecules as potential AR inhibitors [48][49][50]. The already known synthetic AR inhibitors, such as sorbinil and tolrestat, suffer from drawbacks due to their poor permeation and safety concerns [46].…”

Biocatalytic Construction of Spiro-Oxazolidinones via Halohydrin Dehalogenase-Catalyzed Ring Expansion of Spiro-Epoxides

“…Oxazolidinones are an important class of five-membered heterocyclic compounds with diverse applications in organic synthesis. − Additionally, they hold great importance in the field of medicinal chemistry because of their ability to exhibit a broad spectrum of biological activities. − An excellent example is the antibacterial agent linezolid, which is used to treat infections caused by susceptible Gram-positive bacteria. , In the past decades, spirocyclic scaffolds have gained significant attention and have found widespread applications in the fields of pharmaceutical and natural product. − In particular, spiro-oxazolidinones possess a distinct combination of spirocyclic and oxazolidinone motifs, which confer unique properties to these compounds and open up new avenues for drug design and development. As shown in Scheme , spiro-oxazolidinones have demonstrated a wide range of biological activities, including anticancer, anti-inflammatory, antiviral, antithrombosis, and antidiabetic complications. − Fenspiride, for example, possesses selective β2-adrenergic receptor agonist activity and is used to treat respiratory conditions …”