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.
Highlights
Diabetes mellitus (DM) is one of the most common chronic metabolic disorders, characterized by elevated levels of blood glucose
With the aim to extend the structure-activity relationship (SAR) study of this class of compounds, we describe the synthesis of new molecules, 3-13, in which a series of structural modifications have been performed as following reported: (a) replacement of the spirooxazolidine ring in the core structure of 1 and 2 with a spiromorpholone or with a spiromorpholine nucleus; (b) replacement of the phenyl ring in the 2-position of the benzopyran scaffold with small lipophilic groups such as the methyl ones and (c) change in the conformational freedom of spirooxazolidine derivatives 1 and 2 through the cleavage of the C2-C3 bond within the benzopyran core
We described the design, synthesis and biological evaluation of three small series of spirooxazolidinone, spiromorpholinone and benzyloxy acetic acid derivatives, proposed as novel ALR2 inhibitors
Summary
Diabetes mellitus (DM) is one of the most common chronic metabolic disorders, characterized by elevated levels of blood glucose (hyperglycemia). The DM etiopathology is very complex and is closely related to the onset of chronic complications such as neuropathy, nephropathy, cataracts, retinopathy, accelerated atherosclerosis, and increased cardiovascular risk [2]. An impairment of cellular defense against oxidative injury occurs, leading to the onset of both micro- and macrovascular complications such as retinopathy, peripheral vascular disease and coronary artery disease These events are frequently found in DM and are well known as “complications of secondary diabetes”. Many studies demonstrated an ALR2-dependent increase of ROS levels in cells cultured under high glucose conditions, confirming the leading role of this enzyme in the pathogenesis of many diabetic complications [4]. The first enzyme of the polyol pathway, is the key determinant for the pathogenesis of long term diabetic complications. Its inhibition represents the major therapeutic strategy to treat this kind of pathologies
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