Synthesis and Biological Evaluation of 2′‐Oxo‐2,3‐dihydro‐3′H‐ spiro[chromene‐4,5′‐[1,3]oxazolidin]‐3′yl]acetic Acid Derivatives as Aldose Reductase Inhibitors

Abstract

Aldose reductase (ARL2) is the first enzyme in the polyol pathway which catalyzes the NADPH-dependent reduction of glucose to sorbitol. Its involvement on diabetic complications makes this enzyme a challenge therapeutic target widely investigated to limit and/or prevent them. On this basis, a limited series of 4-spiro-oxazolidinone-benzopyran derivatives (1-7) were synthesized to evaluate them as potential ARL2 inhibitors. The activity was determined spectrophotometrically by monitoring the oxidation of NADPH catalyzed by ALR2. Within the series of compounds, the 4-methoxy derivative 1b showed to be the most active compound, exhibiting inhibitory levels in the submicromolar range. In addition, the activity against the aldehyde reductase isoform (ARL1) was also evaluated. Unlike sorbinil (reference drug) that lack of selectivity towards the two enzyme all the tested compounds resulted to be devoid of ARL1 inhibitory activity (IC(50) > 10 µM), thus proving to be selective.

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

“…Briefly, the reaction of aminoalcohols 14 , 15 [12] and chloroacetyl chloride in a heterogeneous phase yielded the chloroacetamides 16 , 17 which were submitted to a base-catalized ( t- BuOK) cyclization to afford the spiromorpholone derivatives 18 , 19 . The subsequent reaction of 18 , 19 with ethyl bromoacetate and NaH in DMF gave the corresponding esters, which were then cleaved in high yields to the carboxylic acids 3 and 4 , respectively.…”

“…Recently, we developed a new class of small molecules bearing a benzopyran scaffold that displayed inhibitory activity against ARL2, with a high degree of selectivity when compared to the effects induced against ARL1 [12]. …”

“…Moving from our previously developed spirochromanes 1 and 2 [12], and through suitable chemical manipulation of both their substitution pattern and their main heterocyclic structure, we succeeded in obtaining a novel set of analogues which proved to inhibit the target enzyme showing IC 50 values in the micromolar/low micromole range.…”

“…A solution of NaOH (0.19 g, 4.75 mmol) in H 2 O (8.5 mL) was added to a solution appropriate amine 14-15 (4.00 mmol) [12] in CH 2 Cl 2 (12 mL). The mixture was stirred, cooled to 0° C and treated dropwise with chloroacetyl chloride (0.73 g, 6.5 mmol).…”

“…2 ), as effective ARIs [12]. The previously synthesized ALR2 inhibitors possessed IC 50 values in the submicromolar range and a good selectivity against the target enzyme.…”