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



Maria Digiacomo§, Stefania Sartini§, Giulia Nesi, Simona Sestito, Vito Coviello, Concettina La Motta*, Simona Rapposelli*
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy


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© Digiacomo et al.; Licensee Bentham Open

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to these authors at the Department of Pharmacy, University of Pisa via Bonanno, 6 56126 Pisa, Italy; Tel: (+) 390502219582, (+) 390502219593; E-mails: simona.rapposelli@unipi.it, concettina.lamotta@unipi.it


§ These authors equally contributed.


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.

Keywords: Aldose reductase enzyme, Diabetic complications, Spiromorpholinone derivatives, Aldose reductase inhibitors (ARI), Spiro-oxazolidinones, Spirobenzopyran derivatives, ARL2.