Synthesis, Activity, and Molecular Modeling of a New Series of Tricyclic Pyridazinones as Selective Aldose Reductase Inhibitors

• DOI: 10.1021/jm960124f
• Publication Date: 2002-07-26T06:00:31Z
• Authors: Luca Costantino; Giulio Rastelli; Katia Vescovini; Giorgio Cignarella; Paola Vianello; Antonella Del Corso; Mario Cappiello; Umberto Mura; Daniela Barlocco
• Keywords: Aldehyde Reductase; Tricyclic; Sorbitol dehydrogenase; Molecular model

Three new series of tricyclic pyridazinones have been synthesized and tested in vitro order to assess (i) their ability inhibit aldose reductase enzyme (ALR2) (ii) specificity toward the target with respect other related oxidoreductases, such as aldehyde reductase, sorbitol dehydrogenase, glutathione reductase. The inhibitory capability most effective compounds (IC50 values ranging from 6.44 12.6 microM) appears be associated a rather significant for ALR2. Molecular mechanics molecular dynamic calculations performed on ALR2-inhibitor complex give indications specific interaction sites responsible binding, thus providing information design inhibitors improved affinity enzyme.