Novel substituted N-benzyl(oxotriazinoindole) inhibitors of aldose reductase exploiting ALR2 unoccupied interactive pocket

Abstract

Recently we have developed novel oxotriazinoindole inhibitors (OTIs) of aldose reductase (ALR2), characterized by high efficacy and selectivity. Herein we describe novel OTI derivatives design of which is based on implementation of additional intermolecular interactions within an unoccupied pocket of the ALR2 enzyme. Four novel derivatives, OTI-(7-10), of the previously developed N-benzyl(oxotriazinoindole) inhibitor OTI-6 were synthetized and screened. All of them revealed 2 to 6 times higher ALR2 inhibitory efficacy when compared to their non-substituted lead compound OTI-6. Moreover, the most efficient ALR2 inhibitor OTI-7 (IC50 = 76 nM) possesses remarkably high inhibition selectivity (SF ≥ 1300) in relation to structurally related aldehyde reductase (ALR1). Derivatives OTI-(8-10) bearing the substituents -CONH2, -COOH and -CH2OH, possess 2-3 times lower inhibitory efficacy compared to OTI-7, but better than the reference inhibitor OTI-6. Desolvation penalty is suggested as a possible factor responsible for the drop in ALR2 inhibitory efficacy observed for derivatives OTI-(8-10) in comparison to OTI-7.

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

“…Introduction of additional substituents with a variable H-bonding ability and lipophilicity into N 2 position. Additional interactions with the unoccupied interactive pocket of ALR2 are expected to increase the selectivity as suggested by Hlavac et al [ 80 ].…”

“…In the next stage, we focused on the development of novel oxotriazinoindole inhibitors of aldose reductase designed to fit an unoccupied ALR2 pocket shown in PDB: 4QX4 surrounded by the amino acid residues Trp219, Ala299, and Leu301. In order to utilize this pocket for additional ligand–enzyme interactions, novel N -benzyl(oxotriazinoindole) derivatives 8a – d have been designed and developed ( Table 7 ) [ 80 ].…”

“… Predicted binding pose and interaction analysis of 8a in the binding site of an ALR2 (PDB: 4QX4). Reprinted with permission from [ 80 ]. Copyright (2021) Elsevier.…”

“…Blue color indicates water accessible parts. Reprinted with permission from [ 80 ]. Copyright (2021) Elsevier.…”

Designed multiple ligands for the treatment of type 2 diabetes mellitus and its complications: discovery of (5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)alkanoic acids active as novel dual-targeted PTP1B/AKR1B1 inhibitors

“…AKR1B1 inhibitors were shown to prevent or control the progression of DM-associated pathologies, including neuropathy and retinopathy. Thus, AKR1B1 inhibitors represent promising agents for the treatment of hyperglycemia-induced pathologies associated with DM, as well as of other inflammatory diseases [14][15][16].…”