Evaluation of rat kidney aldose reductase inhibitory activity of some N-acetyl dehydroalanine derivatives

Abstract

Aldose reductase (AR) is an enzyme that catalyzes the conversion of glucose to sorbitol, which is in turn converted to fructose by sorbitol dehydrogenase. Increased AR activity has been implicated in the pathogenesis of diabetic complications such as neuropathy, nephropathy, retinopathy, and cataract. Inhibitors of AR thus seem to have the potential to prevent or treat diabetic complications. At present, however, side effects and/or insufficient pharmacokinetic profiles have made most of the drug candidates undesirable. In this study, the synthesis (l-o) and ARI activity of 15 N-acetyl dehydroalanine derivatives (a-o) are described. The synthesized compounds mainly contained aliphatic and aromatic side chains. The insertion of ethyl and chloro propyl side chains were shown to be more effective than the rest of the compounds. Between the synthesized compounds N-ethyl (b) and N-propylchloride (h) derivatives showed the best ARI activities.

Synthesis and Aldose Reductase Inhibitory Effect of Some New Hydrazinecarbothioamides and 4-Thiazolidinones Bearing an Imidazo[2,1-b]Thiazole Moiety

“…As a continuation of our previous studies on 4-thiazolidinone derivatives with ARIs [37][38][39][40][41][42][43] or different biological activities, [44][45][46][47][48] we report the synthesis of some novel imidazo[2,1-b]thiazole derivatives incorporating two known bioactive nuclei such as hydrazinecarbothioamide or 4-thiazolidinone.…”

A new series of hydrazones as small‐molecule aldose reductase inhibitors

“…Hydrazones have emerged as favorable ligands for the management of DM targeting a plethora of enzymes related to the pathogenesis of DM ranging from α‐glucosidase to AR due to their unique features allowing them to interact with key residues of biological targets. [ 16–24 ]…”

“…The aforementioned findings [ 16–27 ] encouraged us to design a novel series of tetrazole‐hydrazone hybrids as small‐molecule AR inhibitors. In this context, the facile and efficient synthesis of new hydrazones was carried out and in vitro and in silico studies were conducted to evaluate their potency as AR inhibitors.…”

“…[9][10][11][12][13][14][15] Hydrazones have emerged as favorable ligands for the management of DM targeting a plethora of enzymes related to the pathogenesis of DM ranging from α-glucosidase to AR due to their unique features allowing them to interact with key residues of biological targets. [16][17][18][19][20][21][22][23][24] Tetrazole stands out as a privileged motif ranking among the top 25 most commonly used nitrogen heterocycles in therapeutic agents. [25] Tetrazole is a well-known bioisostere of the carboxylic acid group, [26] which is found in AR inhibitors (e.g., epalrestat).…”

“…[11,27] The tetrazole scaffold is superior to the carboxylic acid group in terms of its enhanced metabolic stability and lipophilicity, which are important features for prolonged half-life and better membrane penetration, respectively. [26,27] The aforementioned findings [16][17][18][19][20][21][22][23][24][25][26][27] encouraged us to design a novel series of tetrazole-hydrazone hybrids as small-molecule AR inhibitors. In this context, the facile and efficient synthesis of new hydrazones was carried out and in vitro and in silico studies were conducted to evaluate their potency as AR inhibitors.…”