Biological effects of bis-hydrazone compounds bearing isovanillin moiety on the aldose reductase

• Published in: Bioorganic chemistry Vol. 117; pp. 105473 - 105487
• Main Authors: Yapar, Gönül, Esra Duran, Hatice, Lolak, Nebih, Akocak, Suleyman, Türkeş, Cüneyt, Durgun, Mustafa, Işık, Mesut, Beydemir, Şükrü
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.12.2021; Elsevier
• Subjects: ADME-Tox; Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - metabolism; Aldose reductase; Benzaldehydes - chemistry; Benzaldehydes - pharmacology; Biochemistry & Molecular Biology; Bis-hydrazones; Chemistry; Chemistry, Organic; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Epalrestat; Humans; Hydrazones - chemical synthesis; Hydrazones - chemistry; Hydrazones - pharmacology; In silico study; Life Sciences & Biomedicine; Molecular Docking Simulation; Molecular Structure; Physical Sciences; Science & Technology; Structure-Activity Relationship; ADME-Tox; Epalrestat; Aldose reductase; Bis-hydrazones; In silico study; VITRO; CARBONIC-ANHYDRASE I; PHENOLIC-COMPOUNDS; INHIBITORY-ACTIVITY; SILICO EVALUATION; CALCIUM-CHANNEL BLOCKERS; MOLECULAR DOCKING; POTENTIAL ACETYLCHOLINESTERASE; VII; HISTAMINE SCHIFF-BASES
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105473

[Display omitted] •The synthesis of a series of novel macrocyclic hydrazone compounds bearing isovanilline moiety (GY1-12) was reported.•ALR2 enzyme was purified with 2.99% yield and 2.10 EU/mg specific activity.•All compounds exhibited a high inhibitory effect on ALR2 as competitive and non-competitive inhibition types.•In silico, molecular docking was carried out to study binding of the most active compounds. Aldose reductase (ALR2), one of the metabolically important enzymes, catalyzes the formation of sorbitol from glucose in the polyol pathway. ALR2 inhibition is required to prevent diabetic complications. In the present study, the novel bis-hydrazone compounds bearing isovanillin moiety (GY1-12) were synthesized, and various chromatographic methods were applied to purify the ALR2 enzyme. Afterward, the inhibitory effect of the synthesized compounds on the ALR2 was screened in vitro. All the novel bis-hydrazones demonstrated activity in nanomolar levels as AR inhibitors with IC50 and KI values in the range of 12.55–35.04 nM, and 13.38–88.21 nM, respectively. Compounds GY-11, GY-7, and GY-5 against ALR2 were identified as the highly potent inhibitors, respectively, and were superior to the standard drug, epalrestat. Moreover, a comprehensive ligand-receptor interactions prediction was performed using ADME-Tox, Glide XP, and MM-GBSA modules of Schrödinger Small-Molecule Drug Discovery Suite to elucidate the novel bis-hydrazone derivatives, potential binding modes versus the ALR2. As a result, these compounds with ALR2 inhibitory effects may be potential alternative agents that can be used to treat or prevent diabetic complications.