Adenosine deaminase – A target for new piperazine derivatives

• Published in: Biophysical chemistry 2021-10, Vol.277, p.106658, Article 106658
• Main Authors: Bakaryan, Anahit, Karapetyan, Luiza, Hakobyan, Naira, Camaioni, Emidio, Mardanyan, Sona, Antonyan, Alvard
• Format: Article
• Language: English
• Subjects: Adenosine Deaminase - chemistry; Adenosine Deaminase - metabolism; Adenosine Deaminase Inhibitors - chemical synthesis; Adenosine Deaminase Inhibitors - chemistry; Adenosine Deaminase Inhibitors - pharmacology; Adenosine deaminase isoforms; Animals; Cattle; Enzyme inhibition; Fluorescence quenching; Molecular docking; Molecular Docking Simulation; Molecular Structure; Piperazines - chemistry; Piperazines - metabolism; Piperazines - pharmacology; Protein-ligand interaction; Structure-Activity Relationship
• ISSN: 0301-4622; 1873-4200; 1873-4200
• DOI: 10.1016/j.bpc.2021.106658

The level of adenosine deaminase (ADA) activity increases in pathological effusions. Therefore, the concentration of its substrate, anti-inflammatory adenosine, decreases, thereby aggravating inflammation. Hence, the quest for ADA inhibiting compounds is an actual problem in medicine and pharmacology. This work describes the inhibition of bovine ADA by new synthesized piperazine compounds. 15 compounds were screened; IC50 values for 5 more potent ones of them were between 3.4 and 98.6 μg/ml. The inhibition of activity of intracellular and ecto- forms of ADA by the most effective “compound 1” was of competitive nature. For these two forms of enzyme, the inhibition constants, Ki (1.5 and 115 μM) and IC50 values (6.5 and 480 μM), respectively, differed by nearly two orders. The constant of bimolecular interaction KSV between “compound 1” and the tryptophan residues in ADA was estimated in fluorescence quenching study as of 0.145 ± 0.027 μM. Finally, the molecular interactions between “compound 1” and the bovine enzyme ADA were highlighted through molecular docking studies. [Display omitted] •Tertiary amino alcohols substituted piperazine compounds inhibit adenosine deaminase.•Ki and IC50 values in inhibition of small and large ADA isoforms differ by two orders.•Piperazine derivative with benzhydryl group inhibits ADA in arthritis synovial fluid.•The quenching of Trp fluorescence in ADA by piperazine derivative was studied.•The molecular docking for ADA interaction with piperazine derivative was performed.