Synthesis and DNase I inhibitory properties of some 4‐thiazolidinone derivatives

Abstract

Twelve new thiazolidinones were synthesized and, together with 41 previously synthesized thiazolidinones, evaluated for inhibitory activity against deoxyribonuclease I (DNase I) in vitro. Ten compounds inhibited commercial bovine pancreatic DNase I with an IC below 200 μM and showed to be more potent DNase I inhibitors than crystal violet (IC = 365.90 ± 47.33 μM), used as a positive control. Moreover, three compounds were active against DNase I in rat liver homogenate, having an IC below 200 μM. (3-Methyl-1,4-dioxothiazolidin-2-ylidene)-N-(2-phenylethyl)ethanamide (41) exhibited the most potent DNase I inhibition against both commercial and rat liver DNase I with IC values of 115.96 ± 11.70 and 151.36 ± 15.85 μM, respectively. Site Finder and molecular docking defined the thiazolidinones interactions with the most important catalytic residues of DNase I, including the H-acceptor interaction with residues His 134 and His 252 and/or H-donor interaction with residues Glu 39 and Asp 168. The three most active compounds against both commercial and rat liver DNase I (31, 38, and 41) exhibited favorable physico-chemical, pharmacokinetic, and toxicological properties. These observations could be utilized to guide the rational design and optimization of novel thiazolidinone inhibitors. Thiazolidinones as novel DNase I inhibitors could have potential therapeutic applications due to the significant involvement of DNase I in the pathophysiology of many disease conditions.

1,2,3,4‐Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors

“…In addition, active compounds 2 , 15 , 18 , and 22 exhibited, respectively 2.70‐, 2.45‐, 2.43‐ and 2.44‐times better inhibitory activity in comparison to crystal violet used as a positive control. Observed DNase I inhibitory potential of active 1,2,3,4‐tetrahydroisoquinolines is in line with a multitude of other small organic DNase I inhibitors, whose IC 50 mainly range between 70 and 150 μM, [28–34] whereas the most potent small natural products inhibitors of DNase I are cyclocariol F and schisanlactone E with IC 50 s of 12.5±2 μM and 30±3 μM, respectively [35] …”

Repurposing of 8‐Hydroxyquinoline‐Based Butyrylcholinesterase and Cathepsin B Ligands as Potent Nonpeptidic Deoxyribonuclease I Inhibitors

“…Sixteen identified DNase I inhibitors with IC 50 values below 80 μM ( 7 – 9 , 11 , 12 , 14 – 24 ), exceeded the inhibitory activity of all previously reported small‐molecule DNase I inhibitors [8,19,21–29] . To the best of our knowledge, compounds 8 and 22 are among the most potent synthetic non‐peptide DNase I inhibitors reported to date, with the natural product cyclocariol F inhibiting DNase I with a lower IC 50 value (IC 50 =12.5±2 μM) [30] .…”

“…The inhibitory potencies of the compounds against bovine pancreatic DNase I was evaluated in vitro by spectrophotometric measurement of the formation of acid‐soluble nucleotides at 260 nm according to procedures reported previously [8,21–23] . Briefly, the compounds studied were tested for their DNase I inhibition at a concentration of 100 μM.…”

Deoxyribonuclease I Inhibitory Properties, Molecular Docking and Molecular Dynamics Simulations of 1‐(Pyrrolidin‐2‐yl)propan‐2‐one Derivatives

“…According to the obtained results, tested compounds 1 and 2 posses 1.89‐ and 2.73‐times better DNase I inhibitory properties (respectively) compared to crystal violet (IC 50 ±SD=362.45±35.55 μM) used as a positive control, given the general lack of ‘golden standard’ in DNase I assays. In addition, the activity of tested 1‐(pyrrolidin‐2‐yl)propan‐2‐one derivatives against DNase I is comparable to the majority of known small organic DNase I inhibitors [9–15] …”