Benzimidazoles as novel deoxyribonuclease I inhibitors

Abstract

Inhibitory potential of 19 benzimidazoles against bovine pancreatic deoxyribonuclease I (DNase I) was investigated in vitro. Three compounds inhibited DNase I with IC below 100 μM and proved to be more potent DNase I inhibitors than crystal violet (IC = 351.82 ± 29.41 μM), used as a positive control. Compound 9 showed the most potent DNase I inhibition with an IC value of 79.46 ± 11.75 μM. To further explore the relationship between inhibitory activity and 2D pharmacophore features, Pharma/E-State R-group quantitative structure-activity relationship (RQSAR) models were generated and validated using Schrödinger Suite. RQSAR models showed a significant enhancement of benzimidazoles activity using hydrogen-bond acceptor substituents at the R2, R3, and R4 positions, or aryl substituents at the R4 position. The Site Finder module and molecular docking defined the benzimidazoles interactions with the most important catalytic residues of DNase I, including H-acceptor interaction with residue His 134 and His 252 and/or H-donor interaction with residue Glu 39. We also found a positive correlation between IC inhibition values and relative binding free energies of the most active benzimidazoles. In addition, a molecular dynamics simulation was performed for DNase I-compound 9 docking complex in Desmond. Trajectory analysis showed that docking complex and intermolecular interactions were stable throughout the entire production part of simulations. Furthermore, the results of protein structure alignment module suggested the potential translational impact of benzimidazoles against human DNase I. Due to the significant involvement of DNase I in the pathophysiology of many disease conditions, benzimidazoles as DNase I inhibitors could have potential therapeutic applications.

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] …”