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

Abstract

A library of 31 butyrylcholinesterase (BChE) and cathepsin B (CatB) inhibitors was screened in vitro for inhibition of deoxyribonuclease I (DNase I). Compounds 22, 8 and 7 are among the most potent synthetic non‐peptide DNase I inhibitors reported to date. Three 8‐hydroxyquinoline analogues inhibited both DNase I and BChE with IC50 values below 35 μM and 50 nM, respectively, while two nitroxoline derivatives inhibited DNase I and Cat B endopeptidase activity with IC50 values below 60 and 20 μM. Selected derivatives were screened for various co‐target binding affinities at dopamine D2 and D3, histamine H3 and H4 receptors and inhibition of 5‐lipoxygenase. Compound 8 bound to the H3 receptor and is highlighted as the most promising multifunctional ligand with a favorable pharmacokinetic profile and one of the most potent non‐peptide DNase I inhibitors. The present study demonstrates that 8‐hydroxyquinoline is a structural fragment critical for DNase I inhibition in the presented series of compounds.

Synthesis and DNase I Inhibitory Properties of New Squaramides

“…The residues Asn7, Arg9, Glu39, Arg41, Gly72, Arg73, Asn74, Ser75, Tyr76, Glu78, Ser110, Arg111, His134, Ser135, Ala136, Pro137, Ser138, Asp168, Asn170, Tyr175, Thr203, Ala204, Thr205, Thr207, Cys209, Tyr211, Asp251 and His252 constituted BS2. This is consistent with similar studies using different docking tools [ 35 , 39 , 43 ]. A total of 228 (65%) poses out of the 351 were placed at BS2: 67 of 3a , 84 of 3b , and 77 of 3c .…”

“…Compound 3c , having a 1-(pyridin-3-yl)propan-2-yl moiety, stood out as the most potent DNase I inhibitor, having a slightly higher IC 50 value (48.04 ± 7.98 µM) compared to those of 2-(pyridin-3-yl)ethyl (compound 3a ) and 2-(pyridin-4-yl)ethyl (compound 3b ) analogues (IC 50 = 54.53 ± 8.07 and 57.81 ± 9.67 µM, respectively). It is important to point out that compounds 3a – 3c are among the most potent small organic DNase I inhibitors tested to date [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ].…”

“…It has been reported that residues Tyr76 and Arg41 formed contacts in the minor groove of the octanucleotide leading to geometry changes, namely a great distortion of the phosphate backbone conformation, and the base-pair orientation and stacking [ 43 ]. Our results showed that both residues were involved in intermolecular interactions between the studied inhibitors and the enzyme.…”

Mechanochemical synthesis and antiproliferative activity of novel ferrocene quinoline/quinolone hybrids

“…4,[12][13][14] The quinoline and quinolone N-heterocycles are privileged pharmacophores that play a pivotal role in the drug development process, having diverse biological properties, particularly antimalarial and anticancer activities. [15][16][17][18][19][20][21][22][23][24] A ferrocene-containing quinolone, ferroquine, was developed as an organometallic antimalarial F I G U R E 1 Rational behind the design of N-heterocycle ferrocene derivatives 5a-5d, 6a-6d, 7a, 7b, 8a, and 8b.…”

“…The quinoline and quinolone N ‐heterocycles are privileged pharmacophores that play a pivotal role in the drug development process, having diverse biological properties, particularly antimalarial and anticancer activities 15–24 . A ferrocene‐containing quinolone, ferroquine, was developed as an organometallic antimalarial agent currently undergoing Phase II human clinical trials 25 .…”