Evaluation of 4-aminoquinoline derivatives with an n-octylamino spacer as potential multi-targeting ligands for the treatment of Alzheimer's disease

Matošević, Ana; Opsenica, Dejan; Spasić, Marta; Maraković, Nikola; Zandona, Antonio; Žunec, Suzana; Bartolić, Marija; Kovarik, Zrinka; Bosak, Anita

doi:10.1016/j.cbi.2023.110620

Cited by 11 publications

(11 citation statements)

References 66 publications

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“…However, both enzymes displayed poor affinity for olesoxime in the lower micromolar range and its solubility was impaired at concentrations above 100 µM even with the added methanol. Total cholinesterase inhibition was not achieved and we approximated IC 50 to be over 200 µM for AChE and around 100 µM for BChE, which is more than 3 orders of magnitude lower than that of tacrine [43]. Our results are consistent with other studies where bulkier molecules were generally more potent BChE inhibitors due to the difference in active site size [27,34,37,42,44].…”

Section: Resultssupporting

confidence: 89%

Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases

Kolić,

Šinko,

Jean

et al. 2024

Biomolecules

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Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10–30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.

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Section: Resultssupporting

confidence: 89%

Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases

Kolić,

Šinko,

Jean

et al. 2024

Biomolecules

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“…In this case, it turns out that BChE is an additional target for the active pharmaceutical ingredients developed for AD‐related dementia disorders [43] . Moreover, an in vivo study proved that selective inhibition of BChE both increased learning ability and decreased β ‐amyloid peptide levels in rodents [43,44] . The data obtained from the inhibition studies of AChE, which is responsible for so many and rapidly developing diseases, are shown in Table 2.…”

Section: Resultsmentioning

confidence: 97%

Identification of hCA I, hCA II, AChE and BChE Inhibitory Properties of Some Norcantharimide Derivatives; Molecular Docking, SAR and in silico ADME Studies

Polat Köse,

Köse

2024

ChemistrySelect

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Abstract(3aR,4S,7R,7aS)‐2‐Alkyl/aryl‐3a,4,7,7a‐tetrahydro‐1H‐4,7‐epoxyisoindole‐1,3(2H)‐diones, which are norcantharimide derivatives, were synthesized and their effects on carbonic anhydrase I (hCA I) and II (hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activity were investigated. For enzyme activity studies, hCA I and II isoenzymes purified from human erythrocytes and the commercially available enzymes AChE and BChE, which are both markers and significantly affect the known symptoms of Alzheimer's disease, were used. The two derivatives exerted efficient inhibition with IC50=4.530 nM (Ki=4.483) and 4.426 nM (Ki=4.696) against hCA I and with IC50=3.825 nM (Ki=3.854) and 3.457 nM (Ki=3.292) against hCA II, respectively. The another two derivatives exerted considerable inhibition with IC50=0.526 nM (Ki=0.224) and 0.575 nM (Ki=0.292) against AChE and with IC50=0.135 nM (Ki=0.057) and IC50=0.180 nM (Ki=0.070) against BChE, respectively. The compounds showed activity at the nanomolar level. These remarkable inhibition results were compared with those of standard inhibitors (acetazolamide for hCA I and II and tacrine for AChE and BChE) of each enzyme, reported, and graphed. In addition, molecular docking studies were carried out by in silico methods and the structure–activity relationship was discussed. The poses of compound 4 c are presented along with the ligand–receptor interaction against all metabolic enzymes.

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“…A high-quality drug candidate should not only have sufficient efficacy against the therapeutic target but also show appropriate ADME properties at a therapeutic dose. For potential AChE- and BChE-targeted therapeutics, it is important to have good absorption and high potential to cross the BBB to achieve its biological activity on AChE and BChE in the brain [ 21 , 22 ].…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, our results confirmed those from a previous study on (thiophen-2-yl)-aldoximes, which reported that the hetero atom, due to its potential for polarization, helps to stabilize the negative charge of its anionic form, similarly to the pyridinium ring of the standard oxime 2-PAM [ 20 ]. The affinity of native ChE for these compounds is still not as high as for the cholinergic agonist tacrine [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

Mlakić,

Čadež,

Šinko

et al. 2024

Biomolecules

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New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain–blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents–sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. In silico analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

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Evaluation of 4-aminoquinoline derivatives with an n-octylamino spacer as potential multi-targeting ligands for the treatment of Alzheimer's disease

Cited by 11 publications

References 66 publications

Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases

Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases

Identification of hCA I, hCA II, AChE and BChE Inhibitory Properties of Some Norcantharimide Derivatives; Molecular Docking, SAR and in silico ADME Studies

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

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