A comprehensive review of multi-target directed ligands in the treatment of Alzheimer’s disease

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 144, P. 107152 - 107152

Published: Jan. 27, 2024

Language: Английский

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New insights into butyrylcholinesterase: Pharmaceutical applications, selective inhibitors and multitarget-directed ligands

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 275, P. 116569 - 116569

Published: June 5, 2024

Language: Английский

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Analysis of skeletal diversity of multi-target directed ligands (MTDLs) targeting Alzheimer’s disease

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 286, P. 117277 - 117277

Published: Jan. 18, 2025

Language: Английский

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Novel Dibenzoazepine-Substituted Triazole Hybrids as Cholinesterase and Carbonic Anhydrase Inhibitors and Anticancer Agents: Synthesis, Characterization, Biological Evaluation, and In Silico Studies

ACS Omega, Journal Year: 2024, Volume and Issue: 9(47), P. 46860 - 46878

Published: Nov. 16, 2024

The new dibenzoazepine-substituted triazole hybrids (12–20) were designed by molecular hybridization approach and synthesized utilizing the Cu(I)-catalyzed click reaction. hybrid structures obtained in high yields (74–98%) with a simple two-step synthesis strategy fully characterized. These compounds assessed for their influence on various metabolic enzymes including human carbonic anhydrase isoenzymes (hCA I hCA II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE). Ki values concerning I, II, AChE, BChE ranges 29.94–121.69, 17.72–89.42, 14.09–44.68, 1.15–48.82 nM, respectively. Compound 13 was 49.70-fold more active than tacrine (standard drug) 5.49-fold AChE. 14 4.16-fold acetazolamide 5.79-fold II. cytotoxic effects of products investigated triple-negative breast cancer cell lines. IC50 most effective calculated between 12.51 ± 1.92 18.07 2.14 μM MDA-MB-231 BT-549 cells. Molecular docking ADME predictions performed. Then, vitro analyzed dynamics (MD) simulation MM/GBSA calculation. Consequently, showed good cytotoxicity inhibition potential colony formation

Language: Английский

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Combining Experimental and Computational Methods to Produce Conjugates of Anticholinesterase and Antioxidant Pharmacophores with Linker Chemistries Affecting Biological Activities Related to Treatment of Alzheimer’s Disease

Molecules, Journal Year: 2024, Volume and Issue: 29(2), P. 321 - 321

Published: Jan. 9, 2024

Effective therapeutics for Alzheimer's disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of 4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities pertaining AD treatment. Here, report significant extensions these studies, including the use variable-length spacers more detailed biological characterizations. Conjugates were potent inhibitors acetylcholinesterase (AChE, most active was

Language: Английский

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Alzheimer’s Disease: A Suitable Case for Treatment with Precision Medicine?

Medical Principles and Practice, Journal Year: 2024, Volume and Issue: 33(4), P. 301 - 309

Published: Jan. 1, 2024

Alzheimer’s disease (AD) is the most common cause of neurodegenerative impairment in elderly people. Clinical characteristics include short-term memory loss, confusion, hallucination, agitation, and behavioral disturbance. Owing to evolving research biomarkers, AD can be discovered at early onset, but currently considered a continuum, which suggests that pharmacotherapy efficacious preclinical phase, possibly 15–20 years before discernible onset. Present developments therapy aim respond this understanding go beyond drug families relieve clinical symptoms. Another important factor development emergence precision medicine aims tailor treatment specific patients or patient subgroups. This relatively new platform would categorize on basis parameters like aspects, brain imaging, genetic profiling, genetics, epidemiological factors. review enlarges recent progress design use antisense molecules, antibodies, antioxidants, small gene editing stop reverse relevant biomarkers.

Language: Английский

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Multifunctional Inhibitors of Cholinesterases for the Therapy of Alzheimer’s Disease (A Review)

Russian Journal of General Chemistry, Journal Year: 2023, Volume and Issue: 93(S2), P. S528 - S549

Published: Dec. 1, 2023

Language: Английский

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A novel approach to low-cost, rapid and simultaneous colorimetric detection of multiple analytes using 3D printed microfluidic channels

Royal Society Open Science, Journal Year: 2024, Volume and Issue: 11(1)

Published: Jan. 1, 2024

This research paper presents an inventive technique to swiftly create microfluidic channels on distinct membrane papers, enabling colorimetric drug detection. Using a modified DIY RepRap 3D printer with syringe pump, (µPADs) are crafted flexible nylon-based substrate. allows simultaneous detection of four common drugs single reagent. An optimized blend polydimethylsiloxane (PDMS) dissolved in hexane is used hydrophobic various filter papers. The PDMS-hexane mixture infiltrates the paper's pores, forming barriers that confine liquids within channels. These cured printer's hot plate, controlling channel width and preventing spreading. Capillary action drives fluid along these paths without novel approach provides versatile solution for rapid creation integration offers precise control faster curing. accurately forms barriers, containing desired resulting system holds potential portable, cost-effective sensing applications.

Language: Английский

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Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit β-amyloid self-aggregation: potential therapeutic agents for Alzheimer’s disease

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 9, 2023

We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carboxylesterase (CES). also studied abilities new compounds to interfere with self-aggregation β-amyloid (Aβ 42 ) in thioflavin test as well their antioxidant ABTS FRAP assays. used molecular docking, dynamics simulations, quantum-chemical calculations explain experimental results. All weakly inhibited AChE off-target CES. Dihydroacridines aryl substituents phosphoryl moiety BChE; most active were dibenzyloxy derivative 1d its diphenethyl bioisostere 1e (IC 50 = 2.90 ± 0.23 µM 3.22 0.25 µM, respectively). Only one acridine, 2d , an analog dihydroacridine, was effective BChE inhibitor 6.90 0.55 μM), consistent docking Aβ self-aggregation; (58.9% 4.7% 46.9% 4.2%, dihydroacridines 1 demonstrated high •+ -scavenging iron-reducing comparable Trolox, but acridines 2 almost inactive. Observed features explained by calculations. ADMET parameters calculated for all predicted favorable intestinal absorption, good blood–brain barrier permeability, low cardiac toxicity. Overall, best results obtained two dihydroacridine derivatives moiety. These displayed inhibition activity self-aggregation, activity, profiles. Therefore, we consider lead further in-depth studies potential anti-AD preparations.

Language: Английский

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Conjugates of amiridine and thiouracil derivatives as effective inhibitors of butyrylcholinesterase with the potential to block β‐amyloid aggregation

Archiv der Pharmazie, Journal Year: 2023, Volume and Issue: 357(2)

Published: Dec. 10, 2023

Abstract New amiridine‐thiouracil conjugates with different substituents in the pyrimidine fragment (R = CH 3 , CF 2 Н, (CF ) H) and spacer lengths ( n 1–3) were synthesized. The rather weakly inhibit acetylcholinesterase (AChE) exhibit high inhibitory activity (IC 50 up to 0.752 ± 0.021 µM) selectivity butyrylcholinesterase (BChE), which increases elongation; lead compounds are 11c 12c 13c . mixed‐type reversible inhibitors of both cholinesterases practically do not structurally related off‐target enzyme carboxylesterase. results molecular docking AChE BChE consistent experiment on inhibition explain structure–activity relationships, including low anti‐AChE anti‐BChE long‐chain conjugates. displace propidium from peripheral anion site (PAS) at level reference compound donepezil, agrees mechanism main mode binding active due interaction moiety PAS. This indicates ability studied block AChE‐induced aggregation β‐amyloid, thereby exerting a disease‐modifying effect. According computer calculations, all synthesized have an ADME profile acceptable for drugs.

Language: Английский

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