Sürdürülebilir Kalkınma Amaçları
Yayınlar
- MakaleAçık Erişim2026Mono- and Bis-Ureido Sulfapyridines as Nanomolar Dual Cholinesterase Inhibitors: Enzyme Kinetics, Molecular Docking, and ADME/Tox Insights
Yapar, Gonul; Akocak, Suleyman; Lolak, Nebih; Topal, Meryem; Türkes, Cuneyt; Topal, Fevzi; Durgun, Mustafa; Koçyigit, Umit Muhammet; Isik, Mesut; Beydemir, Sukru
A series of mono- and bis-ureido sulfapyridine derivatives (SP-1-SP-10) were synthesized and evaluated as dual cholinesterase inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). All compounds exhibited nanomolar inhibition. The most potent AChE inhibitors were SP-8 (K-i = 5.25 +/- 0.73 nM), SP-9 (5.09 +/- 0.44 nM), and SP-10 (5.74 +/- 0.55 nM), significantly outperforming tacrine (K-i = 105.03 +/- 8.85 nM) under identical conditions. For BChE, SP-9 showed the strongest inhibition (K-i = 26.38 +/- 2.07 nM) compared with tacrine (172.03 +/- 32.42 nM). Kinetic analyses revealed competitive inhibition toward AChE for all derivatives, whereas BChE inhibition displayed both competitive and noncompetitive patterns depending on structural features. Glide XP docking using AChE (PDB: 7XN1) and BChE (PDB: 4BDS), complemented by MM-GBSA binding free energy calculations, supported favorable ligand accommodation within the catalytic pockets and highlighted the importance of aromatic and hydrophobic interactions. In silico ADME/Tox analysis revealed a potency-drug-likeness trade-off: mono-ureido derivatives complied with Lipinski's rule of five and showed high predicted oral absorption, whereas bis-ureido derivatives, despite superior enzymatic potency, exhibited multiple drug-likeness violations. These findings identify the ureido-sulfapyridine scaffold as a potent enzymatic dual cholinesterase inhibitory framework, warranting further structural optimization to improve pharmacokinetic properties.
- MakaleYalnız künye2026Novel Approach to Synthesis of Diaryl Tacrine Derivatives and Evaluation of Their Inhibitory Effects on Cholinesterase Enzymes
Topal, Fevzi; Ökten, Salih; Misir, Busra Albayrak; Koçyigit, Umit Muhammet; Derin, Yavuz; Atalay, Vildan Enisoglu; Tutar, Ahmet; Topal, Meryem
The development of effective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors remains a crucial objective in the treatment of neurodegenerative diseases, including Alzheimer's disease (AD). In this study, a novel synthetic approach was established to prepare a series of diaryl-substituted tacrine derivatives. Initially, brominated aminobenzonitrile was subjected to Suzuki-Miyaura cross-coupling reactions with various aryl boronic acids to yielding diaryl-substituted aminobenzonitriles at yields of 60%-72%. These intermediates were then cyclized with cyclohexanone and cycloheptanone under Friedl & auml;nder conditions using BF3 & centerdot;OEt2 as a catalyst, affording six- and seven-membered diaryl tacrine analogues in yields of 52%-68%. All synthesized compounds were characterized by NMR, IR, and elemental analysis. The inhibitory activities of these compounds (7-16) against AChE and BChE were evaluated, and several analogs demonstrated potent dual-enzyme inhibition at nanomolar concentrations. Notably, compounds 8 and 13 exhibited half maximal inhibitory concentration (IC50) values of 6.848 and 8.545 nmol/L for BChE, respectively, indicating strong potential as selective cholinesterase inhibitors. The structure-activity relationship (SAR) analysis revealed the influence of aryl substituents on the potency and selectivity of enzyme inhibition. Compared to previously reported tacrine derivatives, the newly synthesized analogs exhibited superior inhibitory profiles, indicating their potential as lead compounds for further development in AD therapeutics. [GRAPHICS] .
- MakaleAçık Erişim2025Sulfonamide-Bearing Pyrazolone Derivatives as Multitarget Therapeutic Agents: Design, Synthesis, Characterization, Biological Evaluation, In Silico ADME/T Profiling and Molecular Docking Study
Lolak, Nebih; Akocak, Suleyman; Topal, Meryem; Koçyigit, Umit Muhammet; Isik, Mesut; Türkes, Cuneyt; Topal, Fevzi; Durgun, Mustafa; Beydemir, Sukru
The research and design of new inhibitors for the treatment of diseases such as Alzheimer's disease and glaucoma through inhibition of cholinesterases (ChEs; acetylcholinesterase, AChE and butyrylcholinesterase, BChE) and carbonic anhydrase enzymes are among the important targets. Here, a series of novel sulfonamide-bearing pyrazolone derivatives (1a-f and 2a-f) were successfully synthesized and characterized by using spectroscopic and analytical methods. The inhibitory activities of these newly synthesized compounds were evaluated both in vitro and in silico for their effect on carbonic anhydrases (hCA I and hCA II isoenzymes) and ChEs. The in vitro studies showed that these novel compounds demonstrated potential inhibitory activity, with K-I values covering the following ranges: 18.03 +/- 2.86-75.54 +/- 4.91 nM for hCA I, 24.84 +/- 1.57-85.42 +/- 6.60 nM for hCA II, 7.45 +/- 0.98-16.04 +/- 1.60 nM for AChE, and 34.78 +/- 5.88-135.70 +/- 17.39 nM for BChE. Additionally, many of these compounds showed promising inhibitory activity, and some showed higher potency than reference compounds. While the in silico studies have also identified the potential binding positions of these compounds, using the crystal structures of hCA I, II, AChE and BChE receptors. The varying affinities demonstrated by these designed compounds for ChEs and hCA isoenzymes show that these compounds could hold promise as potential alternative agents for selectively inhibiting ChEs and hCAs in the treatment of diseases such as Alzheimer's disease and glaucoma.
- MakaleAçık Erişim2024Design and Synthesis of Pyrazole Carboxamide Derivatives as Selective Cholinesterase and Carbonic Anhydrase Inhibitors: Molecular Docking and Biological Evaluation
Durgun, Mustafa; Akocak, Suleyman; Lolak, Nebih; Topal, Fevzi; Koçyigit, Umit Muhammet; Türkes, Cueneyt; Isik, Mesut; Beydemir, Sukru
The present study focused on the synthesis and characterization of novel pyrazole carboxamide derivatives (SA1-12). The inhibitory effect of the compounds on cholinesterases (ChEs; AChE and BChE) and carbonic anhydrases (hCAs; hCA I and hCA II) isoenzymes were screened as in vitro. These series compounds have been identified as potential inhibitors with a KI values in the range of 10.69 +/- 1.27-70.87 +/- 8.11 nM for hCA I, 20.01 +/- 3.48-56.63 +/- 6.41 nM for hCA II, 6.60 +/- 0.62-14.15 +/- 1.09 nM for acetylcholinesterase (AChE) and 54.87 +/- 7.76-137.20 +/- 9.61 nM for butyrylcholinesterase (BChE). These compounds have a more effective inhibition effect when compared to the reference compounds. In addition, the potential binding positions of the compounds with high affinity for ChE and hCAs were demonstrated by in silico methods. The results of in silico and in vitro studies support each other. As a result of the present study, the compounds with high inhibitory activity for metabolic enzymes, such as ChE and hCA were designed. The compounds may be potential alternative agents used as selective ChE and hCA inhibitors in the treatment of Alzheimer ' s disease and glaucoma. image