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.
- 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.