Tan, Ayse; Dilek, Esra

In vitro anticholinesterase activities of a series of 1,2,3-triazole derivatives, 9(a-e) and 10(f-l), were evaluated against electric eel acetylcholinesterase (eeAChE) and equine serum butyrylcholinesterase (eqBuChE), using donepezil as a reference inhibitor. Enzyme inhibitory activities were characterized by IC50, inhibition constants (Ki), and inhibition mechanisms. All target compounds exhibited potent inhibitory activity against both enzymes. 9e demonstrated the highest activity against eeAChE (Ki = 7.69 ± 1.24 nM), outperforming donepezil (Ki = 25.28 ± 5.79 nM). 9b showed the strongest inhibition against eqBuChE (Ki = 3.36 ± 0.67 nM), whereas donepezil displayed comparatively weak activity (Ki = 43.48 ± 10.36 nM). To further elucidate ligand–enzyme interactions, molecular docking, molecular dynamics simulation (MDS), MM/GBSA, and structure–activity relationship studies were performed. Docking results indicated that all target compounds exhibited higher binding affinities for both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE than for BuChE. MDS and MM/GBSA analyses confirmed the stability of the selected complexes, without significant fluctuations over 50 ns, and showed that while 9e was selective for hAChE-CAS, 9b bound similarly to both hBuChE sites. Taken together, all target compounds, particularly 9e and 9b, may serve as novel dual AChE/BuChE inhibitor candidates.

Çakmak, Reşit; Başaran, Eyüp; Akkoç, Senem; Türkmenoğlu, Burçin; Köprü, Semiha; Bingül, Murat

In this study, a series of indolyl hydrazone derivatives (5–10) were designed and synthesized from 2,4-dimethoxybenzaldehyde (DMBA) (1) as potential chemotherapeutic agents. The structures of the synthesized compounds were confirmed by elemental analysis, FT-IR, 1D, and 2D NMR spectroscopy, and high-resolution mass spectrometry (HRMS). Their cytotoxic activities were evaluated against human breast (MCF-7), liver (HepG2), and colorectal (DLD-1) cancer cell lines. All compounds exhibited cytotoxic effects at micromolar concentrations, with IC50 values ranging from 8.97–26.07 µM for MCF-7, 22.50–70.99 µM for HepG2, and 5.93–66.31 µM for DLD-1 cells. Compound 10 demonstrated the strongest activity against MCF-7 and DLD-1 cells, with IC50 values of 8.97 ± 0.31 and 5.93 ± 0.11 µM, respectively. Compound 7 showed the highest antiproliferative activity against HepG2 cells (22.50 ± 1.23 µM), exceeding the activity of cisplatin (37.27 ± 2.42 µM). Molecular docking studies revealed favorable binding affinities of the most active compounds (7 and 10) toward selected targets. In addition, in silico ADME-toxicity analyses predicted acceptable physicochemical and pharmacokinetic properties, supporting the potential of these derivatives as promising anticancer candidates.

Sarıoğlu, Ahmet Oral; Sogukomerogullari, Hatice Gamze; Türkmenoğlu, Burçin; Taşdemir, Demet; Aytar, Emine; Sürmelihindi, Bahar; Alyamaç, İbrahim Tahsin

This study reports the synthesis and characterization of mixed-ligand Cu(II), Co(II), and Mn(II) complexes derived from 2-(((2-hydroxyphenyl)imino)methyl)-4-methoxy-6-nitrophenol (L1) and 5-nitro-1,10-phenanthroline (L2). The ligand and complexes were characterized by 1H/13C NMR (L1 only), FT-IR, UV–vis, LC-MS/MS, TGA, and elemental analysis. Cytotoxicity studies against A549 and HTB-54 lung cancer cells identified the Cu(II) complex as the most active compound, with IC50 values of 24.05 and 22.08 µM, respectively, while showing lower toxicity toward BEAS-2B normal cells (IC50 = 39.08 µM). The Cu(II) complex significantly inhibited cell migration and induced apoptosis, supported by increased Bax expression in qPCR analysis. Molecular docking with selected cancer-related protein targets further supported its proposed anticancer mechanism. The catalytic activity of the complexes was investigated for the solvent-free cycloaddition of CO2 with epoxides. The Co(II) complex exhibited the highest catalytic performance, affording 86.5% yield and 97.0% selectivity in the presence of DMAP under optimized conditions. Density functional theory (DFT) calculations provided the EHOMO, ELUMO, chemical potential, hardness, softness, electrophilicity index, and MEP profile of the ligand and complexes, demonstrating their multifunctional potential for anticancer and sustainable catalytic applications.

Yapar, Gönül; Akocak, Suleyman; Lolak, Nebih; Topal, Meryem; Türkeş, Cüneyt; Topal, Fevzi; Durgun, Mustafa; Koçyiğit, Ümit Muhammet; Işık, Mesut; Beydemir, Şükrü

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 (Ki = 5.25 ± 0.73 nM), SP-9 (5.09 ± 0.44 nM), and SP-10 (5.74 ± 0.55 nM), significantly outperforming tacrine (Ki = 105.03 ± 8.85 nM) under identical conditions. For BChE, SP-9 showed the strongest inhibition (Ki = 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.

Kanberoglu, Gulsah Saydan; Kaya, Nurcan; Coldur, Fatih; Hashemi-Moghaddam, Hamid; Soylak, Mustafa

This study presents the development of a novel ion-selective electrode (ISE) for the selective and sensitive potentiometric detection of maprotiline (MAP). Due to the limited number of electrochemical maprotiline-selective sensors in the literature and the lack of molecularly imprinted polymer (MIP)-based potentiometric sensors, this study employed a MAP-imprinted polymer/metal organic framework (MIP/MOF) hybrid material as the ionophore component in the membrane structure of the MAP-selective electrode for the first time. For the design of the sensor, a europium oxide metal-organic cage (Eu-MOF)-based MIP (Eu-MOF@MAP-MIP) was synthesized, which offers advantages for molecular imprinting due to its large surface area, tunable pore architecture, and adaptable chemical functionality. The sensor exhibited a wide linear operating range from 1.0 × 10−10 to 1.0 × 10−2 M, a near-Nernstian slope of 52.3 mV/decade, and a remarkably low detection limit of 9.0 × 10−11 M. The analytical applicability was demonstrated by using it as an indicator electrode in the potentiometric titration of MAP and by directly determining the MAP content in two commercial drug formulations. The obtained high recovery percentages solidly confirm the practical suitability and high accuracy of the developed sensor for MAP analysis in real and complex matrices.

Akkoc, Senem; Çağlar-Yavuz, Sevtap; Türkmenoğlu, Burçin; Tuğrul Zeyrek, Celal; Ilhan, Ilhan Ozer; Alhag, Sadeq K.; Al-Shuraym, Laila A.

In this study, seven known compounds (5a–g) were tested towards four human cancer cell lines including DLD-1, HepG2, MDA-MB-231, and MCF-7 for 48 h. In addition, all compounds were also tested in a normal human cell line (Wl-38). The results showed that a compound 5e in particular had cytotoxic effects in DLD-1, HepG2, and MCF-7. The molecular modeled structures of seven investigated compounds 5a–g in the ground state were optimized using density functional theory (DFT). The chemical parameters were determined by DFT calculations. HOMOs and LUMOs of 5a–g were revealed to provide a reasonable qualitative indication of their excitation properties. To support experimental studies, compounds (5a, 5c, and 5e) with anticancer effects were interacted with epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR-2), which were determined as possible targets. As a result of these interactions, binding parameter values (docking score, Glide e-model, Glide energy) between ligand and target were calculated.

Şimşek, Samed

In this study, silver nanoparticles (AgNPs) were green-synthesized for the first time using the methanolic extract of Thymus pectinatus (TP), and their physicochemical properties as well as biological activities were systematically evaluated. The conversion and stabilization of Ag+ to Ag0 were confirmed by FTIR, XRD, and SEM-EDX analyses, which demonstrated the involvement of functional groups such as hydroxyl and amine. The synthesized TP-AgNPs exhibited high crystallinity with a dominant (111) XRD peak and spherical morphology (20–40 nm). Antioxidant analyses demonstrated that TP-AgNPs had superior activity compared to the extract, showing lower IC50 values in the DPPH• (13.45 µg/mL) and ABTS•+ (5.67 µg/mL) assays, together with significantly higher reducing power (879.92 mg TE/g). Antifungal activity against Monilinia fructigena and Verticillium dahliae showed stronger inhibition (65.79% at 400 ppm), with lower LC50 values (298.96 and 267.34 ppm). In addition, TP-AgNPs demonstrated significantly stronger antibacterial activity, with wider inhibition zones and lower MICs compared to the extract. These findings confirm that TP-AgNPs exhibit multiple bioactivities, highlighting their potential as multifunctional agents.

Şimşek, Samed; Akşit, Hüseyin; Bayar, Yusuf; Karakurt, Tuncay

This study investigates the antifungal properties of verbascoside isolated from Verbascum ozturkii. The primary objective is to evaluate its efficacy against two agriculturally significant plant pathogens, Phytophthora infestans and Verticillium dahliae. Verbascoside was isolated using preparative high-performance liquid chromatography (HPLC) and its structure was elucidated via nuclear magnetic resonance (NMR) spectroscopy. In vitro antifungal assays demonstrated moderate inhibitory effects with verbascoside (2 mg/mL) reducing mycelial growth by 23.49% for P. infestans and 19.42% for V. dahliae. To elucidate the antifungal mechanism, quantum chemical calculations and molecular docking studies were conducted. Analyses of frontier molecular orbitals (HOMO-LUMO) and molecular electrostatic potential (MEP) identified critical interaction sites. Molecular docking demonstrated that verbascoside binds favorably to the protein structures of V. dahliae (PDB: 5xmz) and P. infestans (PDB: 6jyg). Molecular dynamics simulations confirmed the stability of these interactions with molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations indicating more favorable binding free energy for the verbascoside-6jyg complex. This research underscores the potential of verbascoside as a natural antifungal agent highlighting the significance of protein-specific interactions. The findings contribute to the development of alternative antifungal strategies and emphasize the novelty of verbascoside activity against these plant pathogens.

Alagoz, Mehmet Abdullah; Resitoglu, Meryem Temiz; Kuzu, Burak; Sabrie, Zainab; Yetkin, Derya; Zobi, Cengiz; Tiftik, Rukiye Nalan; Firat, Seyhan Sahan; Gursoy, Sule; Hepokur, Ceylan

Clinical use of mTOR inhibitors in cancer treatment is well established due to the critical role of mTOR signaling in tumor progression. In this study, we report the structure-based design and biological evaluation of a series of benzoxazole derivatives as potential mTOR inhibitors. Cytotoxicity studies using MTT assays showed that compounds B4, B11, B12, and B20 exhibited significant antiproliferative effects against breast cancer cell lines with IC₅₀ values between 4.96 and 9.82 µM. Colorimetric enzymatic assays further revealed that among these, only B12 and B20 effectively inhibited mTOR phosphorylation at Ser2448 in MCF-7 cells. Additionally, both compounds modulated the expression of key apoptotic proteins, including Bax, caspase-3, p53, and Bcl2. Molecular docking studies against the 4JT5 protein demonstrated binding affinities with docking scores ranging from −7.084 to −7.426 kcal/mol, comparable to the reference compound P2X (−7.309 kcal/mol). Molecular dynamics simulations over 150 ns confirmed the stability of B12 and B20 in the active site, with an average RMSD of 2.8 Å and 3.0 Å, respectively. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the synthesized compounds were evaluated in silico. Among them, B4, B11, B12, and B20 exhibited drug-like characteristics and showed no undesirable toxic effects. These findings highlight the potential of B12 and B20 as lead compounds for the development of novel mTOR inhibitors in breast cancer therapy.

Biyik, Busra; Tarıkogulları, Ayse H.; Alagoz, Mehmet Abdullah; Demir, Yeliz; Gulcin, Ilhami; Burmaoglu, Serdar; Algul, Oztekin

The increasing incidence of diseases and the constraints of current treatments require expedited drug development. Drug repositioning presents an effective approach for discovering new therapeutic applications for drugs already in clinical use. This study examines the efficacy of metronidazole and secnidazole, which are presently utilized as antiprotozoal agents, in the treatment of Alzheimer's disease via ester modifications. The secondary alcohol group in nitroimidazole structures underwent esterification with acetyl, pivaloyl, cyclopropyl, and cyclohexyl carbonyl chlorides. The compounds exhibited significant inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with Ki values between 52.40 ± 6.99 nM and 240.80 ± 45.56 nM for AChE and 77.82 ± 18.01 nM and 323.70 ± 56.21 nM for BChE. Molecular docking studies demonstrated significant interactions of the most active compounds (MNZ 8 and MNZ 4) with essential residues, including Trp84 and Phe330 in AChE, as well as Trp82 and active-site water molecules in BChE. These findings corroborate their inhibitory potential, notwithstanding initial positional alterations observed during simulations. The synthesized compounds' absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties were also assessed in silico. All compounds demonstrated drug-like properties and did not exhibit undesirable toxic effects. The findings indicate that repositioned derivatives of metronidazole and secnidazole may serve as promising lead compounds for the development of cholinesterase inhibitors aimed at treating Alzheimer's disease.