Serdaroğlu, Vildan; Demir, Fatma; Aydın, Ali; Türkmenoğlu, Burçin; Kahriman, Nuran

In this research, a series of novel bioactive heterocyclic polar compounds were designed and synthesized by incorporating various functional groups to enhance their biological and functional properties. The work involved the synthesis of chalcone (1–9, 10–18), boron difluoride complex (19–21), pyrazoline (22–25), and pyrimidine (26–37) compounds with their structures characterized through spectral techniques including NMR (1H, 13C (APT), 1H–1H COSY), FT-IR spectroscopies, LC-MS spectrometry. The anticancer potential of all compounds was assessed using lung cancer cell lines (A549, Calu1, H1650), brain cancer cell lines (A172, C6, B35), as well as normal lung (Beas2B) and chondrocyte (HC) cell lines. Compounds exhibiting a GI50 value below 3.0 µg/mL and a TGI value under 100 µg/mL were classified as having anticancer activity, based on comparisons with the reference drug 5-fluorouracil (5FU). Overall, compounds 24, 34, and 36 emerged as the most promising lead candidates by combining potent antiproliferative activity, favorable GI50-derived selectivity indices, and low toxicity toward normal cells, whereas compounds 2, 32, and 35 demonstrated the highest overall biological potency across multiple cancer cell lines. Representative GI50 values as low as 1.0–1.2 µg/mL, TGI values as low as 1.3–2.5 µg/mL, and LC50 values generally exceeding 500 µg/mL in normal cell lines were obtained in the most responsive models, supporting the potential of these derivatives for further anticancer development. To support these detailed in vitro studies, the most active compounds targeting TP53, EGFR, Akt1, mTOR, ERK2, and caspase 3, which are effective in lung and brain cancer pathways, were interacted via in silico molecular docking. Through molecular docking, the interaction values of compounds 2, 6, 7, 8, 13, 14, 17, 18, 24, 27, 32, 35, 36, and 37 with the determined targets were calculated, and their potential as promising lead candidates for drug development was analyzed.

Kılıç, Selçuk; Aktekin, Mine Buga; Turkmenoglu, Burcin; Sert, Yusuf; Caglar, Bulent; Çırak, Çağrı; Algul, Oztekin

In this study, the structural, spectroscopic, and biological properties of a benzazole-2-carboxamide derivatives, N-(1H-benzo[d]imidazole-2-yl)-4-chlorobenzamide, were comprehensively investigated through both experimental and theoretical approaches. First, the crystal structure of the compound was revealed with the help of single-crystal X-ray diffraction (XRD). Subsequently, density functional theory (DFT) calculations were performed using Gaussian 09 W to optimize the molecular geometry, simulate vibrational spectra, predict nuclear magnetic resonance (NMR) parameters, analyze frontier molecular orbitals HOMO (Highest Occupied Molecular Orbital) - LUMO (Lowest Unoccupied Molecular Orbital), and generate molecular electrostatic potential (MEP) surface maps. To enhance the accuracy of vibrational assignments, potential energy distribution (PED) analysis was conducted via the VEDA4 software. Furthermore, theoretical infrared (IR) and NMR data were compared with experimental results, with results from FT-IR, ¹H-NMR, and ¹³CNMR spectra demonstrating strong agreement and validating the computational models. In addition to spectroscopic characterization, the antiproliferative activity of the synthesized compound against human breast cancer cell line MCF7 and a normal mouse fibroblast cell line (L929) was evaluated. Among the tested compounds, those exhibiting the highest inhibitory activity against MCF7 cells were selected for further analysis. In order to explain the underlying molecular interactions, molecular placement studies were carried out with the help of the Schrödinger Maestro software program, which targets the basic protein binding sites to predict binding affinity and interaction patterns. Collectively, this integrated study provides valuable insights into the structural, spectroscopic, and biological behavior of benzazole-based derivatives, highlighting the synergy between experimental techniques and computational modeling in modern drug discovery research.

Faydali, Nagihan; Erol, Meryem; Arpaci, Özlem Temiz; Küçükoğlu, Kaan; Dilek, Esra; Muhammed, Muhammed Tilahun

In this study, ten original 3,5-disubstituted-1,2,4-oxadiazole derivatives were successfully synthesized and characterized by mass spectrometry and ¹H and ¹³C NMR spectroscopy. The potential of these compounds to inhibit butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) was assessed, and the results were reported as IC50 and Kᵢ values. The compounds' Ki values ranged from 21.82 ± 7.87 to 83.67 ± 22.16 nM against BChE and from 9.52 ± 2.10 to 34.99 ± 11.33 nM against AChE. Consequently, it was found that all compounds, except 4f, demonstrated more effective inhibitory action against BChE than donepezil, and that 4g, 4e, and 4i demonstrated more effective inhibitory activity against AChE than donepezil. All compounds were subjected to molecular docking against AChE and BChE, and hydrogen bonding and π-interactions between the compounds and the enzymes were observed. Stabilities of enzyme-compound complexes generated from the docking were investigated by molecular dynamics (MD) simulation. The generated complexes were determined to be stable during the simulation period. To further deepen our understanding, computational DFT analysis revealed key insights into the structures, electronic properties, and reactivity of these materials. To broaden our research, absorption, distribution, metabolism, excretion, and toxicity (ADMET) calculations of the compounds were also carried out.

Sirinzade, Hanif; Faydali, Nagihan; Muhammed, Muhammed Tilahun; Dilek, Esra

Acetylcholinesterase (AChE) is a key serum esterase with antiatherosclerotic effects by preventing lipid peroxide oxidation. AChE inhibitors also serve as therapeutic targets for Alzheimer's disease. Newly developed halo-substituted quinolinecarboxaldehyde-hydrazone derivatives (1a–1 s) show significant pharmacological potential due to their broad biological activities. This study evaluated the inhibitory effects of halo-substituted quinolinecarboxaldehyde-hydrazone derivatives on AChE. Acetylcholine esterase IC₅₀ values ranged from 0.143 to 2.015 µM, and Kᵢ values from 0.078 ± 0.030 to 1.074 ± 0.105 µM. Tacrine served as the positive control. Molecular docking studies revealed that compounds 1b and 1k displayed pi-pi interactions (pi-alkyl, pi-pi stacking) and conventional hydrogen bonding. The molecular dynamics simulation study disclosed that compounds 1b and 1k formed stable complexes with the enzyme structure. Moreover, the density functional theory study demonstrated that the active compounds had similar electrical property and reactivity. Together with this, compound 1e was anticipated to exhibit the highest chemical stability among the compounds investigated. All of the compounds were shown to have a high absorption from the gastrointestinal tract and to meet Lipinski's criterion in SwissADME. As a result, it was determined that new halo-substituted quinoline carboxaldehyde-hydrazone derivatives showed strong inhibition effect on this enzyme. In comparison to the reference chemical Tacrine, 1k had the most potent inhibitory activity against AChE. In this context, we anticipate that the findings of this study will aid in identifying the adverse effects of both existing and novel quinolinecarboxaldehyde-hydrazone-based pharmaceutical drugs under development. Additionally, it should be effective in the production of novel AChE inhibitors.

Sarıoğlu, Ahmet Oral; Törer, Hakan; Taşdemir, Demet; Türkmenoğlu, Burçin; Alyamaç, İbrahim Tahsin; Sönmez, Mehmet

This work covers the synthesis, cytotoxicity evaluation, and molecular docking study of new metal complexes formed by the coupling of 2-(((2-hydroxyphenyl)imino)methyl)-4-nitrophenol (L1) and 1,10-phenanthroline (L2) ligands. The ligand (L1) and its mixed ligand complexes with Cu(II), Co(II), and Ni(II) salts were analyzed using elemental analysis, FT-IR, TGA, UV-Vis, LC-MS/MS, NMR (just for the ligand L1), and magnetic susceptibility assessments. To our knowledge, this is the first report evaluating the cytotoxic and apoptotic effects of these complexes on A549 lung carcinoma and SH-SY5Y neuroblastoma cells. Among all synthesized compounds, copper complexes ([Cu(L1)(L2)H₂O] and [Cu(L1)2(H₂O)2]) exhibited significant cytotoxicity with IC50 values of 14.18 µM and 5.17 µM in A549 cells, and 37.96 µM and 23.35 µM in SH-SY5Y cells, respectively. Annexin V/PI apoptosis assays confirmed that the copper complexes induced both early and late apoptosis more effectively than cisplatin in A549 cells. Molecular docking studies further validated these findings, revealing strong interactions of copper complexes with B-DNA, EGFR, VEGFR-2, and ERK2, consistent with the observed anticancer activities. These results suggest that Cu(II)–Schiff base complexes represent promising lead compounds for future anticancer drug development.

Bozbey Merde, İrem; Aykaç, Okan; Hepokur, Ceylan; Yaşa, Yaren Zişa; Taşkor Önel, Gülce; Türkmenoğlu, Burçin

A series of novel pyridazinone derivatives linked ethyl-bridged-1,2,4-triazole were synthesized starting from p-chloroacetophenone. The chemical structures of the compounds 5(a-f) were identified by 1HNMR, 13CNMR and LC-QTOF-MS analysis. In this study, the DDPH method was used to evaluate the antioxidant properties of the compounds. The anticancer activity of the compounds was investigated by MTT method in MCF-7, MDA-MB-231 and L929 cell lines. Gene expression levels of Bcl2, Bax and Casp9 genes were compared, and stages of cell death were determined with high accuracy by flow cytometry. Since compound 5a showed promising cytotoxic effects, molecular docking study was performed to support these results and binding values against Bcl2 anti-apoptotic (PDB ID: 6QGG), Bcl-2 (PDB ID: 4IEH) and tubulin regulation (PDB ID: 1SA0) targets were calculated.

Faydali, Nagihan; Erol, Meryem; Temiz Arpaci, Özlem; Dilek, Esra; Muhammed, Muhammed Tilahun

Alzheimer's disease (AD), the most worrisome neurological condition in the world, is one of the primary causes of dementia and is characterized by cognitive and memory loss. This disease is multifactorial, and there is currently no cure, although treatments based on the cholinergic hypothesis have been successful in relieving symptoms. This study examined the inhibitory effects of 11 compounds with a sulfonamide group at position 5 of the benzoxazole ring system on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Two of these 11 compounds are original, and FT-IR, ¹H NMR, ¹³C NMR, and mass spectrometry were used to characterize their structures. The compounds showed significantly greater biological activity as inhibitors of both AChE and BChE than the reference drug, donepezil. In particular, 2a showed the highest activity against AChE with a Ki value of 7.45 ± 2.79 nM, and 1b showed the highest activity against BChE with a Ki value of 3.37 ± 0.68 nM. Furthermore, a molecular docking study was performed to investigate the interaction modes of the active compounds with the active sites of the crystal structures of AChE and BChE. Hydrogen bond and π interactions were observed in the protein–ligand interactions. The stabilities of the complexes obtained from docking were assessed using a molecular dynamics (MD) simulation. The MD simulation revealed that the complexes remained stable throughout. Density functional theory (DFT) analysis was also conducted to determine the compounds' most stable conformers and investigate their chemical stability and reactivity.

Algul, Oztekin; Mete, Burak; Turkmenoglu, Burcin; Saglamtas, Ruya; Alagoz, M.Abdullah; Dogen, Aylin; Gulcin, Ilhami; Burmaoglu, Serdar

This study presents the synthesis and bioactivity screening of a series of substituted bisbenzimidazoles (3a–l), assessed for their inhibitory effects on α-glycosidase, α-amylase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), as well as their antibacterial activities and metal chelation properties. Compound 3e exhibited the most significant inhibitory activity against intestinal α-glycosidase and α-amylase, showing IC50 values of 15.51 µM and 18.18 µM, respectively. All bisbenzimidazole derivatives demonstrated significant inhibitory activities, with Ki values between 0.99 and 2.98 nM for AChE and 0.40 to 2.18 nM for BChE. Antimicrobial analyses revealed significant antibacterial efficacy in compounds 3c and 3f, with IC50 values ranging from 10.75 to 12.83 μg/μL. This article presents a thorough evaluation of the pharmacological activities associated with bisbenzimidazole compounds 3a–l. To validate experimental results, selected compounds exhibiting notable enzyme inhibitory potential were subjected to molecular docking studies, which demonstrated their binding interactions within the active sites of target enzymes. Molecular dynamics simulation studies were carried out for 100 ns to determine the stability of the compounds in target proteins. During the simulation, it was observed that 3 h, 3 g, 3l, and 3e were stable in 4EY7, 4BDS, 3TOP, and 2QV4, respectively. Compounds 3 h, 3 g, 3e, and 3l have been identified as promising candidates for the inhibition of AChE, BChE, α-glycosidase, and α-amylase, respectively.

Sarıoğlu, Ahmet Oral; Türkmenoğlu, Burçin; Kahraman, Demet Taşdemir; Güler, Semih; Sürmelihindi, Bahar; Morcali, Mehmet Hakan

The present study examines the synthesis of Schiff bases through the reaction between 2‑hydroxy-5-nitrobenzaldehyde and sulfacetamide (N-(4-aminophenylsulfonyl)acetamide). The structure of the ligand and metal complexes (Cu+2, Ni+2, Co+2) was characterized using a variety of techniques, including elemental analysis, magnetic susceptibility, molar conductivity, UV–Vis, FT-IR, NMR, and LC-MS/MS. The cytotoxic effects of the complexes and ligand were tested on three cell lines: human epidermoid carcinoma (HTB-54), lung adenocarcinoma (A549), and neuroblast (SH-SY5Y). Furthermore, the antibacterial capabilities of Schiff base and its metal complexes were evaluated against a range of bacterial strains, including B. cereus and S. aureus, as well as resistant gram-positive and gram-negative bacteria like S. typhimurium and E. coli, and fungi like C. albicans. In the computational chemistry section, the physicochemical properties of the synthesized compounds, including EHOMO, ELUMO, ΔEGap, electrophilic index, chemical hardness, chemical potential, electrophilicity index, and chemical softness, were investigated using the B3LYP/6–31G* basis set of density functional theory (DFT).

Hassani, Issam Ameziane El; Brandán, Silvia A.; Altay, Ahmet; Yeniçeri, Esma; Alsalme, Ali; Oulmidi, Afaf; Ansar, M'hammed; Karrouchi, Khalid

A new pyrazole-hydrazide hydrazone derivative, named 5-methyl-N'-(thiophen-2-ylmethylene)-1H-pyrazole-3-carbohydrazide (TMPC) has been synthesized and characterized by FT-IR, UV–Vis, 1H NMR, 13C NMR, and HRMS-ESI. Its cytotoxic activity was tested on various cancer and healthy cell lines using the XTT method. In addition, the advanced anticancer mechanism was investigated by flow cytometry analysis. Hybrid B3LYP/6–311++G** calculations reveal two stable C1 and C2 conformers of TMPC with energy differences of 28.96 kJ/mol in the gas phase and 8.50 kJ/mol in ethanol solution. Comparisons among the experimental NMR, UV and infrared spectra with the predicted ones support the presence of both forms in solution. The presence of dimer C2 justify the intensities and numerous bands observed in the IR spectrum in the 2000–10 cm−1 region. Probably, the repulsion between the N7 and O1 atoms in C1 explain its lower stability and the higher solvation energy (-108.20 kJ/mol) observed for this form in ethanol than C2 (-88.01 kJ/mol). NBO calculations suggest that both forms are stable in the two media while the AIM analyses evidence the higher stability of C2 than C1 due to the N9-H22···N7 interaction observed only for this conformer in the gas phase. Gap values suggest high reactivities of both forms, as compared with similar pyrazole-carbohydrazide species. Full vibrational assignments are reported for both forms of TMPC together with the main scaled force constants. The XTT results showed that TMPC exhibited a selective cytotoxic effect on the tested cancer cell lines in a dose- and time-dependent manner, and also displayed the most potent cytotoxic activity against breast cancer MCF-7 cells with an IC50 value of 22.79 µM after 48 h Flow cytometric analyses showed that TMPC induced apoptosis and suppressed PI3K/Akt signaling in MCF-7 cells.