Browsing by Author "Kuzu, Burak"

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2-Phenyl Substituted Benzimidazole Derivatives: Design, Synthesis, and Evaluation of Their Antiproliferative and Antimicrobial Activities
(Springer Birkhauser, 2022) Ersan, Ronak Haj; Kuzu, Burak; Yetkin, Derya; Alagoz, Mehmet Abdullah; Dogen, Aylin; Burmaoglu, Serdar; Algul, Oztekin
The inability to meet the desired outcomes of anticancer treatment and decrease in treatment success of bacterial and fungal infections accelerated research in these areas. Our research group has conducted numerous studies, especially on benzimidazole ring systems' antiproliferative and antimicrobial activities. In this study, the antiproliferative activity of benzimidazole compounds was tested against A549, A498, HeLa, A375, and HepG2 cancer cell lines by MTT assay. All compounds exhibited good to potent antiproliferative activity against all tested cancer cell lines. Compounds 6-chloro-2-(4-fluorobenzyl)-1H-benzo[d] imidazole (30) and 6-chloro-2-phenethyl-1H-benzo[d]imidazole (46) were especially active against HeLa and A375 cancer cell lines with IC50 values in the range of 0.02-0.04 mu M. In contrast, compounds 6-chloro-2-((p-tolyloxy)methyl)-1H-benzo[d] imidazole (67) and 5(6)-chloro-2-((4-hydroxyphenoxy)methyl)-1H-benzimidazole (68) were active against A549 and A498 cancer cell lines with an IC50 value of 0.08 mu M. These compounds (30, 46, 67, and 68) were less toxic to normal human cells than the positive control compound methotrexate, which was screened to determine its toxicity against normal cell lines (HEK293). In the second part of the study, all compounds were tested to demonstrate their antimicrobial properties. All compounds exhibited moderate activity against all tested bacteria and fungi. However, some phenoxy methyl derivatives 5-chloro-2-((4-chlorophenoxy)methyl)-1H-benzo[d]imidazole (69) and 5,6-dichloro-2-((4-chlorophenoxy)methyl)-1H-benzo[d] imidazole and (74) were most active against Candida (<3.90 mu g/mL). Molecular docking studies were carried out against certain proteins in order to identify potential targets of the antiproliferative effects of the synthesized compounds. The docking scores of the compounds were found to be significantly compatible with the antiproliferative activity results. [GRAPHICS] .
Copper-Catalyzed Synthesis of Fused Imidazopyrazine N-Oxide Skeletons
(Georg Thieme verlag Kg, 2019) Tasdemir, Volkan; Kuzu, Burak; Tan, Meltem; Genc, Hasan; Menges, Nurettin
N-Propargyl-2-aroylimidazoles synthesized and converted into the corresponding ketoximes. Under various conditions, several mono- and diketoxime imidazole derivatives were formed by converting the carbonyl or carbonyl and propargyl groups into oxime groups. N-Propargyl monooxime imidazole derivatives were cyclized by treatment with CuI to give various imidazopyrazine N-oxides. Several copper salts, such as CuOAc, CuSO (4) , and CuOTf, formed the same cyclization product. This cyclization reaction occurred only in the presence of Cu(I) or Cu(II) salts; other transition metals such as Au, Ag, In, and Fe did not yield cyclic products. The nucleus-independent chemical shift method was used to calculate the aromaticity of the bicyclic rings.
Design, Synthesis and in Vitro Antiproliferation Activity of Some 2-Aryl and -Heteroaryl Benzoxazole Derivatives
(Newlands Press Ltd, 2022) Kuzu, Burak; Hepokur, Ceylan; Turkmenoglu, Burcin; Burmaoglu, Serdar; Algul, Oztekin
Background: Phortress produces reactive electrophilic metabolites that form DNA adducts only in sensitive tumor cells. The authors converted the 2-phenylbenzothiazole nucleus in phortress to 2-aryl and -heteroaryl benzoxazole derivatives (11 new and 14 resynthesized). All synthesized compounds were studied for antitumor activity in various cancer cells. Materials & methods: Cytotoxicity, cell morphology, flow cytometry and cell-cycle analyses of compounds were performed and more active derivatives were tested in the MCF-7 cell line. Conclusion: Methyl 2-(thiophen-2-yl)benzo[d]oxazole-6-carboxylate (BK89) has a higher effect than fluorouracil to induce apoptotic cell death (apoptosis value of 49.44%). Cell-cycle analysis shows that the compounds BK89 and methyl 2-(furan-2-yl)benzo[d]oxazole-6-carboxylate (BK82) can be used as potential cell-cycle blockers by arresting MCF-7 cells in G0/G1 phase at rates of 63% and 85%, respectively. Plain language summary There is an urgent need to develop potent and selective anticancer agents. In this study, the design and applications of compounds sensitive to specific cancer cells and targeting cancer cells were investigated. The results show that the synthesized compounds can be antiproliferative drug candidates for breast cancer. These compounds may shed light on cancer treatment and cancer research.
Design, Synthesis, and Antiproliferative Activities of Novel Thiazolyl-Pyrazole Hybrid Derivatives
(Springer Birkhauser, 2023) Kuzu, Burak; Erguc, Ali; Karakus, Fuat; Arzuk, Ege
In this study, a series of derivatives of thiazolyl-pyrazole hybrid structures were designed to search for new heterocyclic compound-based antitumor agents. The designed target structures were synthesized with easy, practical, and efficient procedures. The antiproliferative effect of the synthesized compounds against cancer cell lines A549, MCF-7, and HepG2 was evaluated regarding inhibition concentration and selectivity index against healthy cell line CCD-34Lu. The results overall showed that the compounds had high antiproliferation against cancer cells compared to the doxorubicin-positive control. In particular, compound 11 A549 (SI: 3.58) and HepG2 (SI: 12.36) had high selectivity in cancer cell lines, while compounds 10h and 10o had high selectivity (SI: 10.74 for both) in MCF-7 cancer cell lines. The calculated theoretical pharmacokinetic properties revealed that they could be suitable drug candidates. In addition, in vitro test results indicate a correlation between the structure-activity relationships of the compounds. The various molecular modifications of thiazolyl-pyrazole hybrid compounds are promising for developing new anticancer drug candidates.
Design, Synthesis, and Applications of Nucleic Acid-Specific Benzoxazole-N, N-Dialkylphenylamines Derivatives for Nucleolus Imaging in the Cells
(Elsevier, 2024) Kuzu, Burak; Acikgoz, Eda; Cakir, Mustafa
Considered the brain of the nucleus, alterations in the structure and function of the nucleolus are linked to numerous cellular functions and, consequently, contribute to several diseases. The identification of nucleolar morphology and activity via novel biomarkers presents new avenues for the development of therapeutic approaches for a variety of human diseases, including cancer, neurodegeneration, and aging. Therefore, specific detection of the nucleolus with fluorescence probes is of critical importance for clinical applications. In the present study, a series of benzoxazole- N,N -dialkylphenylamines derivative compounds were designed and synthesized based on the benzothiazole-based fluorescence probe Thioflavin T (ThT). Among the compounds, BX-3 and BX-16, which carry electron -withdrawing substituents in the benzoxazole ring, were observed to have higher fluorescence emission at wavelengths of 470 and 465 nM, respectively. The general morphology and divisions of the cells were examined under inverted and light microscopes, respectively, and the fluorescence potentials of selected compounds were determined using immunofluorescence microscopy. The fluorescence intensity of molecules and 3D interactive surface plot images of cells were analyzed using ImageJ software. Cell imaging analyses showed that BX-6 and BX-13, like ThT, specifically stain the cell nucleolus. Moreover, molecular docking studies showed that the compounds could identify the RNA -rich nucleolus by binding with high affinity to the guanine region in the RNA structure. The results suggest that the compounds may be an initial route in developing specific biosensor compounds for nucleolus imaging.
Design, Synthesis, And Evaluation Of Antibacterial Potential Of Hydrazone-Tethered Pyrazole-Thiazole Derivatives
(University of Ankara, 2025) Kuzu, Burak; Yiğit, Aybek; Karakuş, Fuat
Amaç: Bu çalışma, literatürdeki antimikrobiyal kısım olarak belirlenen tiyazol, hidrazon ve pirazol sistemlerinin hibridizasyonu ile tasarlanan bir seri bileşiğin antimikrobiyal etki potansiyelinin araştırılmasını içermektedir. Tasarlanan bileşiklerin ilaçlanabilirlik parametreleri ile filtrasyonu, seçilen bileşiklerin sentezi ve antibakteriyel etki potansiyelinin in siliko ve in vitro test edilmesi hedeflenmiştir. Gereç ve Yöntem: Sentezlenen bileşiklerin ilaçlanabilirlik özellikleri online tarayıcılar ile belirlenmiş ve en düşük toksisite profiline sahip bileşiklerin E. coli ve S. aureus şujlarındaki potansiyel etkisi disk difüzyon yöntemi ile belirlenmiştir. Ayrıca bileşiklerin dihidrofolat redüktaz (DHFR) enzimine karşı inhibisyon potansiyelini belirlemek için Autodock 4.2 yazılımı kullanılmıştır. Sonuç ve Tartışma: Çalışmamızda, yeni tasarlanan hidrazon bağlı pirazol-tiyazol bileşikleri arasında, ilaçlanabilirlik parametrelerine (17a-c) göre belirlenen bileşikler yüksek verimlilikle sentezlendi. Antibakteriyel aktivite için test edilen bileşikler arasında, Bileşik 17c, 80 μg/ml konsantrasyonunda E. coli suşuna karşı 8 mm ve S. aureus suşuna karşı 9 mm'lik bir zon çapı oluşturdu. Ayrıca, Bileşik 17c, 40 μg/ml konsantrasyonunda E. coli bakteri suşunda 7 mm'lik, S. aureus bakteri suşunda 8 mm’lik bir zon çapı oluşturdu. İlaveten, sunulan bileşiklerin ADMET profilleri, bunların potansiyel antibakteriyel ajanlar olarak uygun ilaçlanabilirlik parametrelerine sahip olabileceğini göstermektedir.
Design, Synthesis, and Evaluation of Pyrrolopyrazine-Substituted Benzoxazole/Benzothiazole Derivatives Targeting Aurora Kinase a in Mcf-7 Cells
(Wiley-V C H Verlag Gmbh, 2025) Kuzu, Burak; Kostekci, Sedat; Karakus, Fuat; Tuluce, Yasin
This study reports the synthesis, characterization, and biological evaluation of 19 benzoxazole/benzothiazole hybrids (19a-s). The compounds were synthesized through a multi-step process and structurally confirmed via NMR, elemental, and MS analyzes. Their antiproliferative effects were assessed on MCF-7 breast cancer and HME1 healthy epithelial cells. MTT assays identified 15 compounds with significant cytotoxic activity, among which 19e, 19g, 19i, 19j, and 19k exhibited high selectivity for MCF-7 cells. ELISA results demonstrated that 19g, 19i, 19j, and 19k significantly reduced AURKA protein levels in MCF-7 cells, while sparing healthy cells, suggesting their role in inhibiting cancer cell proliferation. These findings highlight 19g, 19i, 19j, and 19k as promising selective AURKA-targeted agents for breast cancer therapy.
Development of Benzoxazole Derivatives Targeting Mtor: a Promising Approach for Breast Cancer Therapy
(Wiley-V C H Verlag Gmbh, 2025) Alagoz, Mehmet Abdullah; Resitoglu, Meryem Temiz; Kuzu, Burak; Sabrie, Zainab; Yetkin, Derya; Zobi, Cengiz; Algul, Oztekin
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 mu M. 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 & Aring; and 3.0 & Aring;, 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.
Discovery of New Pyrazole-Tosylamide Derivatives as Apoptosis Inducers Through Bcl-2 Inhibition and Caspase-3 Activation
(Wiley-v C H verlag Gmbh, 2025) Kuzu, Burak; Arzuk, Ege
In this presented study, a series of new carbonitrile-substituted pyrazole-tosyl amide derivatives were designed and synthesized according to previous studies. The antiproliferative effects of the synthesized compounds on MDA-MB-231, MCF-7, HepG2, PC-3, and A549 cancer cell lines were assessed by MTT assay compared with non-cancerous cells. The results demonstrate that compounds 9d, 9e, and 9f had a higher antiproliferative effect (IC50 <10 mu M) against both breast cancer cells. To investigate the ability of these compounds (9d-f) to induce apoptosis against breast cancer cells, BCL-2 levels and Caspase-3 activities of compound-treated breast cancer cell lines were measured by ELISA. The results revealed that these compounds significantly inhibited the levels of anti-apoptotic protein BCL-2 and increased the activity of apoptotic protein Caspase-3 in MDA-MB-231 and MCF-7 cells. Molecular docking studies confirmed that the selected compounds have high binding affinity towards the active site in the crystal structures of BCL-2 and Caspase-3. Moreover, drug-likeness and pre-ADMET evaluation showed that the compounds had suitable drug properties. This study may be a new milestone in terms of the promising importance of carbonitrile-substituted pyrazole-tosyl amide scaffolds as apoptosis-inducing agents for cancer therapy in the future.
An Easy Synthetic Protocol for Imidazo-1,4 and Evaluation of Their Toxicities
(Wiley-hindawi, 2018) Kuzu, Burak; Genc, Hasan; Taspinar, Mehmet; Tan, Meltem; Menges, Nurettin
Imidazo-1,5-alkynyl alcohol derivatives were synthesized, and they were cyclized to imidazo-1,4-oxazines by means of cesium carbonate. Propargyl-allene isomerization was examined, and the reaction mechanism was proposed. Moreover, cytotoxicity of synthesized molecules against LN405 cell lines was investigated by means of structure-activity relationship (SAR). With SAR study, toxicities of some functional groups have been shown. In addition, two lead compounds were tested against DNA damaging.
Excited State Intramolecular Proton Transfer (esipt)-Based Sensor for Ion Detection
(Springer/plenum Publishers, 2021) Kuzu, Burak; Ekmekci, Zeynep; Tan, Meltem; Menges, Nurettin
C-2 and C-5 substituted imidazole skeleton was synthesized through a one-pot two-step strategy. Synthesized molecule emits the light on ESIPT (excited-state intramolecular proton transfer). This molecule was utilized for its proton donor ability, and we have observed that fluoride and cyanide ions can be detected selectively. Different cations and anions were selected to observe the response of the synthesized molecule. However, there were not any fluorometric and colorimetric response except for fluoride and cyanide ions. Detection limits of fluoride and cyanide ions were found to be 9.22 mu M and 11.48 mu M, respectively. H-1-NMR spectra for the solution of the sensor and TBAF (tetrabuthylammoniumfluoride) were used for the identification of [L](-)[HF2](-) species. 3 equiv. TBAF saturated the solution of the sensor in d(6)-DMSO, and some of the proton resonances shifted to upfield due to the through-bond effect. The disappearance of NH proton with 0.5 equiv. TBAF or TBACN (tetrabuthylammoniumcyanide) showed that there was a proton abstraction by fluoride and cyanide ions, instead of the hydrogen bond. Solid-state application was utilized, and paper test strips were applied. Emission differences emerged when the sensor loaded strips were reacted with TBAF. Time resolved experiments revealed that solution of the sensor and TBAF in DMSO have multiexponential decay, and one of the lifetime was measured as 13.4 ns.
Exploring New 5-Nitroimidazole Derivatives as Potent Acetylcholinesterase and Butyrylcholinesterase Enzyme Inhibitors
(Wiley-v C H verlag Gmbh, 2024) Gursoy, Sule; Satici, Doruk; Kuzu, Burak; Turkmenoglu, Burcin; Dilek, Esra; Algul, Oztekin
Discovering new compounds capable of inhibiting physiologically and metabolically significant drug targets or enzymes is of paramount importance in biological chemistry. With this aim, new 5-nitroimidazole derivatives (1-4) were designed and synthesized, and their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were discovered using acetyl (butyryl) thiocholine and Ellman's reagents for spectrophotometric assay. The inhibitory profiles of the synthesized compounds were assessed by comparing their IC50 and Ki values. Results demonstrate significant inhibitory activity of all synthesized compounds against both AChE and BuChE compared to the reference compound, donepezil. Notably, compound 4 exhibited dual inhibition of these enzymes, showing the highest activity against Electrophorus electricus AChE (EeAChE) with a Ki value of 0.024 +/- 0.009 nM and against equine BuChE (eqBuChE) with a Ki value of 0.087 +/- 0.017 nM. Furthermore, molecular modeling was conducted to study the interaction modes of the most potent compound (4) and donepezil in the active site of their related enzymes' crystal structures (PDB ID: 4EY7 and 4BDS, respectively). Additionally, drug-likeness, ADME, and toxicity profiles of the compounds and metronidazole were predicted. The above results indicated that the dual inhibition of these enzymes is considered as a promising strategy for the treatment of neurological disorder especially Alzheimer's disease.
Imidazo[1,2-A]pyridine Mannich Bases: Synthesis, Anticholinesterase Evaluation, and in Silico Studies
(Springer int Publ Ag, 2025) Kuzu, Burak; Demir, Yeliz
In this study, a series of imidazo[1,2-a]pyridine-mannich bases were designed and synthesized for the inhibition of cholinesterases, one of the important pathways in the treatment of Alzheimer's dementia. The imidazopyridine scaffold, which is found in the structure of many active compounds in pharmaceutical use, is derived from Mannich-bases containing morpholine and various aromatic groups. In vitro AChE and BChE enzyme activities and enzyme kinetics studies of new potential drug candidates (9a-j) that can target the critical binding regions of cholinesterases were conducted. In vitro evaluation with donepezil, tacrine (control compounds), and 9a-j, it was found that naphthalene-substituted compound 9j exhibited the most potential anti-cholinesterase activity (IC50s: 57.75 nM for AChE; 99.0 nM for BChE). Molecular docking studies performed with hAChE and hBChE enzyme crystal structures revealed that compound 9j has a higher binding affinity by targeting the CAS and PAS binding sites. Additionally, drug-likeness and pre-ADMET evaluation of the compounds showed that compound 9j had the most favorable drug properties. These results might be a new milestone in terms of the promising importance of the imidazopyridine scaffold in future drug design for the treatment of AD.
Imidazopyridine Scaffold as an Effective Tubulin Polymerization Inhibitor
(Istanbul Univ, Fac Pharmacy, 2024) Kuzu, Burak
Tubulin and the tubulin cycle, which have many vital cellular functions in living cells, are privileged targets for the development of anticancer drug candidates. In the processing of cellular processes, especially cell division, alpha and beta tubulin polymerize to form microtubules and continue the cycle by depolymerizing again. Disruption of the polymerization-depolymerization dynamics of microtubules by various agents causes mitotic cell arrest and subsequent cell death via apoptosis. This review summarizes the tubulin cycle, cancer, and target regions. Tubulin has three main target binding sites: taxane, vinca, and colchicine. In particular, the colchicine binding site, which is the current target for disrupting the tubulin cycle, is inhibited by various synthetic compounds, and the common properties of these compounds are emphasized. The results show that highly effective cytotoxic agents can be developed by modifying the imidazopyridine scaffold, which remains open to exploration. The remarkable antitubulin and cytotoxic effects of recently developed compounds with an imidazopyridine ring are interesting. A detailed report of anti-tubulin agents with imidazopyridine structures, among the tubulin polymerization inhibitors developed to date, and an evaluation of the structure-activity relationship is presented here. In addition, the new molecular topology established in this review based on the structure-activity relationships of imidazopyridine will inspire research groups to develop new imidazopyridine-based anti-tubulin agents with clinical anticancer potential in the near future.
An in Silico Analysis of Dicofol-Induced Neurotoxicity Mechanisms in Humans
(Pergamon-elsevier Science Ltd, 2025) Karakus, Fuat; Kuzu, Burak
Dicofol (DCF) is an organochlorine pesticide that has recently been recognized as a persistent organic pollutant. This study begins by investigating the neurotoxicity of DCF and its metabolites through in silico tools. It subsequently explores the molecular mechanisms and key targets associated with DCF-induced neurotoxicity in humans by employing network toxicology, multi-level bioinformatics approaches, and molecular docking analyses. The prediction results indicate that both DCF and its metabolites can traverse the blood-brain barrier, penetrating the central nervous system, and inducing neurotoxicity. A thorough analysis has identified 56 potential targets linked to DCF-induced neurotoxicity. Gene Ontology enrichment analysis revealed significant associations with pathways related to sodium ion transmembrane transport, sodium/potassium-exchanging ATPase complexes, and P-type calcium transporter activity. Pathway enrichment analysis suggests that DCFinduced neurotoxicity arises from disruptions in ion transport via P-type ATPases. Further examination of gene-gene and protein-protein interactions, along with centrality analysis, identified 11 hub targets, including ATP1A1, ATP1A2, ATP1A3, ATP1A4, ATP1B1, ATP1B2, and MAPK1, as key players. Notably, six of these targets are subunits of the Na+/K+-ATPase, a P-type ATPase. Molecular docking results demonstrated that DCF binds more effectively to the ATP1A3-ATP1B1 protein complex than to its natural ligand, ATP. These findings suggest that DCF may inhibit Na+/K+-ATPase through ATP1A3, resulting in an imbalance of sodium and potassium gradients and ultimately leading to neurotoxicity.
In Silico Network Toxicology, Molecular Docking, and Multi-Level Bioinformatics Reveal Methyl Eugenol-Induced Hepatocellular Carcinoma Mechanisms in Humans
(Wiley, 2025) Karakus, Fuat; Tanriverdi, Zuebeyde; Kuzu, Burak
BackgroundMethyl eugenol (ME), a natural compound found in various essential oils, has recently been classified as a Group 2A carcinogen by the International Agency for Research on Cancer.MethodsThis study aims to investigate the potential molecular mechanisms and underlying ME-induced hepatocellular carcinoma (HCC) in humans using network toxicology, molecular docking, and integrative bioinformatics approaches, including transcriptomic and survival analyses of human HCC datasets.ResultsEnrichment analysis highlighted significant associations with pathways related to steroid metabolic processes, extracellular exosomes, and diverse binding activities. KEGG pathway enrichment further implicated metabolic pathways in ME-induced HCC development. Integration of STRING and Cytoscape analyses identified 14 hub targets, including key proteins such as AURKB, CCNB1, CDK1, and PLK1. Molecular docking studies demonstrated weak binding affinities of ME to these targets compared to their specific inhibitors. However, microarray data and survival analyses of human HCC samples revealed that AURKB, CCNB1, CDK1, and PLK1 are upregulated in HCC, with higher expression levels correlating with poorer overall survival, particularly for CCNB1.ConclusionsThese findings suggest that ME exposure may enhance the expression of these genes in hepatocytes, disrupting the cell cycle and promoting proliferation. This study provides valuable insights into the molecular mechanisms of ME-induced HCC in humans and highlights potential therapeutic targets, such as CCNB1, for further investigation.
Indole-Containing New Types of Dyes and Their Uv-Vis and Nmr Spectra and Electronic Structures: Experimental and Theoretical Study
(Pergamon-elsevier Science Ltd, 2016) Kuzu, Burak; Menges, Nurettin
Indole containing dyes were synthesized via a simple method with high yield. These molecules have different colors and UV-vis spectra of them were recorded. Impact of solvents on absorbances was investigated and it was observed that basic solvent such as DMF and pyridine have blue shift. TD-DFT calculations were done and results were compared with experimental data. NMR data of molecules were analyzed and tautomeric forms of colorants and their ratio were determined. It was find out that two tautomers might be formed in solution, called indole and indolenine form. HOMO-LUMO and energy gaps were calculated and plotted. Furthermore, molecular electrostatic potentials were simulated to find out electrophilic and nucleophilic regions. (C) 2016 Elsevier B.V. All rights reserved.
Mechanisms of Developmental Neurotoxicity of Dechlorane Plus, a Recently Identified Persistent Organic Pollutant: An in Silico Study
(Elsevier, 2025) Karakus, Fuat; Tanriverdi, Zubeyde; Kuzu, Burak
Dechlorane Plus (DP), a polychlorinated flame retardant, has recently been recognized as a persistent organic pollutant. In this study, the molecular mechanisms and targets associated with DP-induced developmental neurotoxicity (DNT) in humans were investigated through network toxicology, multi-level bioinformatics approaches, and molecular docking. Through comprehensive database analysis, 32 potential targets associated with DP-induced DNT were identified. Gene Ontology terms enrichment analysis revealed significant enrichment in pathways related to the nervous system processes, GABA-A receptor complex, and various binding and channel activities. KEGG pathway enrichment analysis indicated that DP-induced DNT is mediated through complex interactions involving neuroactive ligand-receptor interaction pathways. Further analysis using GeneMANIA, STRING, Cytoscape tools, and MCODE identified 11 hub targets, including GABRA1, GABRB1, GABRB3, and GABRG2 as key targets. Molecular docking revealed that DP binds to the GABRB3-GABRA1-GABRG2 protein complex to a degree comparable to the control bicuculline, a potent and selective antagonist of the GABA-A receptor. These findings suggest that DP may have antagonistic effects on the GABA-A receptor, potentially increasing neuronal excitability. This study offers valuable insights into the molecular mechanisms underlying DP-induced DNT and provides data for in vitro or in vivo studies.
Mechanistic Analysis of Decabromodiphenyl Ether-Induced Neurotoxicity in Humans Using Network Toxicology and Molecular Docking
(Springer, 2025) Karakus, Fuat; Kuzu, Burak
Commercial decabromodiphenyl ether (c-decaBDE) is a widely used additive flame retardant in textiles and plastics. This formulation predominantly consists of the congener BDE-209, with trace amounts of other brominated diphenyl ether congeners, such as nonabromodiphenyl ether and octabromodiphenyl ether. Recognized as a persistent organic pollutant due to its potential for long-range environmental transport, c-decaBDE poses significant environmental threats and serious human health risks, including endocrine, reproductive, developmental, and neurotoxic effects. The mechanisms underlying its neurotoxicity remain largely undefined. This study investigates the neurotoxic effects of BDE-209 in humans through network toxicology, multi-level bioinformatics approaches, and molecular docking analyses. Prediction results indicate that BDE-209 can cross the blood-brain barrier, entering the central nervous system and inducing neurotoxic effects. A comprehensive analysis has identified 294 potential targets linked to the neurotoxicity induced by BDE-209. Gene-gene interaction and pathway enrichment analyses revealed significant associations related to cellular responses to chemical stress and synaptic transmission. Further investigation of protein-protein interactions, combined with centrality analysis, identified 14 hub targets, including CaMK-II alpha, PSD-95, GluR-1, and GluN2B, as key proteins in this process. Molecular docking results indicate that BDE-209 exhibits a stronger binding affinity to GluN2B, a subunit of the N-methyl-D-aspartate (NMDA) receptors, compared to other key targets. These findings suggest that BDE-209 may disrupt the function of GluN2B-containing NMDA receptors, potentially leading to their inhibition. Such inhibition could result in reduced excitatory neurotransmission, impairing synaptic potentiation and plasticity, and ultimately contributing to neurotoxicity.
Mono- or Di-Substituted Imidazole Derivatives for Inhibition of Acetylcholine and Butyrylcholine Esterases
(Academic Press inc Elsevier Science, 2019) Kuzu, Burak; Tan, Meltem; Taslimi, Parham; Gulcin, Ilhami; Taspinar, Mehmet; Menges, Nurettin
Mono- or di-substituted imidazole derivatives were synthesized using a one-pot, two-step strategy. All imidazole derivatives were tested for AChE and BChE inhibition and showed nanomolar activity similar to that of the test compound donepezil and higher than that of tacrine. Structure activity relationship studies, docking studies to on X-ray crystal structure of AChE with PDB code 1B41, and adsorption, distribution, metabolism, and excretion (ADME) predictions were performed. The synthesized core skeleton was bound to important regions of the active site of AChE such as the peripheral anionic site (PAS), oxyanion hole (OH), and anionic subsite (AS). Selectivity of the reported test compounds was calculated and enzyme kinetic studies revealed that they behave as competitive inhibitors, while two of the test compounds showed noncompetitive inhibitory behavior. ADME predictions revealed that the synthesized molecules might pass through the blood brain barrier and intestinal epithelial barrier and circulate freely in the blood stream without binding to human serum albumin. While the toxicity of one compound on the WS1 (skin fibroblast) cell line was 1790 mu M, its toxicity on the SH-SY5Y (neuroblastoma) cell line was 950 mu M.