Sürdürülebilir Kalkınma Amaçları
Yayınlar
- ArticleYalnız künye2026Esculetin attenuates doxorubicin-induced cardiac toxicity: Evidence from gene expression, enzyme activity, and molecular docking analyses
Demir, Yeliz; Ceylan, Hamid; Yeşilkent, Esra Nur; Kizir, Duygu; Karaman, Melike; Türkeş, Cüneyt; Beydemir, Şükrü
Doxorubicin (DOX) is a potent chemotherapeutic agent whose dose-dependent cardiotoxicity is associated with oxidative stress, inflammation, and enzymatic dysfunction. This study evaluates the cardioprotective potential of esculetin, a natural coumarin derivative, against DOX-induced cardiac injury in rats. Forty-eight male Sprague-Dawley rats were divided into six groups, including control, DOX, esculetin (50 and 100 mg/kg), and combination treatments. DOX markedly altered the expression of oxidative stress-related genes (Ache, Ar, Sord upregulated; Pon1, Gst downregulated) and impaired enzyme activities, accompanied by increased malondialdehyde and depleted glutathione levels. Esculetin administration, particularly at 100 mg/kg, reversed these molecular and biochemical disturbances, restoring antioxidant defense and normalizing gene expression. Molecular docking revealed strong binding interactions of esculetin with the active sites of key enzymes including AR, SORD, AChE, GST, and PON1, supporting its regulatory role. These findings suggest that esculetin exerts multi-targeted protective effects and may serve as a promising candidate for mitigating chemotherapy-induced cardiotoxicity. Further research is warranted to explore its integration into clinical cardioprotective strategies.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2026Marine algae-derived polyamines and phlorotannins as cholinesterase inhibitors: In vitro and in silico analysis
Necip, Adem; Işık, Mesut; Türkeş, Cüneyt; Ünal, Dilek; Kırboğa, Kevser Kübra; Beydemir, Şükrü; Rudrapal, Mithun
The limitations of conventional cholinesterase inhibitors in Alzheimer's disease (AD) therapy namely, their short half-lives and adverse side effects—necessitate the exploration of natural alternatives. This investigation examined the inhibitory potential of selected polyamines (putrescine and spermidine) and a phlorotannin derivative (phloroglucinol), naturally present in the macroalgae species Cystoseira crinita and Stypopodium schimperi, against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using in vitro and in silico approaches. Additionally, radical scavenging potentials of each sample were determined. Enzyme activity assays employing the Ellman method revealed that putrescine and spermidine reached similar inhibition levels (approximately 32 %), while Cystoseira crinita acetone extract demonstrated superior potency with an IC50 of 0.085 mg/mL, indicating robust enzyme modulation. Complementary molecular docking studies conducted with Schrödinger Maestro 2020 elucidated the formation of stable enzyme-ligand complexes through hydrogen bonding and π-π interactions with critical residues including HIS447, TYR337, and TRP86 within the AChE active site. Moreover, crude macroalgal extracts, particularly those derived from C. crinita and S. schimperi, exhibited marked AChE inhibition, further substantiating the therapeutic potential of these marine-derived compounds. Collectively, these findings demonstrate that the polyamines and phlorotannin derivative studied not only effectively regulate cholinesterase activity but also offer naturally derived structural frameworks for the development of novel AD treatments. Phloroglucinol showed a high scavenging of DPPH (85%) and ABTS (98%) radicals, close to the activity of the reference compound trolox (96% for DPPH and 94% for ABTS). Further pharmacokinetic and toxicological evaluations are warranted to ascertain their clinical viability in AD management.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2026Mono- and Bis-Ureido Sulfapyridines as Nanomolar Dual Cholinesterase Inhibitors: Enzyme Kinetics, Molecular Docking, and ADME/Tox Insights
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.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025New N-(1,3,4-thiadiazole-2-yl)acetamide derivatives as human carbonic anhydrase I and II and acetylcholinesterase inhibitors
Dawbaa, Sam; Türkeş, Cüneyt; Nuha, Demokrat; Demir, Yeliz; Evren, Asaf Evrim; Yurttaş, Leyla; Beydemir, Şükrü
Various carbonic anhydrase (CA) enzyme isoforms are known today. In addition to the use of CA inhibitors as diuretics, antiepileptics and antiglaucoma agents, the inhibition of other specific isoforms of CA was reported to have clinical benefits in cancers. In this study, two groups of 1,3,4-thiadiazole derivatives were designed and synthesized to act as human CA I and II (hCA I and hCA II) inhibitors. The activities of these compounds were tested in vitro and evaluated in silico studies. The activity of the synthesized compounds was also tested against acetylcholinesterase (AChE) to evaluate the relation of the newly designed structures to the activity against AChE. The synthesized compounds were analyzed by 1H NMR,13C NMR and high-resolution mass spectroscopy (HRMS). The results displayed a better activity of all the synthesized compounds against hCA I than that of the commonly used standard drug, Acetazolamide (AAZ). The compounds also showed better activity against hCA II, except for compounds 5b and 6b. Only compounds 6a and 6c showed superior activity against AChE compared to the standard agent, tacrine (THA). In silico studies, including absorption, distribution, metabolism and excretion (ADME) and drug-likeness evaluation, molecular docking, molecular dynamic simulations (MDSs) and density functional theory (DFT) calculations, were compatible with the in vitro results and presented details regarding the structure–activity relationship.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025Therapeutic potential of Laurus nobilis extract by experimental and computational approaches: phenolic content and bioactivities for antioxidant, antidiabetic, and anticholinergic properties
Altın, Sevgi; Işık, Mesut; Alp, Cemalettin; Dikici, Emrah; Köksal, Ekrem; Kırboğa, Kevser Kübra; Rudrapal, Mithun; Rakshit, Gourav; Beydemir, Şükrü; Khan, Johra
Introduction: Laurus nobilis (LN), has traditional medicinal uses, and this study investigates its therapeutic potential by focusing on its phenolic content and bioactivities such as antioxidant, antidiabetic, and anticholinergic properties. Phenolic compounds play key roles in reducing oxidative stress and modulating enzymatic activities, relevant to metabolic and neurodegenerative disorders. Methods: LN leaf extracts were prepared via ethanol maceration, followed by filtration and concentration. Phenolic content was analyzed using LC-MS/MS. Antioxidant activity was assessed through ferric thiocyanate, DPPH, ABTS, and FRAP assays. Enzyme inhibition assays targeted AChE, BChE, and α-GLY, with IC50 values from dose-response curves. In silico analyses were conducted using molecular docking techniques to predict the binding mechanisms of identified phenolic compounds with the active sites of target enzymes, evaluating binding affinities and interaction profiles. Results: Vanillic acid and catechin hydrate were the most abundant phenolics. LN extract showed strong lipid peroxidation inhibition (50.53%) compared to Trolox (28.33%) and α-tocopherol (37.79%). Moderate radical scavenging and metal reduction potentials were observed. IC50 values were 2.57 µg/L for AChE, 3.78 µg/L for BChE, and 4.65 µg/L for α-GLY, indicating notable bioactivity. In silico studies confirmed strong binding affinities of phenolics to target enzymes. Discussion: LN extracts demonstrated promising antioxidant, antidiabetic, and anticholinergic activities, attributed to high phenolic content. Enzyme inhibition results suggest potential in managing metabolic and neurodegenerative disorders. In silico findings support these bioactivities, highlighting LN’s therapeutic potential.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2025Esculetin Attenuates Doxorubicin-Induced Cardiotoxicity via Modulation of Apoptotic and Mitochondrial Gene Expression Networks
Demir, Yeliz; Ceylan, Hamid; Karağaç, Medine Sibel; Türkeş, Cüneyt; Karaman, Melike; Beydemir, Şükrü
Doxorubicin (DOX), although widely used as a potent chemotherapeutic agent, is limited by its dose-dependent cardiotoxicity. Esculetin (E), a naturally occurring coumarin derivative, has been reported to exert antioxidant and anti-apoptotic effects in various tissues. This study aimed to evaluate the cardioprotective effects of esculetin against DOX-induced cardiac injury in rats by examining changes in the expression of genes related to apoptosis, oxidative stress, and mitochondrial function. Male Wistar rats were randomly assigned into six groups (Control, DOX, E50, E100, DOX + E50, DOX + E100). Cardiotoxicity was induced by administering DOX was administered as six intraperitoneal injections of 5 mg/kg each over 14 days (cumulative dose = 30 mg/kg). Serum cardiac markers (CK-MB, LDH, and cTn-I) were measured, and cardiac tissues were subjected to histopathological examination and RT-qPCR analysis for target gene expression. In addition, hierarchical clustering heatmap was employed to evaluate multidimensional gene expression patterns across groups. DOX treatment significantly elevated serum cardiac injury markers and upregulated pro-apoptotic genes (Casp3, Casp9, Anf, Bnp, β-Mhc), while downregulating genes associated with mitochondrial biogenesis (Pgc1α) and antioxidant response (Foxo1, Cox2). These findings suggest esculetin as a potential adjunctive candidate for cardioprotection during DOX chemotherapy. However, given the absence of protein-level validation, further studies are warranted to confirm whether the observed gene expression changes translate into corresponding alterations at the protein level.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025Novel Schiff Base Sulfonate Derivatives as Carbonic Anhydrase and Acetylcholinesterase Inhibitors: Synthesis, Biological Activity, and Molecular Docking Insights
Yaşar, Ümit; Demir, Yeliz; Gönül, İlyas; Özaslan, Muhammet Serhat; Çelik, Gizem Gümüşgöz; Türkeş, Cüneyt; Beydemir, Şükrü
Sulfonate derivatives are an essential class of compounds with diverse pharmacological applications. This study presents the synthesis and detailed characterization of six novel Schiff base sulfonate derivatives (L1–L6) through spectroscopic techniques (FT-IR and NMR). Their inhibitory potential was evaluated against human carbonic anhydrase isoenzymes (hCA I and hCA II) and acetylcholinesterase (AChE), which are crucial therapeutic targets for diseases such as glaucoma, epilepsy, and Alzheimer's disease. The KI values for the compounds concerning AChE, hCA I, and hCA II enzymes were in the ranges of 106.10 ± 14.73 to 422.80 ± 17.64 nM (THA: 159.61 ± 8.41 nM), 116.90 ± 24.40 to 268.00 ± 35.84 nM (AAZ: 439.17 ± 9.30 nM), and 177.00 ± 35.03 to 435.20 ± 75.98 nM (AAZ: 98.28 ± 1.69 nM), respectively. Molecular docking analyses revealed key interactions within the active sites of the enzymes, including hydrogen bonding with critical residues and π–π stacking interactions. Notably, L3 demonstrated superior inhibition against hCA I (KI: 116.90 ± 24.40 nM) and AChE (KI: 106.10 ± 14.73 nM), positioning it as a promising lead compound. This comprehensive investigation contributes to the development of isoform-specific inhibitors for therapeutic use and provides valuable insights into their binding mechanisms. The findings underscore the potential of Schiff base sulfonates as scaffolds in drug discovery for neurodegenerative and metabolic disorders.
RDL Kalıcı Kaydıİncele - ArticleAçık 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; Koçyiğit, Ümit Muhammet; Işık, Mesut; Türkeş, Cüneyt; Topal, Fevzi; Durgun, Mustafa; Beydemir, Şükrü
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 KI 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.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2025Phenolic Content, Antioxidant Capacity, and Therapeutic Potential of Mango (Mangifera indica L.) Leaves
Işık, Mesut; Dikici, Emrah; Altın, Sevgi; Alp, Cemalettin; Kırboğa, Kevser Kübra; Köksal, Ekrem; Beydemir, Şükrü
The phenolic composition, antioxidant capacity, and enzyme inhibition activities of Mangifera indica L. leaf (MLs) ethanol extract were comprehensively evaluated to explore its therapeutic and industrial applications. Quantitative profiling of 21 phenolic compounds was performed using the LC–MS/MS method, with vanillic acid (1242.47 μg/L), gallic acid (283.58 μg/L), and quercetin (102.40 μg/L) identified as the most abundant constituents. Antioxidant activities were assessed through DPPH, ABTS, FRAP, and CUPRAC assays, revealing moderate radical scavenging (DPPH: 26.87% ± 2.25%, ABTS: 14.65% ± 1.83%) and metal reduction capacities (FRAP: 0.118 ± 0.07, CUPRAC: 0.172 ± 0.03). In addition, MLs extract demonstrated dose-dependent inhibitory effects on acetylcholinesterase (AChE, IC50: 18.73 μg/mL), butyrylcholinesterase (BChE, IC50: 8.56 μg/mL), and α-glucosidase (IC50: 10.83 μg/mL), highlighting its potential in the management of neurodegenerative diseases such as Alzheimer's and metabolic disorders including diabetes. The findings emphasize the bioactive potential of M. indica leaves, positioning them as a promising resource for sustainable valorization. By showcasing the applicability of this agricultural by-product, the study provides a foundation for innovations in the food, nutraceutical, and pharmaceutical sectors. Nevertheless, further in vivo and clinical investigations are essential to fully validate their safety and therapeutic efficacy.
RDL Kalıcı Kaydıİncele - ArticleAçık 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; Koçyiğit, Ümit Muhammet; Türkeş, Cüneyt; Işık, Mesut; Beydemir, Şükrü
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.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024The effects of morin and methotrexate on pentose phosphate pathway enzymes and GR/GST/TrxR enzyme activities: An in vivo and in silico study
Caglayan, Cuneyt; Temel, Yusuf; Türkeş, Cüneyt; Ayna, Adnan; Ece, Abdulilah; Beydemir, Şükrü
In this study, the mechanisms by which the enzymes glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), glutathione reductase (GR), glutathione-S-transferase (GST), and thioredoxin reductase (TrxR) are inhibited by methotrexate (MTX) were investigated, as well as whether the antioxidant morin can mitigate or prevent these adverse effects in vivo and in silico. For 10 days, rats received oral doses of morin (50 and 100 mg/kg body weight). On the fifth day, a single intraperitoneal injection of MTX (20 mg/kg body weight) was administered to generate toxicity. Decreased activities of G6PD, 6PGD, GR, GST, and TrxR were associated with MTX-related toxicity while morin treatment increased the activity of the enzymes. The docking analysis indicated that H-bonds, pi–pi stacking, and pi–cation interactions were the dominant interactions in these enzyme-binding pockets. Furthermore, the docked poses of morin and MTX against GST were subjected to molecular dynamic simulations for 200 ns, to assess the stability of both complexes and also to predict key amino acid residues in the binding pockets throughout the simulation. The results of this study suggest that morin may be a viable means of alleviating the enzyme activities of important regulatory enzymes against MTX-induced toxicity.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Novel asymmetric biscarbothioamides as Alzheimer's disease associated cholinesterase inhibitors: synthesis, biological activity, and molecular docking studies
Muğlu, Halit; Yakan, Hasan; Erdoğan, Musa; Topal, Fevzi; Topal, Meryem; Türkeş, Cüneyt; Beydemir, Şükrü
Exploring novel frameworks for treating Alzheimer's disease is an ambitious objective. In this particular context, a range of asymmetric biscarbothioamide derivatives (3a-l) with varying substitutions have been meticulously designed and effectively synthesized. The newly synthesized compounds have all been definitively characterized using established spectroscopic techniques such as 1H-NMR, 13C-NMR, FT-IR, and elemental analysis. In vitro, all the derivatives (3a-l) were evaluated to assess their inhibitory potential against cholinesterase enzymes (acetylcholinesterase, AChE, and butyrylcholinesterase, BChE). The outcomes demonstrated that these derivatives were potent and exhibited selectivity in inhibiting AChE, except for compounds 3b and 3e, which specifically inhibited BChE, showcasing varying degrees of KI values. Significantly, compounds 3j (KIs of 11.91 ± 2.25 nM for AChE and 77.76 ± 8.02 nM for BChE) and 3h (KIs of 14.73 ± 2.30 nM for AChE and 59.54 ± 6.20 nM for BChE) emerged as the most potent dual inhibitors of AChE and BChE within the series, respectively, with KI constants even lower than those of the standard drug tacrine (KIs of 68.70 ± 5.39 nM for AChE and 111.60 ± 10.52 nM for BChE). Furthermore, their potential scavenging activity against DPPH and ABTS radicals was evaluated. To further validate the experimental findings, molecular docking studies were performed in silico to ascertain the binding modes of these compounds with the active pockets of AChE and BChE enzymes.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Protective effects of esculetin against doxorubicin-induced toxicity correlated with oxidative stress in rat liver: In vivo and in silico studies
Köroğlu, Zeynep; Kizir, Duygu; Karaman, Melike; Demir, Yeliz; Türkeş, Cüneyt; Beydemir, Şükrü
Doxorubicin (DOX) is widely used in cancer treatment but the dose-related toxicity of DOX on organs including the liver limit its use. Therefore, there is great interest in combining DOX with natural compounds with antioxidant properties to reduce toxicity and increase drug efficacy. Esculetin is a natural coumarin derivative with biological properties encompassing anti-inflammatory and antioxidant activities. In light of these properties, this study was meticulously crafted to investigate the potential of esculetin in preventing doxorubicin (DOX)-induced hepatotoxicity in Sprague-Dawley rats. The rats were divided into a total of six groups: control group, DOX group (administered DOX at a cumulative dose of 5 mg/kg intraperitoneally every other day for 2 weeks), E50 group (administered 50 mg/kg of esculetin intraperitoneally every day), E100 group (administered 100 mg/kg of esculetin intraperitoneally every day) and combined groups (DOX + E50 and DOX + E100) in which esculetin was administered together with DOX. The treatments, both with DOX alone and in combination with E50, manifested a reduction in catalase (CAT mRNA) levels in comparison to the control group. Notably, the enzymatic activities of superoxide dismutase (SOD), CAT, and glutathione peroxidase (GPx) witnessed significant decreases in the liver of rats treated with DOX. Moreover, DOX treatment induced a statistically significant elevation in malondialdehyde (MDA) levels, coupled with a concurrent decrease in glutathione (GSH) levels. Additionally, molecular docking studies were conducted. However, further studies are needed to confirm the hepatoprotective properties of esculetin and to precisely elucidate its mechanisms of action.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024New naphthoquinone thiazole hybrids as carbonic anhydrase and cholinesterase inhibitors: Synthesis, crystal structure, molecular docking, and acid dissociation constant
Efeoglu, Cagla; Selcuk, Ozge; Demir, Bunyamin; Sahin, Ertan; Sari, Hayati; Türkeş, Cüneyt; Demir, Yeliz; Nural, Yahya; Beydemir, Şükrü
In this study, N-[3-(3-amino-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-R-thiazol-2(3H)-ylidene]-2,6-difluorobenzamide derivatives as new 1,4-naphthoquinone thiazole hybrids were synthesized by reacting of N-[(3-amino-1,4-dioxo-1,4-dihydronaphthalen-2-yl)carbamothioyl]-2,6-difluorobenzamide with various α-bromoketones in 76–92% yields. Their molecular structures were characterized by 1H NMR, 13C NMR, 19F NMR, FT-IR, and HRMS, and the stereochemistry of one of the hybrids was determined by single crystal x-ray diffraction study. These synthesized new compounds (3a–e) were found to be effective inhibitor molecules for cholinesterases (butyrylcholinesterase (BChE) and acetylcholinesterase (AChE)), and carbonic anhydrase I and II (hCA I and hCA II) enzymes. KI values were found to be in the range of 45.03–84.43 nM for BChE, 26.12–98.42 nM for AChE, 67.86–161.60 nM for hCA I, and 55.27–87.48 nM for hCA II. The acid dissociation constants (pKa) of 1,4-naphthoquinone thiazole hybrids were determined in 25% (v/v) DMSO:water (25.0 ± 0.1 °C, I = 0.1 M by NaCl). Three pKa values for each hybrid were calculated with the HYPERQUAD program from the data obtained as a result of potentiometric titrations. The results obtained from molecular docking studies indicate that the compounds in question favorably fit within the active sites of hCAs and ChEs. Additionally, the acceptability of these compounds, as determined by Lipinski's and Jorgensen's rules, was estimated using the ADME/T results. Based on these estimations, it can be concluded that the synthesized molecules have the potential to be developed as effective and safe inhibitors of hCAs and ChEs, thus making them suitable lead agents for glaucoma and Alzheimer's disease.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Novel beta-lactam substituted benzenesulfonamides: in vitro enzyme inhibition, cytotoxic activity and in silico interactions
Güleç, Özcan; Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Dincer, Busra; Ece, Abdulilah; Beydemir, Şükrü
In this study, a library of twelve beta-lactam-substituted benzenesulfonamides (5a–l) was synthesized using the tail-approach method. The compounds were characterized using IR, 1H NMR, 13C NMR and elemental analysis techniques. These newly synthesized compounds were tested for their ability to inhibit the activity of two carbonic anhydrases (hCA) isoforms, I and II, and acetylcholinesterase (AChE) in vitro. The results showed that the synthesized compounds were potent inhibitors of hCA I, with K Is in the low nanomolar range (66.60–278.40 nM) than the reference drug acetazolamide (AAZ), which had a K I of 439.17 nM. The hCA II was potently inhibited by compounds 5a, 5d–g and 5l, with K Is of 69.56, 39.64, 79.63, 74.76, 78.93 and 74.94 nM, respectively (AAZ, K I of 98.28 nM). Notably, compound 5a selectively inhibited hCA II with a selectivity of > 4-fold over hCA I. In terms of inhibition of AChE, the synthesized compounds had K Is ranging from 30.95 to 154.50 nM, compared to the reference drug tacrine, which had a K I of 159.61 nM. Compounds 5f, 5h and 5l were also evaluated for their ability to inhibit the MCF-7 cancer cell line proliferation and were found to have promising anticancer activity, more potent than 5-fluorouracil and cisplatin. Molecular docking studies suggested that the sulfonamide moiety of these compounds fits snugly into the active sites of hCAs and interacts with the Zn2+ ion. Furthermore, molecular dynamics simulations were performed for 200 ns to assess the stability and dynamics of each enzyme-ligand complex. The acceptability of the compounds based on Lipinski’s and Jorgensen’s rules was also estimated from the ADME/T results. These results indicate that the synthesized molecules have the potential to be developed into effective and safe inhibitors of hCAs and AChE and could be lead agents. Communicated by Ramaswamy H. Sarma.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Novel spiroindoline derivatives targeting aldose reductase against diabetic complications: Bioactivity, cytotoxicity, and molecular modeling studies
Güleç, Özcan; Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Dincer, Busra; Ece, Abdulilah; İrfan Küfrevioğlu, Ömer; Beydemir, Şükrü
Despite significant developments in therapeutic strategies, Diabetes Mellitus remains an increasing concern, leading to various complications, e.g., cataracts, neuropathy, retinopathy, nephropathy, and several cardiovascular diseases. The polyol pathway, which involves Aldose reductase (AR) as a critical enzyme, has been focused on by many researchers as a target for intervention. On the other hand, spiroindoline-based compounds possess remarkable biological properties. This guided us to synthesize novel spiroindoline oxadiazolyl-based acetate derivatives and investigate their biological activities. The synthesized molecules' structures were confirmed herein, using IR, NMR (1H and 13C), and Mass spectroscopy. All compounds were potent inhibitors with KI constants spanning from 0.186 ± 0.020 μM to 0.662 ± 0.042 μM versus AR and appeared as better inhibitors than the clinically used drug, Epalrestat (EPR, KI: 0.841 ± 0.051 μM). Besides its remarkable inhibitory profile compared to EPR, compound 6k (KI: 0.186 ± 0.020 μM) was also determined to have an unusual pharmacokinetic profile. The results showed that 6k had less cytotoxic effect on normal mouse fibroblast (L929) cells (IC50 of 569.58 ± 0.80 μM) and reduced the viability of human breast adenocarcinoma (MCF-7) cells (IC50 of 110.87 ± 0.42 μM) more than the reference drug Doxorubicin (IC50s of 98.26 ± 0.45 μM and 158.49 ± 2.73 μM, respectively), thus exhibiting more potent anticancer activity. Moreover, molecular dynamic simulations for 200 ns were conducted to predict the docked complex's stability and reveal significant amino acid residues that 6k interacts with throughout the simulation.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Synthesis of N-substituted 4-phenyl-2-aminothiazole derivatives and investigation of their inhibition properties against hCA I, II, and AChE enzymes
Biçer, Abdullah; Çağlayan, Cüneyt; Demir, Yeliz; Türkeş, Cüneyt; Altundaş, Ramazan; Akyıldız, Hasan; Beydemir, Şükrü
In this study, thiazole derivatives containing sulphonamide, amide, and phenyl amino groups were synthesized to protect the free amino groups of 5-methyl-4-phenyl-2-aminothiazole and 4-phenyl-2-aminothiazole. Halogenated reactions of N-protected thiazole derivatives have been investigated. LCMS, FT-IR, 1H NMR, and 13C NMR spectroscopy techniques were used to elucidate the structures of the synthesized compounds. Inhibition effects of the N-protected thiazole derivatives against human carbonic anhydrase I, II (hCA I, hCA II), and acetylcholinesterase (AChE) were investigated. The best results among the synthesized N-protected thiazole derivatives showed Ki values in the range of 46.85–587.53 nM against hCA I, 35.01–578.06 nM against hCA II, and in the range of 19.58–226.18 nM against AChE. Furthermore, in silico studies with the target enzyme of the thiazole derivatives (9 and 11), which showed the best results experimentally, have examined the binding interactions of the related compounds at the enzyme active site.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Interactions of novel 1,3-diaryltriazene-sulfamethazines with carbonic anhydrases: Kinetic studies and in silico simulations
Lolak, Nabih; Türkeş, Cüneyt; Akocak, Suleyman; Duran, Hatice Esra; Işık, Mesut; Durgun, Mustafa; Beydemir, Şükrü
Sulfonamides, recognized as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, are crucial in treating diverse diseases, including epilepsy, glaucoma, bacterial infections, and various pathological processes, e.g., high blood pressure, rheumatoid arthritis, ulcerative colitis, pain, and inflammation. Additionally, therapeutically, 1,3-diaryl-substituted triazenes and sulphamethazines (SM) are integral components in various drug structures, and the synthesis of novel compounds within these two categories holds substantial significance. Herein, ten 1,3-diaryltriazene-substituted sulphamethazine derivatives SM(1–10), which were created by reacting the diazonium salt of sulphamethazine with substituted aromatic amines, were synthesized and the physiologically and pharmacologically relevant human (h) isoforms hCA I and II, cytosolic isozymes, were included in the study. The synthesized compounds showed excellent inhibition versus hCAs; the 4-butoxy (SM7, KI of 5.69 ± 0.59 nM) compound exhibited a potent inhibitory effect against the hCA I compared with the reference drug acetazolamide (AAZ, KI of 116.00 ± 8.48 nM). The 4-cyano (SM4, KI of 5.87 ± 0.57 nM) compound displayed higher potency than AAZ (KI of 57.25 ± 4.15 nM) towards hCA II. Meanwhile, among the synthesized molecules, the 3,4-dimethoxy (SM9, KI of 74.98 ± 10.49 nM, SI of 9.94) compound (over hCA I) displayed a noticeable selectivity for hCA isoform II. The target compounds in the molecular docking investigation were determined to take part in various hydrophilic and hydrophobic interactions with nearby amino acids and fit nicely into the active sites of the hCAs. This research has yielded compounds displaying varying affinity toward hCA isoenzymes, ultimately serving as potent and selective hCA inhibitors. Given its substantial biological inhibitory potency, this particular derivative series is determined to hold the potential to serve as a promising lead compound against these hCAs.
RDL Kalıcı Kaydıİncele - ArticleYalnız künye2024Bioactivity, cytotoxicity, and molecular modeling studies of novel sulfonamides as dual inhibitors of carbonic anhydrases and acetylcholinesterase
Güleç, Özcan; Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Dincer, Busra; Ece, Abdulilah; Küfrevioğlu, Ömer İrfan; Beydemir, Şükrü
In the present medical epoch, the prevailing approach of drug discovery, which focuses on inhibiting a single target, has been superseded by the concept of designing drugs that target more than one specific site. Herein, we present the design and synthesis of a novel series of 1-oxo-3,4-dihydronaphthalene substituted sulfonamides (5a-j) with human carbonic anhydrase (hCA) and acetylcholinesterase (AChE) inhibitory activities as potential dual-target agents. The design of target compounds 5a-j incorporated two key elements: i) The sulfonamide group, which is widely recognized for its high affinity for the active site of hCAs, and ii) the effectiveness of 2-benzylidene-1-tetralone class compounds in some neurodegenerative disorders. All reported sulfonamides were evaluated for their inhibitory effect against hCA I, II isoforms, and AChE. Both hCAs, and AChE were potently inhibited by 5a-j with KI constants in the nanomolar range; 47.71–113.20 nM, 28.05–206.60 nM, and 87.38–136.60 nM, respectively, compared to standard inhibitors, acetazolamide (KIs of 439.17 and 98.28 nM for hCA I and hCA II, respectively) and tacrine (KI of 159.61 nM). 5i exhibited the best multi-target inhibitory activity against hCA I (KI of 47.71 nM), hCA II (KI of 30.75 nM), and AChE (KI of 88.97 nM), while 5b showed a selectivity index (hCA I/II) of 3.61. Moreover, a cytotoxic activity assay for sulfonamides 5a-j was applied on the human breast adenocarcinoma MCF-7 cell line as well as on the non-tumoral mouse fibroblast L929 cell. Thereafter, extensive molecular dynamics simulations revealed the dynamic behavior of ligand/enzyme complex and predicted vital ligand contacts in the binding pocket.
RDL Kalıcı Kaydıİncele - ArticleAçık Erişim2024Synthesis, α-Glucosidase, α-Amylase, and Aldol Reductase Inhibitory Activity with Molecular Docking Study of Novel Imidazo[1,2-a]pyridine Derivatives
Kaya, Betül; Acar Çevik, Ulviye; Çiftçi, Bilge; Duran, Hatice Esra; Türkeş, Cüneyt; Işık, Mesut; Bostancı, Hayrani Eren; Kaplancıklı, Zafer Asım; Beydemir, Şükrü
Inhibition ofaldose reductase (AR), α-glycosidase (α-GLY), and α-amylase (α-AMY) are some of the essential targets in diabetes mellitus (DM). Here, a series of imidazo[1,2-a]pyridine-based 1,3,4-thiadiazole derivatives (8a-k) were successfully synthesized and characterized using 1H NMR, 13C NMR, and HRMS spectroscopic techniques. The inhibition effects of the synthesized derivatives against AR, α-GLY, and α-AMY were evaluated using both in vitro and in silico methods. In vitro studies revealed that the derivatives (8a-k) showed significant inhibition activity. The results showed that the novel derivatives (8a-k) demonstrated potential inhibitory activity, with KI values covering the following ranges: 23.47 ± 2.40 to 139.60 ± 13.33 nM for AR and 6.09 ± 0.37 to 119.80 ± 12.31 μM for α-GLY, with IC50 values 81.14 to 153.51 μM for α-AMY. Furthermore, many of these compounds exhibited high inhibition activity, while some of them showed higher potency than the reference compounds. Molecular docking of the target compounds was carried out in the active sites of AR (PDB ID: 4JIR) and α-GLY (PDB ID: 5NN8).
RDL Kalıcı Kaydıİncele