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Öğe Antifungal Azole Derivatives Featuring Naphthalene Prove Potent and Competitive Cholinesterase Inhibitors with Potential CNS Penetration According to the in Vitro and in Silico Studies(Wiley-V C H Verlag Gmbh, 2022) Sari, Suat; Akkaya, Didem; Zengin, Merve; Sabuncuoglu, Suna; Ozdemir, Zeynep; Alagoz, M. Abdullah; Karakurt, ArzuCholinesterase inhibition is of great importance in the fight against neurodegenerative disorders such as Alzheimer's disease. Azole antifungals have come under the spotlight with recent discoveries that underline the efficacy and potential of miconazole and its derivatives against cholinesterase enzymes. In this study, we evaluated a library of azoles against acetylcholinesterase and butyrylcholinesterase using in vitro and in silico methods to identify potent inhibitors. Low micromolar IC50 values were obtained for imidazole derivatives, which were further tested and found potent competitive cholinesterase inhibitors via enzyme kinetics study. The active derivatives showed negligible toxicity in in vitro cytotoxicity tests. Molecular modeling studies predicted that these derivatives were druglike, could penetrate blood-brain barrier, and tightly bind to cholinesterase active site making key interactions via the imidazole moiety at protonated state. Thus, current study identifies potent and competitive cholinesterase inhibitor azoles with minor toxicity and potential to pass into the central nervous system.Öğe Development of Potent Type V MAPK Inhibitors: Design, Synthesis, and Biological Evaluation of Benzothiazole Derivatives Targeting p38α MAPK in Breast Cancer Cells(Wiley-V C H Verlag Gmbh, 2025) Zoatier, Bayan; Yildiztekin, K. Gizem; Alagoz, M. Abdullah; Hepokur, Ceylan; Burmaoglu, Serdar; Algul, OztekinType V MAPK inhibitors are distinguished by their capacity to target both the ATP binding site and a specific allosteric site on the enzyme. The present work utilized in silico analysis with Maestro 13.8.135 (Schrodinger) software in conjunction with experimental investigations to enhance the antiproliferative efficacy and forecast the likely mechanism of action of benzothiazole derivatives. Approximately 28 compounds were developed, produced, and assessed for their antiproliferative properties against two breast cancer cell lines: ER+ (MCF7) and ER- (MDA-MB-231), in addition to one normal mouse fibroblast cell line (L929). Their antiproliferative activities were evaluated via the MTT test, with doxorubicin and cisplatin serving as reference drugs for comparison. Consequently, the compounds with the greatest activity against the MCF7 cell line were chosen, and their inhibitory effects on the p38 alpha MAPK enzyme were examined. The molecular docking studies of compounds 15 and 19 demonstrated significant binding affinities for p38 alpha MAPK. Molecular dynamics simulations conducted over 100 ns revealed that compounds 15 and 19 exhibit stability inside both the ATP-binding domain and the lipid domain of p38 alpha MAPK. The research focused on creating effective Type V MAPK inhibitors demonstrate that compounds 15 and 19 possess considerable ability to inhibit p38 alpha MAPK, hence establishing them as promising anticancer agents.Öğe Exploring enzyme inhibition profiles of novel halogenated chalcone derivatives on some metabolic enzymes: Synthesis, characterization and molecular modeling studies(Elsevier Sci Ltd, 2022) Anil, Derya Aktas; Polat, M. Fatih; Saglamtas, Ruya; Tarikogullari, Ayse H.; Alagoz, M. Abdullah; Gulcin, Ilhami; Algul, OztekinEnzyme inhibition is a very active area of research in drug design and development. Chalcone derivatives have a broad enzyme inhibitory activity and function as potential molecules in the development of new drugs. In this study, the synthesized novel halogenated chalcones with bromobenzyl and methoxyphenyl moieties were evaluated toward the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes and human erythrocyte carbonic anhydrase I (hCA I), and II (hCA II) isoenzymes. They showed highly potent inhibition ability toward AChE with Ki values of 1.83 +/- 0.21-11.19 +/- 0.96 nM and BChE with Ki values of 3.35 +/- 0.91-26.70 +/- 4.26 nM; hCA I with Ki values of 29.41 & PLUSMN; 3.14-57.63 & PLUSMN; 4.95 nM, and hCA II with Ki values of 24.00 & PLUSMN; 5.39-54.74 & PLUSMN; 1.65 nM. Among the tested enzyme inhibitions, compounds 14 and 13 were the most active compounds against AChE and BChE. Docking studies were performed to the most active compounds against AChE, BChE, hCA I and hCA II to propose a binding mode in the active site and molecular dynamics simulations were studied to check the molecular interactions and the stability of the ligands in the active site. The results may contribute to the development of new drugs particularly to treat some global disorders including Alzheimer's disease (AD), glaucoma, and diabetes.Öğe Inhibitory effects of carvacrol on glucansucrase from Streptococcus mutans and salivary α-amylase: in silico and in vitro studies(Tubitak Scientific & Technological Research Council Turkey, 2025) Kocabay, Samet; Alagoz, M. Abdullah; Akkaya, BirnurBackground/aim: Streptococcus mutans produces glucansucrase, an enzyme that converts sucrose into lactic acid, which lowers the pH in the oral environment and leads to tooth enamel demineralization, a key factor in dental caries. Additionally, glucansucrase facilitates the formation of extracellular polysaccharides, which promote bacterial adhesion to tooth surfaces. This study investigates the inhibitory effects of carvacrol, a natural compound, on glucansucrase activity both in vitro and in silico. Materials and methods: Glucansucrase enzyme was purified from S. mutans. The inhibitory effects of carvacrol against glucansucrase enzyme were investigated both in vitro and in silico. Results: In the presence of 50 mM carvacrol, glucansucrase and salivary amylase activities were reduced by 51.25% and 14.85%, respectively. Carvacrol did not significantly inhibit (4.73%) the salivary amylase enzyme at 10 mM. Glucansucrase activity decreased by 51.63% in the presence of 10 mM acarbose, which was used as a positive control in glucansucrase enzyme studies. Acarbose inhibited salivary amylase with 82.54% loss of enzyme activity in the presence of 1 mM acarbose. The docking score obtained for carvacrol was -5.262 kcal/mol, while that obtained for acarbose was -6.084 kcal/mol. We carried out molecular dynamics simulation studies for 100 ns to determine the stability of carvacrol in the active site of the protein. Carvacrol demonstrated stable binding to glucansucrase with hydrogen bonds and interactions at key residues (ASP477, GLN960, and ASP909), confirmed by molecular dynamics simulations. Carvacrol remained stable between 16 and 100 ns. Conclusion: Carvacrol selectively inhibits glucansucrase without significantly affecting salivary amylase, making it a more targeted inhibitor compared to acarbose, which inhibits both enzymes. Docking studies indicated that while carvacrol has a lower binding affinity than acarbose, its stable interaction with the enzyme suggests sustained inhibitory action. These findings highlight carvacrol as a promising natural compound for preventing dental caries, offering a more selective alternative to traditional inhibitors. Further in vivo studies are necessary to assess its therapeutic efficacy and safety in clinical applications for oral health.Öğe Investigation of Some Metabolic Enzyme Inhibition Properties of Novel Chalcone-Cu Complexes(Wiley-V C H Verlag Gmbh, 2024) Ebiri, Rustem; Turgut, Muhammet; Anil, Derya Aktas; Demir, Yeliz; Saglamtas, Ruya; Alagoz, M. Abdullah; Algul, OztekinFourteen novel Chalcone-Cu complexes were effectively synthesized in this work. The newly synthesized Chalcone-Cu complexes were assessed for their effects on human carbonic anhydrase isoenzymes I and II, acetylcholinesterase enzymes, and antioxidant activity. The intricate compounds exhibited Ki values ranging from 41.65-190.42 nM against hCA I, 15.79-259.07 nM against hCA II, and 14.36-175.73 nM against AChE enzymes. These complexes demonstrated potent inhibitory profiles against the specified metabolic enzymes, surpassing the inhibitory effects of acetazolamide (for hCA I and II) and tacrine (for AChE). The antioxidant properties of the compounds were assessed using DPPH and ABTS radical scavenging assays, revealing that the complexes had moderate to high efficacy in neutralizing free radicals. All complexes underwent molecular docking experiments. Compounds 14, 22, and 23 yielded the highest docking scores. Compound 14 demonstrated a docking score of -6.414 kcal/mol against hCAI, whereas compound 23 attained a docking score of -6.697 kcal/mol against hCA II. Compound 22 exhibited the most favorable docking score of -9.645 kcal/mol against AChE. The acquired results have the potential to help towards the development of new drugs containing Cu complex structures for the treatment of prevalent ailments such as glaucoma and Alzheimer's diseases. This study unveils the potential of Chalcone-Cu complexes as potent enzyme inhibitors (hCA I and II and AChE) with antioxidant properties. The structural insights, inhibitory profiles, and molecular docking results underscore their therapeutic potential for neurological disorders. The findings present a foundation for further exploration and drug development in the realm of Chalcone-Cu compounds. imageÖğe New chalcone derivatives as effective against SARS-CoV-2 agent(Wiley-Hindawi, 2021) Duran, Nizami; Polat, M. Fatih; Aktas, Derya Anil; Alagoz, M. Abdullah; Ay, Emrah; Cimen, Funda; Tek, ErhanAims Flavonoids and related compounds, such as quercetin-based antiviral drug Gene-Eden-VIR/Novirin, inhibit the protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The alkylated chalcones isolated from Angelica keiskei inhibit SARS-CoV proteases. In this study, we aimed to compare the anti-SARS CoV-2 activities of both newly synthesized chalcone derivatives and these two drugs. Methods Determination of the potent antiviral activity of newly synthesized chalcone derivatives against SARS-CoV-2 by calculating the RT-PCR cycling threshold (C-t) values. Results Antiviral activities of the compounds varied because of being dose dependent. Compound 6, 7, 9, and 16 were highly effective against SARS-CoV-2 at the concentration of 1.60 mu g/mL. Structure-based virtual screening was carried out against the most important druggable SARS-CoV-2 targets, viral RNA-dependent RNA polymerase, to identify putative inhibitors that could facilitate the development of potential anti-coronavirus disease-2019 drug candidates. Conclusions Computational analyses identified eight compounds inhibiting each target, with binding affinity scores ranging from -4.370 to -2.748 kcal/mol along with their toxicological, ADME, and drug-like properties.Öğe Structure-based inhibition of acetylcholinesterase and butyrylcholinesterase with 2-Aryl-6-carboxamide benzoxazole derivatives: synthesis, enzymatic assay, and in silico studies(Springer, 2024) Kuzu, Burak; Alagoz, M. Abdullah; Demir, Yeliz; Gulcin, Ilhami; Burmaoglu, Serdar; Algul, OztekinAn important research topic is the discovery of multifunctional compounds targeting different disease-causing components. This research aimed to design and synthesize a series of 2-aryl-6-carboxamide benzoxazole derivatives that inhibit cholinesterases on both the peripheral anionic and catalytic anionic sides. Compounds (7-48) were prepared from 4-amino-3-hydroxybenzoic acid in three steps. The Ellman test, molecular docking with Maestro, and molecular dynamics simulation studies with Desmond were done (Schrodinger, 12.8.117). Compound 36, the most potent compound among the 42 new compounds synthesized, had an inhibitory concentration of IC50 12.62 nM for AChE and IC50 25.45 nM for BChE (whereas donepezil was 69.3 nM and 63.0 nM, respectively). Additionally, compound 36 had docking values of - 7.29 kcal/mol for AChE and - 6.71 kcal/mol for BChE (whereas donepezil was - 6.49 kcal/mol and - 5.057 kcal/mol, respectively). Furthermore, molecular dynamics simulations revealed that compound 36 is stable in the active gorges of both AChE (average RMSD: 1.98 & Aring;) and BChE (average RMSD: 2.2 & Aring;) (donepezil had average RMSD: 1.65 & Aring; and 2.7 & Aring;, respectively). The results show that compound 36 is a potent, selective, mixed-type dual inhibitor of both acetylcholinesterase and butyrylcholinesterase. It does this by binding to both the catalytically active and peripheral anionic sites of cholinesterases at the same time. These findings show that target compounds may be useful for establishing the structural basis for new anti-Alzheimer agents. [GRAPHICS] .Öğe Substituted bisbenzimidazole derivatives as multiple targeting agents to treat Alzheimer's disease, diabetes, and microbial infections(Elsevier, 2025) Algul, Oztekin; Mete, Burak; Turkmenoglu, Burcin; Saglamtas, Ruya; Alagoz, M. Abdullah; Dogen, Aylin; Gulcin, IlhamiThis study presents the synthesis and bioactivity screening of a series of substituted bisbenzimidazoles (3a-l), assessed for their inhibitory effects on alpha-glycosidase, alpha-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 alpha-glycosidase and alpha-amylase, showing IC50 values of 15.51 mu M and 18.18 mu M, 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 mu g/mu L. 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, alpha-glycosidase, and alpha-amylase, respectively.
