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Öğe The anticholinesterase perspective of dimethoxyindole based benzenesulfonamides: Synthesis, biological investigation and molecular docking applications(John Wiley and Sons Inc., 2024) Bingül, Murat; Ercan, Selami; Boǧa, Mehmet; Arslan, Zehra; Tuneğ, Muhammed; Akocak, Süleyman; Bingül, Alev Arslantürk; Şengül, İbrahim Fazıl; Şahin, HasanDue to the well-known biological potential of benzenesulfonamides for the inhibition of specific enzymes, here in, we propose to investigate anticholinesterase efficiencies of five newly synthesized benzenesulfonamides incorporating dimethoxyindole tails. The targeted compounds were synthesized through the C7 position of the methyl 4,6-dimethoxy-1H-indole-2-carboxylate via Schiff-base reaction. The biological study was directed to identify the acetylcholinesterase (ACh) and butyrylcholinesterase (BCh) enzyme inhibitions. The molecular docking studies were also carried out to determine the possible poses of ligands 8 a–e in binding sites of enzymes and ligand-residue interactions. Molecular dynamics simulations, RMSD and RMSF plots, hydrogen bond analysis, per-residue energy decomposition and MM-PB(GB)/SA calculations were carried out investigate the potentials of the compounds towards the designated enzymes. It is important to note that all the synthesized compounds were found to be selective towards the BChE inhibition with a range of efficiencies. In addition to that the compound 8 a exhibited more potency than the standard Galanthamine with the value of 87.75 % for the same enzyme. The results could be valuable for the determination of new targets which are highly selective for BChE inhibition. The formation of hydrogen bonds and hydrophobic interactions with the residues located on the compounds were responsible for the binding free energy scores. The stability of all the compounds proved by molecular dynamics simulations were also promising for the further directions of the study.Öğe Antioxidant and anticholinesterase potentials of novel 4,6-dimethoxyindole based unsymmetrical azines: Synthesis, molecular modeling, in silico ADME prediction and biological evaluations(Taylor and Francis Ltd., 2023) Bingül, Murat; Ercan, Selami; Boğa, Mehmet; Bingül, Alev ArslantürkChemically and biologically important -C = N-N = C- diimine linkage was used to build unsymmetrical azine systems with indole heterocyclic backbone and substituted aromatic carbaldehydes. Ten novel compounds 7a-j were synthesized by the Schiff base reaction of 4,6-dimethoxyindole-7-hydrazone 5 and a range of substituted carbaldehydes 6a-j with high yields and purities. The biological study was directed to identify the antioxidant potentials due to the expected electronic delocalization capability of designated linkage which is important for possible hydrogen or electron donation. The three different assays, namely DPPH free radical scavenging, ABTS cationic radical decolarization and CUPRAC (cupric reducing antioxidant capacity) were employed to detect the antioxidant properties. The antioxidant potentials were found to be moderate for ABTS and CUPRAC assays and the compound 7j was the most potent candidate for all the antioxidant assays. More importantly, the anticholinesterase properties were investigated by acetylcholinesterase (ACh) and butyrylcholinesterase (BCh) enzyme inhibition assays. The molecular docking studies were also carried out to determine the possible poses of ligands 7a-j in binding sites of enzymes and ligand-residue interactions. The synthesized compounds were found to be more effective for the anticholinesterase activity with three promising candidates 7d, 7h and 7j in the case of BChE inhibitions. The compound 7h was determined as the best candidate with the comparable IC50 values for AChE and better inhibition potency for BChE with 7j. A range of hydrophobic and hydrophilic interactions were detected for the designated compound 7h and 7j through different amino acid residues and the computational results were found to be compatible with the biological counterparts.Öğe Biological and computational evaluation of carbazole-based bis-thiosemicarbazones: A selective enzyme inhibition study between ?-amylase and ?-glucosidase(Istanbul University, 2023) Şahin, Hasan; Bingül, Alev Arslantürk; Şengül, İbrahim Fazıl; Bingül, MuratBackground and Aims: Carbazole heterocyclic systems are an important class of chemicals that have been reported as valuable antidiabetic agents in the literature. Uncoincidentally, the ayurvedic antidiabetic plant Murraya koenigii Spreng (Curry tree) was the source of the first carbazole alkaloids. Another important class of chemicals in terms of antidiabetic activity is thiosemicarbazones. The hybridization of these fragments can create new potential inhibitors for α-amylase and α-glucosidase enzyme inhibitions, which is one approach controlling post-prandial hyperglycemia in type 2 diabetes patients. Methods: The four carbazole-based thiosemicarbazone compounds (4a-d) have been selected from the group library and α-amylase and α-glucosidase inhibition potencies have been evaluated. A molecular modelling study has also been carried out to provide a complementary study on how the molecules behave in terms of the enzymes’ catalytic properties. . Results: All compounds showed higher potencies than the standard acarbose in terms of α-glucosidase inhibition and very low inhibitions toward α-amylase compared to acarbose. Having the number of hydrophobic interactions determine the potency of the compounds was crucial with compound 4a being shown to provide the highest number of conventional H bonds and the highest percentage of inhibition values for both enzymes. Conclusion: Carbazole-based thiosemicarbazone compounds have been found to be promising candidates in terms of both their potency and relative selectivity for developing new inhibitors that lack the usual side effects of current drugs.Öğe Chemical and Biological Perspectives of Monoterpene Indole Alkaloids From Rauwolfia species(Elsevier, 2018) Boğa, Mehmet; Bingül, Murat; Özkan, Esra Eroğlu; Şahin, HasanThe biosynthesis of monoterpene indole alkaloids (MIAs) starts with a geraniol for the terpenoid portion. Secologanin, a secoiridoid glycoside, is derived from 10-hydroxygeraniol, produced in the presence of geraniol 10-hydroxylase. The indole portion of MIAs contain tryptamine, produced by the decarboxylation of tryptophan. Conjugation of secologanin with tryptamine is achieved with strictosidine synthase to produce strictosidine. Over 2500 known MIAs found in many plants from several families, such as Apocynaceae, Loganiaceae, Rubiaceae, and Nyssaceae, are produced by modification of strictosidine. A number of pharmacologically active compounds, namely, reserpine, ajmalicine, ajmaline, serpentine, and yohimbine, isolated from different Rauwolfia species, are examples of MIAsÖğe Comparative analysis of antioxidant, anticholinesterase, and antibacterial activity of microbial chondroitin sulfate and commercial chondroitin sulfate(Wiley-V C H Verlag Gmbh, 2023) Ünver, Tuba; Erenler, Ayşe Şebnem; Bingül, Murat; Boğa, Mehmet; 0000-0002-8655-2716; 0000-0002-1786-5022; 0000-0002-3909-0694; 0000-0003-4163-9962Chondroitin synthesis was performed using the recombinant Escherichia coli(C2987) strain created by transforming the plasmid pETM6-PACF-vgb, which carries the genes responsible for chondroitin synthesis, kfoA, kfoC, kfoF, and the Vitreoscilla hemoglobin gene (vgb). Then, Microbial chondroitin sulfate (MCS)'s antioxidant, anticholinesterase, and antibacterial activity were compared with commercial chondroitin sulfate (CCS). The antioxidant studies revealed that the MCS and CCS samples could be potential targets for scavenging radicals and cupric ion reduction. MCS demonstrated better antioxidant properties in the ABTS assay with the IC50 value of 0.66 mg than CCS. MCS showed 2.5-fold for DPPH and almost 5-fold for ABTS *+ (with a value of 3.85 mg/mL) better activity than the CCS. However, the compounds were not active for cholinesterase enzyme inhibitions. In the antibacterial assay, the Minimum inhibitory concentration (MIC) values of MCS against S. aureus, E. aerogenes, E. coli, P. aeruginosa, and K. pneumoniae (0.12, 0.18, 0.12, 0.18, and 0.18 g/mL, respectively) were found to be greater than that of CCS (0.42, 0.48, 0.36, 0.36, and 0.36 g/mL, respectively). This study demonstrates that MCS is a potent pharmacological agent due to its physicochemical properties, and its usability as a therapeutic-preventive agent will shed light on future studies.Öğe The computational and biological investigation of indole and quinoline based thiosemicarbazones towards ?-glucosidase enzyme inhibition(Gaziantep University, 2022) Bingül, Murat; Şahin, HasanThiosemicarbazones are important classes of Schiff base ligands due to the presence of conjugated N-N-S system providing an important therapeutic potential and have been the subject of many structural and medicinal studies via the interactions of biomolecules. A wide variety of heterocyclic systems have been used for the structural modifications of new thiosemicarbazone based compounds. Due to the presence of the indole and quinoline structures in many natural products, studies have been directed towards investigations of the biological properties of natural indolic and quinolic compounds, and a range of medical uses has been identified. In the present work, the synthetic procedures and chemical characterization of the targeted compounds derived from indole-3-carbaldehyde and 2-chloroquinoline-3-carbaldehyde systems with a range of thiosemicarbazides. The final compounds have been subjected to α-glucosidase enzyme inhibition assay to investigate the antidiabetic efficiency. A complementary study was carried out with the molecular docking study of targeted compounds on the catalytic side of the designated enzyme. The biological aspect of the study revealed that the indole-based compounds possessed more promising potency compared to the quinoline derivatives.Öğe The Hemetsberger reaction: A new approach to the synthesis of novel dihydroindoloindole systems(Arkat Usa Inc, 2020) Bingül, Murat; Kumar, Naresh; Black, David StCThe Hemetsberger indole synthesis provides an alternative method for the preparation of dihydroindoloindole systems. Two novel examples, dimethyl 3,8-dihydroindolo[7,6-g]indole-2,7-dicarboxylate and dimethyl 1,6dihydroindolo[5,4-e]indole- 2,7-dicarboxylate, were succesfully prepared by the Hemetsberger indole sythesis. The ester functionality on the C-2 position was used for the further elaboration of these tetracyclic systems.Öğe Hypoglycemic potential of 4,6-dimethoxyindole-7- and -2-thiosemicarbazone derivatives(Dicle University, 2023) Bingül, Murat; Şahin, HasanThe hybrid molecules, derived from biologically active compounds, have been an open target for the medical researchers due to the possible enhanced biological properties. Hybridization of biologically active compounds for the determination of new possible candidates for drug development has been an attractive idea and allow to detect new successful compounds for drug discovery. With respect to this idea, previously synthesized dimethoxyindole based thiosemicarbazones have been chosen as hybrid molecules derived from indole backbone and thiosemicarbazides which have heavily been used for biological studies and evaluated for inhibition of α-amylase and α-glucosidase to exhibit the hypoglycemic potential. The targeted molecules were found to be potent candidates for α-glucosidase enzyme inhibition compared to the standard. The inhibition potential for α-amylase was not comparable with the acarbose with the studied concentration, however, it was determined that the targeted compounds could be selective candidates for glucosidase enzyme inhibition and the future studies were directed for the identification new compounds for this purpose.Öğe Indolyl imine compounds as multi-target agents; synthesis, antidiabetic, anticholinesterase, antioxidant activities and molecular modeling(Elsevier B.V., 2024) Ceyhan, Sadık M.; Zengin, İrem Nur; Bingül, Murat; Şahin, Hasan; Boǧa, Mehmet; Sağlam, Mehmet F.; Kandemir, HakanA new range of indolyl imine system 3d-l has been successfully prepared from 4,6-dimethoxy-2,3-diphenyl-indole-7-carbaldehyde 2a and 4,6-dimethoxy-3-aryl-indole-7-carbaldehyde 2b-c via Schiff base reaction. The structure of targeted compounds was confirmed by 1H and 13C NMR, FT-IR, mass spectrometry and single crystal X-ray diffraction techniques. The indolyl imine derivatives were also subjected to in vitro antidiabetic activities employing ?-glucosidase and ?-amylase enzymes. In terms of antidiabetic investigation, the ?-glucosidase enzyme was found to be potential target due to the comparable inhibition concentrations with the standard acarbose and the compound 3e exhibited better potency than the standard. The anticholinesterase potency of the compounds was investigated towards the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The compounds displayed moderate efficiency against the BChE enzyme with the best inhibition concentration of 30.48 ?M by the compound 3h. The antioxidant properties of final compounds were determined by DPPH radical scavenging, ABTS Cation Radical Decolarization and CUPRAC Cupric Reducing Antioxidant Capacity assay methods. The ABTS cation scavenging assay provided the best responses for the compounds and the candidates 3k and 3l were determined as promising targets for the antioxidant activity. Plausible binding mode and interaction of ligands with the selected enzyme have been studied by molecular docking, supporting the experimental results. In silico ADME showed high drug likeness of the synthesized compounds. © 2024 Elsevier B.V.Öğe Kumarin ve izokumarin türevlerinin anti-enflamatuar aktivite profillerinin araştırılması(Atatürk Üniversitesi, 2021) Arslan, Zehra; Bingül, MuratKumarinler (2H-1-benzopiran-2-on) ve izokumarinler (1H-2-benzopiran-1-on), çoğunlukla bitkilerde ve mikroorganizmalarda bulunan doğal olarak oluşan biyolojik aktif bileşiklerdir. Çok sayıda kumarin ve izokumarin türevi, farklı mekanizmalar yoluyla hafif ila çok güçlü antienflamatuar aktiviteye sahip olacak şekilde tasarlanmış, sentezlenmiş ve değerlendirilmiştir. Çok sayıda araştırma raporu, kumarin ve izokumarin ana yapısını, antienflamatuar ilaçların geliştirilmesi için potansiyel adaylar olarak göstermiştir. Bu doğal ürünlerin yapısal çeşitliliği ve biyolojik aktivitesi ile ilgili mevcut literatür gözden geçirilmiştir. Bu derleme makalesinde; çeşitli çalışmalar sonucu elde edilen antienflamatuar aktiviteye sahip doğal ve sentetik kumarin ve izokumarin türevlerinin karşılaştırmalı analizi gerçekleştirilmiş ve etkili antienflamatuar ilaçların tasarımında yol gösterici olması amacıyla kumarin ve izokumarin ana yapısı etrafında genel bir yapı-aktivite ilişkisi oluşturulmuştur.Öğe Synthesis and characterisation of novel tricyclic and tetracyclic furoindoles: Biological evaluation as SAHA enhancer against neuroblastoma and breast cancer cells(MDPI, 2021) Bingül, Murat; Arndt, Greg M.; Marshall, Glenn M.; St. Black, David C.C.; Cheung, Belamy; Kumar, Naresh SampathThe dihydropyranoindole structures were previously identified as promising scaffolds for improving the anti-cancer activity of histone deacetylase inhibitors. This work describes the synthesis of related furoindoles and their ability to synergize with suberoylanilide hydroxamic acid (SAHA) against neuroblastoma and breast cancer cells. The nucleophilic substitution of hydroxyin-dole methyl esters with α-haloketones yielded the corresponding arylether ketones, which were subsequently cyclized to tricyclic and tetracyclic furoindoles. The furoindoles showed promising individual cytotoxic efficiency against breast cancer cells, as well as decent SAHA enhancement against cancer cells in select cases. Interestingly, the best IC50 value was obtained with the non-cyclized intermediate.Öğe Synthesis and molecular modeling studies of naphthazarin derivatives as novel selective inhibitors of ?-glucosidase and ?-amylase(Elsevier B.V., 2023) Abadan, Şebnem; Sağlam, Mehmet F.; Koca, Mehmet Serdar; Bingül, Murat; Şahin, Hasan; Zorlu, Yunus; Şengül, İbrahim F.Diabetes mellitus is known as one of the most life-threatening diseases and has attracted the attention of medicinal chemists. The design and synthesis of novel potential candidates for the inhibition of αamylase and α-glucosidase enzymes which are responsible for the digestion of dietary carbohydrates are an important approach for the treatment of diabetes. In this current work, a range of novel mono and naphthazarin derivatives were successfully synthesized by the esterification reaction of naphthazarin with different benzoyl chlorides and heterocyclic acyl chlorides. The synthesized compounds were subjected to in vitro antidiabetic activities through α-glucosidase and α-amylase inhibition properties. Despite the limited inhibition potential against α-amylase enzymes, naphthazarin derivatives would be promising targets for antidiabetic study due to the specificity for α-glucosidase enzyme. The compound 18 revealed a dual inhibition behavior, however all the other active compounds were detected as specific for α-glucosidase inhibition and quite potent compared to the standard acarbose which is promising for eliminating the side effects associated with the non-selectivity of acarbose. The compound 19 was the best candidate for inhibition with IC50 value of 7.4 μM and resulted 150-fold better activity compared to the standard. Free energy calculations support the experimental binding affinity of compound 19 found as the most promising drug candidate for α-glucosidase among the synthesized compounds. The plausible binding mode and the interaction of compound 19 complexed with α-glucosidase has been revealed by MD simulations.Öğe Synthesis of furo[2,3-c]carbazoles as potent α-glucosidase and α-amylase inhibitors(Taylor and Francis Ltd., 2024) Uçar, Tuğçe N. Uslu; Bingül, Murat; Şahin, Hasan; Kandemir, Hakan; Şengül, İbrahim FazılThe carbazole-3-carbaldehyde 2, produced by N-ethyl carbazole via Vilsmeier-Haack reaction, was subjected to Dakin type oxidation with H2O2 and H2SO4 in methanol to produce the carbazole-3-ol 3. The reaction of 3 with a range of commercially available α-haloketones 4a–f in the presence of Al2O3 as catalyst in xylene led to their regio-selective cyclization to afford the furo[2,3-c]carbazoles 5a–f. Identification of the furo[2,3-c]carbazoles 5a–f were performed through 1H NMR,13C NMR, FT-IR and high resolution mass spectrometry. Single crystal X-ray diffraction analysis was employed to further confirm the structures of the some of the targeted compounds. In vitro antidiabetic activities of the newly synthesized furocarbazoles 5a–e were investigated utilizing α-glucosidase and α-amylase enzymes. The biological evaluation revealed the obvious efficiencies of the targeted molecules toward the α-glucosidase enzyme inhibition with the potent IC50 values compared to the standard acarbose. In the case of α-glucosidase inhibition, the furo[2,3-c]carbazoles chloro substituted 5c and nitro substituted 5f were found to be more potent than acarbose with the values of 215.0 and 162.70 μM, respectively. On the other hand, the compound 5f was found to be only promising candidate for α-amylase enzyme but not as effective as the standard acarbose.Öğe Synthesis of Indole-3-Carboxyaldehyde Thiosemicarbazone Derivatives and Investigation of Antioxidant and Anticholinesterase Properties(2019) Bingül, MuratThe synthesis of four indole-3-carboxyaldehyde thiosemicarbazone compounds (3a-d) was achieved viathe Schiff base reaction of the indole-3-carboxyaldehyde and thiosemicarbazides in high yields. Thestructures of thiosemicarbazones 3a and 3b were supported by 1HNMR spectroscopy and confirmedwith the literature data. To the best of our knowledge, our study is the first report for the synthesis ofcompound 3c and literature search revealed that compound 3d was also not fully characterised. Thestructures of compound 3c and 3d were fully characterised by the FT-IR, High Resolution MassSpectrometry (HRMS), 1H and 13CNMR spectroscopy in this work for the first time. Moreover,antioxidant properties of synthesised compounds 3a-d were investigated with the DPPH, ABTS andCUPRAC assays as well as the anticholinesterase properties of designated compounds were determinedby the Acetylcholinesterase (ACh) and Butyrylcholinesterase (BCh) enzyme inhibition assays. Thecompound 3a, 3b and 3d were determined very potent against the ABTS antioxidant assay andcompound 3c was found to be a valuable target molecule for the kinetic measurements to identifymechanism of action in the area of anticholinesterase activity assay.Öğe Synthesis, biologic properties, and molecular modeling studies of bis-indole based thiosemicarbazones(Springer, 2024) Ceyhan, Sadık M.; Bingül, Murat; Şahin, Hasan; Boǧa, Mehmet; Sağlam, Mehmet F.; Kandemir, Hakan; Şengül, İbrahim FazılThe Schiff base condensation reaction of thiosemicarbazides and methylene bridged 2,2′-bisindolylmethanes, prepared from the acid-catalyzed condensation of 3-aryl-4,6-dimethoxyindole-7-carbaldehydes and formaldehyde, produced a series of the targeted bis-indole based thiosemicarbazones. To explore the biological potential of the newly synthesized compounds, antidiabetic, anticholinesterase, and antioxidant activities were investigated. The structural derivatization carried out by the addition of bromophenyl ring at C3 position of the indole backbone increased the enzyme potency towards the anticholinesterase activity. Some of the targeted compounds showed selective the α-glucosidase enzyme inhibition activity. In addition to that, the inhibition concentrations were found to lower that the standard acarbose showing that they may be more efficient agents. Although most of the compounds were effective for the metal chelation capacities (CUPRAC), a couple of examples were found to be favorable for DPPH and ABTS assays. The presence of methyl substituted thiosemicarbazone tail with different indole back bones individually detected as promising targets for ABTS and DPPH activities. The compound methyl substituted thiosemicarbazone was also determined as the most potent agent with the 6 μM inhibition concentration toward CUPRAC assay. Molecular docking study was performed to support the experimental results. Graphical abstract: (Figure presented.)Öğe Synthesis, characterization and biological evaluation of novel dihydropyranoindoles improving the anticancer effects of HDAC inhibitors(MDPI AG, 2020) Bingül, Murat; Arndt, Greg M.; Marshall, Glenn M.; Cheung, Belamy; Kumar, Naresh Sampath; Black, David St ClairThe dihydropyranoindole scaffold was identified as a promising target for improving the anti-cancer activity of HDAC inhibitors from the preliminary screening of a library of compounds. A suitable methodology has been developed for the preparation of novel dihydropyranoindoles via the Hemetsberger indole synthesis using azido-phenylacrylates, derived from the reaction of corresponding alkynyl-benzaldehydes with methyl azidoacetate, followed by thermal cyclization in high boiling solvents. Anti-cancer activity of all the newly synthesized compounds was evaluated against the SH-SY5Y and Kelly neuroblastoma cells as well as the MDA-MB-231 and MCF-7 breast adenocarcinoma cell lines. Biological studies showed that the tetracyclic systems had significant cytotoxic activity at higher concentration against the neuroblastoma cancer cells. More importantly, these systems, at the lower concentration, considerably enhanced the SAHA toxicity. In addition to that, the toxicity of designated systems on the healthy human cells was found to be significantly less than the cancer cells. © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Öğe Synthesis, reactivity and biological properties of methoxy-activated indoles(Society Chimica Italiana, 2021) Şengül, İbrahim F.; Bingül, Murat; Kandemir, Hakan; Kumar, Naresh; Black, David StC.; Attanasi, O.A.; Gabriele, B.; Merino, P.; Spinelli, D.Indoles continue to play a central role in the development of new structures of chemical and biological interest. They are the source of numerous biologically active natural products by virtue of their derivation from tryptophan units which are essential to peptide, protein and enzyme structures. Although the indole unit is electron rich and displays a wide range of reactivity, many naturally-occurring indoles contain methoxy substituents, which enhance their reactivity. The synthesis of methoxyindoles has also become a strategy for diversifying the regiochemical behaviour of indoles. This review brings together a wide range of information relating to indoles incorporating one, two, or three methoxy groups. It deals with aspects of synthesis, reactivity, and biological activity as well as summarizing the scope of important natural products.
