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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] .
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    Bisbenzoxazole Derivatives: Design, Synthesis, in Vitro Antimicrobial, Antiproliferative Activity, and Molecular Docking Studies
    (Taylor & Francis Ltd, 2022) Ersan, Ronak Haj; Alagoz, Mehmet Abdullah; Dogen, Aylin; Duran, Nizami; Burmaoglu, Serdar; Algul, Oztekin
    Four series of bisbenzoxazole derivatives were designed, synthesized, and screened for antiproliferative and antimicrobial activities. Generally, all synthesized bisbenzoxazoles (9-24) displayed significant antiproliferative activity; these effects were shown to be related to oxazole rings and substituents in bisbenzoxazole compounds. Especially, the series bearing chloro-substituent (9-12) exhibited better antiproliferative activity with higher selectivity than the other series (13-24); the IC50 values were observed in the range of 0.045-0.342 mu M. Interestingly, only the compound with a nitro substituent (22) showed maximum potency with an IC50 value of 0.011 mu M, which is two-fold more active than the standard drug methotrexate, with moderate selectivity. The compounds bearing fluoro-substituent (14-16) were found to exhibit potent antibacterial activity against the Gram-positive Enterococcus faecalis, with a MIC value of 62.5 mu g/mL, and moderate activity against Gram-negative bacteria and fungi. Only the compound 23 showed potent activity against Escherichia coli, with a MIC value of 62.5 mu g/mL. In order to better evaluate the activity results, crystal structures of five different proteins Human Anaplastic Lymphoma Kinase (PDB ID: 2XP2), CYP2C8dH complexed (PDB ID: 2NNI), factor-human kinase-beta enzyme IKK-beta enzyme (PDB ID: 4KIK), a tubulin heterodimer complex containing alpha and beta sub-units (PDB ID: 1Z2B) and penicillin-binding protein 4 (PBP4) from Enterococcus faecalis (PDB ID: 6MKI) were used in the docking study to examine antiproliferative and antimicrobial activity. Finally, an ADMET screening test was applied to determine the drug-like, toxicological, and optimum physicochemical properties for all of the synthesized compounds. The strategy applied in this research may act as a perspective for the rational design of potential anticancer drugs.
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    Deep learning approach to the discovery of novel bisbenzazole derivatives for antimicrobial effect
    (Elsevier, 2024) Barcin, Tunga; Yucel, Mehmet Ali; Ersan, Ronak Haj; Alagoz, Mehmet Abdullah; Dogen, Aylin; Burmaoglu, Serdar; Algul, Oztekin
    Because of the growing bacterial resistance to antibiotics, the discovery of new antibiotics is critical. The search for new antimicrobial drugs that are effective in treating new and existing microbial diseases is arduous and timeconsuming. Deep learning (DL) can help find potential candidates resulting in a more efficient, and cost-effective, and it is more useful on large datasets than other algorithms.Our research team focused on developing an effective DL workflow for discovering new antimicrobial agents. Our group has previously synthesized and tested bisbenzazole structures with various linkers for a variety of pharmacological activities. Antimicrobial activities of bisbenzazole compounds have been also reported in the literature. Deep Neural Networks (DNN) were used to predict the activity of all bisbenzazole compounds synthesized by our group against Staphylococcus aureus and Candida albicans. DNN successfully predicted compounds 16, 17, and 30 out of six molecules (11, 16, 17, 29, 30, and 33) with activity results of 31.25 mu g /mL or better results based on in vitro studies. Compounds 13 and 15 out of four molecules (13, 15, 29, and 30) for C. albicans were successfully predicted. Molecular modeling studies were also carried out, and the compounds' docking scores agreed with the DNN models and in vitro antimicrobial activity results. Finally, this workflow, which includes deep learning, molecular docking, and in vitro studies, is a dependable and efficient way of discovering new antimicrobial agents for S. aureus and C. albicans.
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    Exploring bisbenzimidazole-chalcone hybrid compounds: Dual-action as antibacterial agents targeting biofilm formation and E. coli DNA gyrase inhibition
    (Elsevier, 2025) Adal, Ercan; Oksuz, Zehra; Ozkul, Ceren; Nigiz, Seyma; Alagoz, M. Abdulah; Dogen, Aylin; Simsek, Rahime
    The emergence of antibiotic-resistant pathogens has reduced the efficacy of current antimicrobial therapies, emphasizing the need for new therapeutic agents. This study presents the design, synthesis, and evaluation of bisbenzimidazole-chalcone hybrid compounds as potential antimicrobial agents. These compounds were tested for their antimicrobial activity against eleven common pathogens, as well as their ability to inhibit biofilm formation and eradicate preformed biofilms in Escherichia coli. Compounds EA1, EA3, EA4, and EA5 demonstrated antibacterial activity against E. coli comparable to ampicillin (31.25 mu g/mL) and outperformed the other tested compounds. Notably, EA4 and EA5 inhibited biofilm formation at sub-MIC concentrations and effectively eradicated preformed biofilms, as confirmed by the crystal violet assay. The synergistic effects of the most active compounds in combination with ampicillin were assessed using checkerboard synergy testing, with all combinations showing 'indifference' effects. Further analysis of the most potent compounds against E. coli ATCC 25,922 included the inhibition of DNA gyrase using E. coli DNA gyrase and a plasmid-based relaxed DNA kit. Molecular docking and molecular dynamics simulations were conducted to elucidate the binding modes and stability of these compounds within E. coli DNA gyrase enzymes. EA4 exhibited significant affinity for DNA gyrase B subunit (docking score: -4.026 kcal/mol, average RMSD value: 4.4 & Aring;), while EA5 displayed dual affinity for both DNA gyrase B subunit and DNA gyrase A subunit (docking scores: -6.944 and -3.432 kcal/mol, respectively), maintaining stable interactions in the active sites during simulations (average RMSD values of 3.2 & Aring; and 3.1 & Aring;). These results highlight the potential of bisbenzimidazole-chalcone hybrids as promising antibacterial agents, particularly in their dualtargeting capabilities against biofilm formation and DNA gyrase inhibition.
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    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, Ilhami
    This 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.
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    Synthesis, In Vitro Biological Evaluation, and Molecular Docking Studies of Novel Biphenyl Chalcone Derivatives as Antimicrobial Agents
    (Taylor & Francis Ltd, 2022) Burmaoglu, Serdar; Kazancioglu, Elif Akin; Kazancioglu, Mustafa Z.; Alagoz, Mehmet Abdullah; Dogen, Aylin; Algul, Oztekin
    The increasing resistance to antimicrobial drugs has instigated the crucial need for the discovery of novel compounds with different modes of action that could target both sensitive and resistant strains. For this purpose, we developed some new chalcone analogs. Herein, a novel series of hybrid biphenyl chalcones (17-24), which have organohalogens in their B ring, were synthesized and examined for their antimicrobial effect. The position of the substituent on ring B was changed to find the effect of the substitution on antimicrobial activity. Compounds 18, 19, and 24 showed better antibacterial and antifungal activity when compared other compounds. Also, molecular docking studies on ATP binding site of S. aureus DNA gyrase for antibacterial targets were performed to elucidate the mechanism of antibacterial activity of synthesized compounds. Three of the most active compounds could be considered as lead compounds for the development of more new potent agents.