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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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    An efficient synthesis of novel di-heterocyclic benzazole derivatives and evaluation of their antiproliferative activities
    (Taylor & Francis Inc, 2021) Algul, Oztekin; Ersan, Ronak Haj; Alagoz, Mehmet Abdullah; Duran, Nizami; Burmaoglu, Serdar
    A series of unsymmetrical nine di-heterocyclic compounds of benzazole derivatives were synthesized at one step via cyclization reaction. The compounds evaluated forin vitrocytotoxic activity against A549, A498, HeLa, and HepG2 cancer cell lines. The biological evaluation results show that23, 26and29exhibit better activity against HepG2 and HeLa cancer cell lines. Compound23also showed good activity against A549, and A498 cancer cell lines. The analogs were further performed molecular docking studies against human cytochrome P450 2C8 monooxygenase enzyme, calculated some theoretical quantum parameters, ADMET descriptor and molecular electrostatic potential analysis. The strategy applied in this research work may act as a perspective for the rational design of potential anticancer drugs. Communicated by Ramaswamy H. Sarma
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    Head-to-head bisbenzazole derivatives as antiproliferative agents: design, synthesis, in vitro activity, and SAR analysis
    (Springer, 2021) Ersan, Ronak Haj; Alagoz, Mehmet Abdullah; Ertan-Bolelli, Tugba; Duran, Nizami; Burmaoglu, Serdar; Algul, Oztekin
    In the present work, a series of bisbenzazole derivatives were designed and synthesized as antiproliferative agents. The antiproliferative activity of these compounds was investigated using MTT assay. Bisbenzazole derivatives showed significant antiproliferative activity against all the four tested cancer cell lines. Among the various bisbenzazole derivatives, bisbenzoxazole derivatives exhibited the most promising anticancer activity followed by bisbenzimidazole and bisbenzothiazole derivatives. All the derivatives were found to be less toxic as compared to methotrexate (positive control) in normal human cells, indicating selective and efficient antiproliferative activity of these bisbenzazole derivatives. The structure-activity relationships of heteroaromatic systems and linkers present in bisbenzazole derivatives were analyzed in detail. In silico ADMET prediction revealed that bisbenzazole is a drug-like small molecule with a favorable safety profile. Compound31is a potential antiproliferative hit compound that exhibits unique cytotoxic activity distinct from methotrexate. [GRAPHICS]