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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] .
Antioxidant and antithrombotic properties of fruit, leaf, and seed extracts of the Halhal? olive (Olea europaea L.) native to the Hatay region in Turkey
(Kemerovo State Univ, 2023) Batcioglu, Kadir; Kucukbay, Fatumetuzzehra; Alagoz, Mehmet Abdullah; Gunal, Selami; Yilmaztekin, Yakup
The olive (Olea europaea L.) is one of the most important plants grown in many Mediterranean countries that has a high economic value. Olives, which are specific to each region, have different bioactive components. In this study, we investigated the phenolic/flavonoid contents, as well as antioxidant, antimicrobial, and antithrombotic activities of the fruit, leaf, and seed extracts obtained from the Halhali olive grown in Arsuz district of Hatay, Turkey. Antioxidant activities of the phenolic compounds found in the olive fruit, seed, and leaf extracts were determined by employing established in vitro systems. Total phenolics were determined as gallic acid equivalents, while total flavonoids were determined as quercetin equivalents. Also, we evaluated a possible interaction between oleuropein and aggregation-related glycoproteins of the platelet surface via docking studies. The extracts showed effective antioxidant activity. The seed extract had the highest phenolic content of 317.24 mu g GAE, while the fruit extract had the highest flavonoid content of 4.43 mu g. The highest potential for metal chelating activity was found in the leaf extract, with an IC50 value of 13.33 mg/mL. Also, the leaf extract showed higher levels of antioxidant, antithrombotic, and antimicrobial activity, compared to the fruit and seed extracts. The docking scores of oleuropein against the target molecules GPVI, alpha 2 beta 1, and GPIb alpha were calculated as -3.798, -4.315, and -6.464 kcal/mol, respectively. The olive fruit, leaf, and seed extracts used as experimental material in our study have remarkable antioxidant, antimicrobial, and antithrombotic potential.
Assessing the Antiangiogenic Effects of Chalcones and Their Derivatives
(Taylor & Francis Ltd, 2024) Burmaoglu, Serdar; Gobek, Arzu; Anil, Derya Aktas; Alagoz, Mehmet Abdullah; Guner, Adem; Guler, Cem; Hepokur, Ceylan
Pathological angiogenesis plays a critical role in tumorigenesis and tumor progression, and anti-angiogenesis therapies have evinced promising antitumor effects in solid tumors. Chalcone skeleton has been regarded as a potential antitumor agent that also targets angiogenesis. In this study, we designed twenty-one non-fluoro-substituted chalcones (13-18, 24-27) and saturated chalcone derivatives (19-23, 28-33) as anti-angiogenic compounds. During the initial stage, these compounds were assessed for their anti-cancer activities against MCF-7 cancer cell lines according to the MTT assay. The compounds revealed satisfactory anti-proliferative capability. An ex vivo fertilized hens' egg-chorioallantoic membrane (HET-CAM) angiogenic study was conducted for the compounds to gauge their mortality and toxicity, which, in turn, revealed a potent anti-angiogenic effect. Eight compounds (16, 17, 21, 24, 26, 27, 29, and 31) significantly reduced densities of capillaries on CAM, whereas compounds 27 and 29 were the most effective anti-angiogenic agents, when compared with Suramin. Moreover, RT-qPCR analysis demonstrated that the anti-angiogenic activity was associated with the fold changes of VEGFR2. Molecular docking studies were conducted for compounds to investigate their mode of interaction within the binding site of VEGFR-2 kinases. This work provided a basis for further design, structural modification, and development of chalcone derivatives as new anti-angiogenic agents.
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.
CARDIOPROTECTIVE AND ANTIOXI DAN ACTIVITY OF BLUEBERRY ANTHOCYANINE AND POLYPHENOLS IN RATS
(Elsevier Science Bv, 2009) Karakurt, Cemsit; Gursoy, Sule; Alagoz, Mehmet Abdullah; Karakurt, Arzu; Aktays, Goknur; Kocak, Gulendam
[Abstract Not Available]
Coumarin or benzoxazinone based novel carbonic anhydrase inhibitors: synthesis, molecular docking and anticonvulsant studies
(Taylor & Francis Ltd, 2016) Karatas, Mert Olgun; Uslu, Harun; Sari, Suat; Alagoz, Mehmet Abdullah; Karakurt, Arzu; Alici, Bulent; Bilen, Cigdem
Among many others, coumarin derivatives are known to show human carbonic anhydrase (hCA) inhibitory activity. Since hCA inhibition is one of the underlying mechanisms that account for the activities of some antiepileptic drugs (AEDs), hCA inhibitors are expected to have anti-seizure properties. There are also several studies reporting compounds with an imidazole and/or benzimidazole moiety which exert these pharmacological properties. In this study, we prepared fifteen novel coumarin-bearing imidazolium and benzimidazolium chloride, nine novel benzoxazinone-bearing imidazolium and benzimidazolium chloride derivatives and evaluated their hCA inhibitory activities and along with fourteen previously synthesized derivatives we scanned their anticonvulsant effects. As all compounds inhibited purified hCA isoforms I and II, some of them also proved protective against Maximal electroshock seizure (MES) and ScMet induced seizures in mice. Molecular docking studies with selected coumarin derivatives have revealed that these compounds bind to the active pocket of the enzyme in a similar fashion to that previously described for coumarin derivatives.
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.
Design, Synthesis, and Biological Evaluation of Some Benzothiazolone Derivatives as Cholinesterase Inhibitors
(Wiley-V C H Verlag Gmbh, 2022) Alagoz, Mehmet Abdullah; Akkaya, Didem; Arslan, Gulnur; Uludag, Berk; Ozdemir, Zeynep; Barut, Burak; Onkol, Tijen
In this study, nine new benzothiazolone derivatives (6 a-i) were designed and synthesized to identify potent cholinesterase inhibitors. The compounds were tested in vitro against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and found to be selective to BChE. Compound 6 f proved the most potent derivative (IC50=12.25 +/- 0.23 mu M) against BChE and was identified as a mixed-type inhibitor with a K-i value of 4.45 +/- 0.35 mu M according to the kinetic studies. Molecular modelling suggested that the derivatives were druglike and non-PAINS. Compound 6 f showed good fit in BChE active site interacting with the key sites important for enzyme activity according to the molecular docking study.
Development of a Novel Class of Pyridazinone Derivatives as Selective MAO-B Inhibitors
(Mdpi, 2022) Alagoz, Mehmet Abdullah; Oh, Jong Min; Zenni, Yaren Nur; Ozdemir, Zeynep; Abdelgawad, Mohamed A.; Naguib, Ibrahim A.; Ghoneim, Mohammed M.
Sixteen compounds (TR1-TR16) were synthesized and evaluated for their inhibitory activities against monoamine oxidase A and B (MAOs). Most of the derivatives showed potent and highly selective MAO-B inhibition. Compound TR16 was the most potent inhibitor against MAO-B with an IC50 value of 0.17 mu M, followed by TR2 (IC50 = 0.27 mu M). TR2 and TR16 selectivity index (SI) values for MAO-B versus MAO-A were 84.96 and higher than 235.29, respectively. Compared to the basic structures, the para-chloro substituent in TR2 and TR16 increased the inhibitory activity of MAO-B. TR2 and TR16 were reversible MAO-B inhibitors that were competitive, with K-i values of 0.230 +/- 0.004 and 0.149 +/- 0.016 mu M, respectively. The PAMPA method indicated that compounds TR2 and TR16 had the tendency to traverse the blood-brain barrier. Docking investigations revealed that lead compounds were beneficial for MAO-B inhibition via association with key as well as selective E84 or Y326 residues, but not for MAO-A inhibition via interaction primarily driven by hydrophobic contacts. In conclusion, TR2 and TR16 are therapeutic prospects for the management of multiple neurodegenerative diseases.
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
Electrochemical and in Silico Investigations of the Interaction between Nitro Blue Tetrazolium Chloride and Bovine Serum Albumin
(Eurasia Acad Publ Group (Eapg), 2022) Kazici, Dilek; Alagoz, Mehmet Abdullah; Savan, Ebru Kuyumcu
The binding ability of the drug on its interaction with the protein will also significantly affect the apparent volume of distribution of the drugs and, in many cases the rate of elimination of the drugs. The interactions of proteins and other molecules are a fascinating topic applied to surface technologies and sensors. Therefore, it is aimed to determine the NBTCand to elucidate its interaction with Bovine Serum Albumin (BSA) by electrochemical and in silico studies in this paper. The reduction in BSA oxidation signals measured by differential pulse voltammetry upon incubation with different NBTC concentrations indicated that NBTC was bound to BSA. In addition, in silico (molecular modeling and molecular dynamics) studies have been conducted on the interactions of NBTC with proteins in plasma. As a result of the in silico studies investigated the interactions of NBTC with serum albumin, its binding affinity, and the dynamic process in the binding state. In silico studies showed that NBTC binds to BSA with high affinity (with-7.986 kcal/mol docking score), and this binding was stable (with a 3.0 average RMSD value). Eventually, the results of the electrochemical and modeling studies were perfectly matched.
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]
Histological assessment of liver and stomach damage caused by pyridazinone derivative antidepressant agents
(Taylor & Francis Ltd, 2022) Ozdemir, Zeynep; Karakurt, Arzu; Taslidere, Elif; Vardi, Nigar; Alagoz, Mehmet Abdullah; Parlakpinar, Hakan; Uslu, Harun
Depression is a serious psychological disorder that affects a significant population. We investigated the antidepressant activities of four pyridazinone derivatives that contain the hydrazide moiety using the forced swimming test (FST). The compounds tested exhibited good antidepressant activity compared to duloxetine. The most promising compound was compound 2, which reduced the duration of immobility during FST. The toxic effects of the four compounds on the histomorphology of the liver and stomach tissue also was evaluated.
Inhibition of Cholinesterases by Benzothiazolone Derivatives
(Mdpi, 2022) Alagoz, Mehmet Abdullah; Kim, Seong-Min; Oh, Jong Min; Arslan, Gulnur; Ozdemir, Zeynep; Sari, Suat; Ozcelik, Azime Berna
Thirteen benzothiazolone derivatives (M1-M13) were synthesized and evaluated for their inhibitory activity against cholinesterases (ChEs) and monoamine oxidases (MAOs). All the compounds inhibited ChEs more effectively than MAOs. In addition, most of the compounds showed higher inhibitory activities against butyrylcholinesterase (BChE) than acetylcholinesterase (AChE). Compound M13 most potently inhibited BChE with an IC50 value of 1.21 mu M, followed by M2 (IC50 = 1.38 mu M). Compound M2 had a higher selectivity index (SI) value for BChE over AChE (28.99) than M13 (4.16). The 6-methoxy indole group of M13 was expected to have a greater effect on BChE inhibitory activity than the other groups. Kinetics and reversibility tests showed that M13 was a reversible noncompetitive BChE inhibitor with a K-i value of 1.14 +/- 0.21 mu M. In a docking simulation, M13 is predicted to form a hydrogen bond with the backbone carbonyl group of Ser287 of BChE through its methoxy indole moiety and pi-pi interactions between its benzothiazolone group and the side chain of Trp82 with the five-membered pyrrole ring and with the six-membered benzene ring. From these results, it is suggested that M13 is a BChE inhibitor and a potential candidate agent for the treatment of Alzheimer's disease.
Monoamine Oxidase-B (MAO-B) Inhibitors in the Treatment of Alzheimer's and Parkinson's Disease
(Bentham Science Publ Ltd, 2021) Ozdemir, Zeynep; Alagoz, Mehmet Abdullah; Bahcecioglu, Omer Faruk; Gok, Selim
Background: The MAO enzyme is presented in the brain and peripheral tissues and is a significant enzyme that is responsible for the deamination of biogenic amines and thus the regulation of neurotransmitter levels. The reaction of these neurotransmitters with the MAO enzyme produces aldehyde and free amine. MAO enzyme consists of two isoforms, MAO-A and MAO-B, which are characterized by amino acid sequence, three-dimensional structure, substrate preference, and inhibitor selectivity. Dopamine, tyramine, and tryptamine are substrates of both MAO isoforms and MAO inhibitors such as clorgiline and selegiline, which are used as medications in neurodegenerative and neurological diseases. In particular, MAO-A inhibitors are used in the treatment of depression, while MAO-B inhibitors are used in the treatment of Parkinson's disease. It is also investigated whether MAO-B inhibitors are effective in the treatment of Alzheimer's disease. Nowadays, life expectancy has increased, as a result, neurodegenerative diseases such as Parkinson's and Alzheimer's disease have started to occur more frequently. The elderly population is increasing day by day. As a result of these common diseases in elderly people, these people are unable to do their jobs and need care. Therefore, these diseases have become a significant health problem in society. Methods: In this study, review, inclusion, and exclusion criteria were used. Peer -reviewed research articles were searched. The quality of the examined articles was evaluated with standard tools. The information obtained was analyzed conceptually by using qualitative content analysis methodology. Results: One hundred and five papers were included in the review. The current MAO-B inhibitors and their usage areas are discussed together with the structures of the drugs; also, their possible effects in Alzheimer's and Parkinson's treatment are evaluated. In addition, different articles have been compiled in which structures such as arylalkylamines, chalcones, benzoquinone, benzoxazinone, and chromen are substituted with various functional groups and aromatic rings, along with thestructures of 44 different compounds that have recently been developed and their inhibitory effects on MAO-B enzyme. As a result, the structure required for MAO-B inhibition and SAR studies is discussed. Conclusion: Many studies demonstrate that MAO-B activity increases with age in brain tissue, cerebrospinal fluid (CSF), and platelets in Alzheimer's patients. This suggests that MAO-B inhibitor drugs, which may be effective in the treatment of Parkinson's disease, may also be effective in the treatment of Alzheimer's disease. This article was written to explain the multifaceted MAO-B inhibitor molecules.
N-(benzazol-2-yl)-2-substituted phenylacetamide derivatives: Design, synthesis and biological evaluation against MCF7 breast cancer cell line
(Elsevier, 2023) Zoatier, Bayan; Yildirim, Metin; Alagoz, Mehmet Abdullah; Yetkin, Derya; Turkmenoglu, Burcin; Burmaoglu, Serdar; Algul, Oztekin
This work describes the straightforward and efficient one-pot synthesis of a new library of N-(benzazol-2-yl)-2-substituted phenylacetamide derivatives (19-27). Using the MTT assay, these compounds were evaluated for their in vitro anticancer activity against the MCF7 human breast cancer cell line, and the results were compared to the standard doxorubicin. The majority of compounds exhibited an inhibitory effect against the cancer cell line, with compounds 19, 22, and 26 exhibiting exceptional cytotoxicity against MCF7 cells. Using flow cytometry, the most potent compound 19 on the induction of apoptosis in the breast cancer cell line was determined. Compound 19 induced G1-phase cell cycle arrest followed by apoptotic cell death. In silico analyses of potent compounds 19, 22, and 26 were conducted to investigate their interactions with Human DNA topoisomerase II. The energy calculations were found to be in excel-lent agreement with the calculated IC50 values. In addition, drug similarity parameter values for the three active compounds were determined using in silico ADME prediction studies. Considering all of these re-sults, it appears that these N-(benzazol-2-yl)-2-substituted phenylacetamide derivatives may be effective anticancer agents. This work may possibly generate new concepts for the enhancement of inhibitors of human DNA topoisomerase II for breast cancer treatment.(c) 2023 Elsevier B.V. All rights reserved.
Organohalogen chalcones: design, synthesis, ADMET prediction, molecular dynamics study and inhibition effect on acetylcholinesterase and carbonic anhydrase
(Springer, 2024) Aydin, Busra Ozturk; Anil, Derya Aktas; Demir, Yeliz; Alagoz, Mehmet Abdullah
In an effort to discover potential acetylcholinesterase (AChE) and carbonic anhydrase (CA) inhibitors, a novel series of organohalogen chalcone derivatives (12-20, 23-30) was synthesized, and their chemical structures were characterized by spectral analysis. They showed a highly potent inhibition effect on AChE and hCAs (Ki values range from 5.07 +/- 0.062 to 65.53 +/- 4.36 nM for AChE, 13.54 +/- 2.55 to 94.11 +/- 10.39 nM for hCA I, and 5.21 +/- 0.54 to 57.44 +/- 3.12 nM for hCA II). In addition, the chalcone derivatives with the highest inhibitor score docked into the active site of the indicated metabolic enzyme receptors, and their absorption, metabolism, and toxic properties were evaluated according to ADMET's estimation.Compounds 16 and 19 exhibited the highest inhibition score, emerged as lead compounds, and inspired the development of more potent compounds.
QSAR and pharmacophore analysis on pyridazinone derivatives as acetylcholinesterase inhibitors
(2020) Ozdemir, Zeynep; Alagoz, Mehmet Abdullah; Yilmaz, Tuba; Zenni, Yaren Nur; Onkol, Tijen
Aim: The aim of this study is to provide a qualitative and quantitative explanation of the structure activity relationships with pharmacophore analysis and Quantitative Structure Activity Relationship (QSAR) studies of the compounds synthesized as acetylcholinesterase enzyme inhibitor by our research group.Material and Methods: Maestro 11.9 (Schrödinger, New York) was used for pharmacophore model studies. Pharmacophore analysis was performed for all compounds showing acetylcholine esterase inhibitory effect. For QSAR studies, various physicochemical parameters of these compounds were calculated using GaussView 5.0 and ChemDraw 15.0 programs. Regression analysis was performed by using these parameters and QSAR equation was obtained.Results: All compounds overlapped and hypotheses generated. The most appropriate pharmacophore model was created by comparing the hypothesis and activity results of the compounds. The analyses were performed using 8 different parameters for all compounds. R2 value of equation was found 1. Conclusion: The pharmacophore analysis and the QSAR equation are applicable for all compounds synthesized as acetylcholinasterase inhibitory and containing pyridazinon-2-ylacetohydrazide structure. Also, the estimated IC50 values can be calculated before the compounds are synthesized using the QSAR equation.
Synthesis and biological evaluation of new 3(2H)-pyridazinone derivatives as non-toxic anti-proliferative compounds against human colon carcinoma HCT116 cells
(Taylor & Francis Ltd, 2020) Ozdemir, Zeynep; Utku, Semra; Mathew, Bijo; Carradori, Simone; Orlando, Giustino; Di Simone, Simonetta; Alagoz, Mehmet Abdullah
Novel 3(2H)-pyridazinone derivatives were designed, synthesised in satisfactory yields and evaluated in different experimental assays to assess their preliminary toxicity in vivo and anti-proliferative effects against HCT116 cell lines in vitro. Artemia salina lethality test provided LC50 values >100 mu g/mL for all compounds. Successive assays revealed that some compounds were endowed with a promising anti-proliferative effect against HCT116 cells, alone or stimulated by serotonin as a pro-inflammatory factor in order to mimick an inflamed model in vivo of cancer cell microenvironment. Moreover, the kinurenic acid level after treatment with these newly synthesised compounds was monitored as a marker of anti-proliferation in colon carcinoma models. The IC50 values obtained for the best-in-class compounds were comparable to that of daunorubicin as a reference drug. Conversely, these compounds were not able to counteract the spontaneous migration of human cancer HCT116 cell line in the wound healing paradigm.
Synthesis of New 1-Aryl-2-(3,5-dimethylpyrazol-1-yl)ethanone Oxime Ether Derivatives and Investigation of Their Cytotoxic Effects
(Mdpi, 2021) Alagoz, Mehmet Abdullah; Karakurt, Arzu; Hepokur, Ceylan; Salva, Emine; Onkol, Tijen; Ghoneim, Mohammed M.; Abdelgawad, Mohamed A.
In this study, 12 new 1-aryl-2-(3,5-dimethylpyrazol-1-yl)ethanone oxime ether derivatives were designed and synthesized to investigate their cytotoxic effects. The in vitro cytotoxic activities of the compounds were evaluated against cervix, colon, breast, glioma, neuroblastoma, and lung cancer cell lines, as well as a healthy cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazo-lium bromide (MTT) assays with 5-fluorouracil (5-FU) as the reference compound. Compound 5f (IC50 = 5.13 mu M) was found to be more effective than 5-FU (IC50 = 8.34 mu M) in the C6 cancer cell line, and it had no cytotoxic effect on the L929 healthy cell line. Flow cytometry was used to investigate the mechanism of action of compound 5f on the cell cycle of the C6 cell line. The analysis showed that cell death was significantly due to apoptosis. These results indicate that compound 5f induces cell cycle arrest, and may be effective in treating glioma.

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