Publications by authors named "Erden Banoglu"

43 Publications

Synthesis and biological evaluation of novel isoxazole-piperazine hybrids as potential anti-cancer agents with inhibitory effect on liver cancer stem cells.

Eur J Med Chem 2021 Oct 24;221:113489. Epub 2021 Apr 24.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey. Electronic address:

In our effort for the development of novel anticancer therapeutics, a series of isoxazole-piperazine analogues were prepared, and primarily screened for their antiproliferative potential against hepatocellular carcinoma (HCC; Huh7/Mahlavu) and breast (MCF-7) cancer cells. All compounds demonstrated potent to moderate cytotoxicity on all cell lines with IC values in the range of 0.09-11.7 μM. Further biological studies with 6a and 13d in HCC cells have shown that both compounds induced G1 or G2/M arrests resulting in apoptotic cell death. Subsequent analysis of proteins involved in cell cycle progression as well as proliferation of HCC cells revealed that 6a and 13d may affect cellular survival pathways differently depending on the mutation profiles of cells (p53 and PTEN), epidermal/mesenchymal characteristics, and activation of cell mechanisms through p53 dependent/independent pathways. Lastly, we have demonstrated the potential anti-stemness properties of these compounds in which the proportion of liver CSCs in Huh7 cells (CD133+/EpCAM+) were significantly reduced by 6a and 13d. Furthermore, both compounds caused a significant reduction in expression of stemness markers, NANOG or OCT4 proteins, in Mahlavu and Huh7 cells, as well as resulted in a decreased sphere formation capacity in Huh7 cells. Together, these novel isoxazole-piperazine derivatives may possess potential as leads for development of effective anti-cancer drugs against HCC cells with stem cell-like properties.
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http://dx.doi.org/10.1016/j.ejmech.2021.113489DOI Listing
October 2021

Crystal structure and Hirshfeld surface analysis of 4-(4-chloro-phen-yl)-5-methyl-3-{4-[(2-methyl-phen-yl)meth-oxy]phen-yl}-1,2-oxazole.

Acta Crystallogr E Crystallogr Commun 2021 Apr 5;77(Pt 4):346-350. Epub 2021 Mar 5.

Department of Physics, Faculty of Arts and Sciences, Aksaray University, 68100 Aksaray, Turkey.

In the title compound, CHClNO, the mean planes of 4-chloro-phenyl, 2-methyl-phenyl and phenyl-ene rings make dihedral angles of 62.8 (2), 65.1 (3) and 15.1 (2)°, respectively, with the 5-methyl-1,2-oxazole ring. In the crystal, mol-ecules are linked by inter-molecular C-H⋯N, C-H⋯Cl, C-H⋯π contacts and π-π stacking inter-actions between the phenyl-ene groups. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H⋯H (48.7%), H⋯C/C⋯H (22.2%), Cl⋯H/H⋯Cl (8.8%), H⋯O/O⋯H (8.2%) and H⋯N/N⋯H (5.1%) inter-actions.
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http://dx.doi.org/10.1107/S2056989021002383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025860PMC
April 2021

Simple heteroaryl modifications in the 4,5-diarylisoxazol-3-carboxylic acid scaffold favorably modulates the activity as dual mPGES-1/5-LO inhibitors with in vivo efficacy.

Bioorg Chem 2021 Jul 24;112:104861. Epub 2021 Mar 24.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06560 Ankara, Turkey. Electronic address:

Microsomal prostaglandin E synthase-1 (mPGES-1), 5-lipoxygenase (5-LO) and 5- lipoxygenase-activating protein (FLAP) are key for biosynthesis of proinflammatory lipid mediators and pharmacologically relevant drug targets. In the present study, we made an attempt to explore the role of small heteroaromatic fragments on the 4,5-diarylisoxazol-3-carboxylic acid scaffold, which are selected to interact with focused regions in the active sites of mPGES-1, 5-LO and FLAP. We report that the simple structural variations on the benzyloxyaryl side-arm of the scaffold significantly influence the selectivity against mPGES-1, 5-LO and FLAP, enabling to produce multi-target inhibitors of these protein targets, exemplified by compound 18 (IC mPGES-1 = 0.16 µM; IC 5-LO = 0.39 µM) with in vivo efficacy in animal model of inflammation. The computationally modeled binding structures of these new inhibitors for three targets provide clues for rational design of modified structures as multi-target inhibitors. In conclusion, the simple synthetic procedure, and the possibility of enhancing the potency of this class of inhibitors through structural modifications pave the way for further development of new multi-target inhibitors against mPGES-1, 5-LO and FLAP, with potential application as anti-inflammatory agents.
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http://dx.doi.org/10.1016/j.bioorg.2021.104861DOI Listing
July 2021

Encapsulation of the dual FLAP/mPEGS-1 inhibitor BRP-187 into acetalated dextran and PLGA nanoparticles improves its cellular bioactivity.

J Nanobiotechnology 2020 May 14;18(1):73. Epub 2020 May 14.

Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstraße 10, 07743, Jena, Germany.

Background: Dual inhibitors of the 5-lipoxygenase-activating protein (FLAP) and the microsomal prostaglandin E synthase-1 (mPGES-1) may exert better anti-inflammatory efficacy and lower risks of adverse effects versus non-steroidal anti-inflammatory drugs. Despite these advantages, many dual FLAP/mPGES-1 inhibitors are acidic lipophilic molecules with low solubility and strong tendency for plasma protein binding that limit their bioavailability and bioactivity. Here, we present the encapsulation of the dual FLAP/mPGES-1 inhibitor BRP-187 into the biocompatible polymers acetalated dextran (Acdex) and poly(lactic-co-glycolic acid) (PLGA) via nanoprecipitation.

Results: The nanoparticles containing BRP-187 were prepared by the nanoprecipitation method and analyzed by dynamic light scattering regarding their hydrodynamic diameter, by scanning electron microscopy for morphology properties, and by UV-VIS spectroscopy for determination of the encapsulation efficiency of the drug. Moreover, we designed fluorescent BRP-187 particles, which showed high cellular uptake by leukocytes, as analyzed by flow cytometry. Finally, BRP-187 nanoparticles were tested in human polymorphonuclear leukocytes and macrophages to determine drug uptake, cytotoxicity, and efficiency to inhibit FLAP and mPGES-1.

Conclusion: Our results demonstrate that encapsulation of BRP-187 into Acdex and PLGA is feasible, and both PLGA- and Acdex-based particles loaded with BRP-187 are more efficient in suppressing 5-lipoxygenase product formation and prostaglandin E biosynthesis in intact cells as compared to the free compound, particularly after prolonged preincubation periods.
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http://dx.doi.org/10.1186/s12951-020-00620-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227278PMC
May 2020

A Highly Potent TACC3 Inhibitor as a Novel Anticancer Drug Candidate.

Mol Cancer Ther 2020 06 26;19(6):1243-1254. Epub 2020 Mar 26.

Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey.

TACC3, a transforming acidic coiled-coil (TACC) family member, is frequently upregulated in a broad spectrum of cancers, including breast cancer. It plays critical roles in protecting microtubule stability and centrosome integrity that is often dysregulated in cancers; therefore, making TACC3 a highly attractive therapeutic target. Here, we identified a new TACC3-targeting chemotype, BO-264, through the screening of in-house compound collection. Direct interaction between BO-264 and TACC3 was validated by using several biochemical methods, including drug affinity responsive target stability, cellular thermal shift assay, and isothermal titration calorimetry. BO-264 demonstrated superior antiproliferative activity to the two currently reported TACC3 inhibitors, especially in aggressive breast cancer subtypes, basal and HER2+, via spindle assembly checkpoint-dependent mitotic arrest, DNA damage, and apoptosis, while the cytotoxicity against normal breast cells was negligible. Furthermore, BO-264 significantly decreased centrosomal TACC3 during both mitosis and interphase. BO-264 displayed potent antiproliferative activity (∼90% have less than 1 μmol/L GI value) in the NCI-60 cell line panel compromising of nine different cancer types. Noteworthy, BO-264 significantly inhibited the growth of cells harboring FGFR3-TACC3 fusion, an oncogenic driver in diverse malignancies. Importantly, its oral administration significantly impaired tumor growth in immunocompromised and immunocompetent breast and colon cancer mouse models, and increased survival without any major toxicity. Finally, TACC3 expression has been identified as strong independent prognostic factor in breast cancer and strongly prognostic in several different cancers. Overall, we identified a novel and highly potent TACC3 inhibitor as a novel potential anticancer agent, inducing spindle abnormalities and mitotic cell death.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0957DOI Listing
June 2020

Discovery of Novel 5-Lipoxygenase-Activating Protein (FLAP) Inhibitors by Exploiting a Multistep Virtual Screening Protocol.

J Chem Inf Model 2020 03 24;60(3):1737-1748. Epub 2020 Feb 24.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06560 Yenimahalle, Ankara, Turkey.

Leukotrienes (LTs) are proinflammatory mediators derived from arachidonic acid (AA), which play significant roles in inflammatory diseases. The 5-lipoxygenase-activating protein (FLAP) is an integral membrane protein, which is essential for the initial step in LT biosynthesis. The aim of this study was to discover novel and chemically diverse FLAP inhibitors for treatment of inflammatory diseases requiring anti-LT therapy. Both ligand- and structure-based approaches were applied to explain the activities of known FLAP inhibitors in relation to their predicted binding modes. We gained valuable insights into the binding modes of the inhibitors by molecular modeling and generated a multistep virtual screening (VS) workflow in which 6.2 million compounds were virtually screened, and the molecular hypotheses were validated by testing VS-hit compounds biologically. The most potent hit compounds showed significant inhibition of FLAP-dependent cellular LT biosynthesis with IC values in the range from 0.13 to 0.87 μM. Collectively, this study provided novel bioactive chemotypes with potential for further development as effective anti-inflammatory drugs.
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http://dx.doi.org/10.1021/acs.jcim.9b00941DOI Listing
March 2020

Benzimidazole derivatives as potent and isoform selective tumor-associated carbonic anhydrase IX/XII inhibitors.

Bioorg Chem 2020 01 28;95:103544. Epub 2019 Dec 28.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Taç Sok. No:3 Yenimahalle, 06560 Ankara, Turkey. Electronic address:

We describe the synthesis of a series of 2-arylbenzimidazole derivatives bearing sulfonamide functionality (4a-d, 7a-c and 10) as well as hydroxamic acid (15a-b), carboxylic acid (16a-b), carboxamide (17a-b) and boronic acid (22a-b and 26) functionalities, which act as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors. The newly synthesized benzimidazole derivatives were evaluated against 4 physiologically relevant CA isoforms (hCA I, II, IX, and XII), and especially the sulfonamide-containing benzimidazoles demonstrated intriguing inhibitory activity against tumor associated CA IX and XII with K values in the range of 5.2-29.3 nM and 9.9-41.7 nM, respectively. Notably, compound 4c was the most potent and selective CA IX (K = 6.6 nM) and XII (K = 9.9 nM) inhibitor with a significant selectivity ratio over cytosolic CA I and II isoforms in the range of 3.4-25.2. In addition, compounds having hydroxamic acid (15a-b) or carboxylic acid (16a-b) functionalities resulted in greater selectivity ratios for CA IX/XII over CAI/II in the range of 4.1-121.5 although with K values in lower micromolar potency (Ks = 0.36-0.85 μM for CA IX/XII).
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http://dx.doi.org/10.1016/j.bioorg.2019.103544DOI Listing
January 2020

Protective effect of piceatannol and bioactive stilbene derivatives against hypoxia-induced toxicity in H9c2 cardiomyocytes and structural elucidation as 5-LOX inhibitors.

Eur J Med Chem 2019 Oct 10;180:637-647. Epub 2019 Jul 10.

Consorzio Sannio Tech-AMP Biotec, Appia Str. 7, Apollosa, BN, 82030, Italy; Institute of Food Sciences, National Research Council, Roma Str. 64, Avellino, 83100, Italy. Electronic address:

Stilbenes with well-known antioxidant and antiradical properties are beneficial in different pathologies including cardiovascular diseases. The present research was performed to investigate the potential protective effect of resveratrol (1) and piceatannol (2), against hypoxia-induced oxidative stress in the H9c2 cardiomyoblast cell line, and the underlying mechanisms. Compounds 1 and 2 significantly inhibited the release of peroxynitrite and thiobarbituric acid levels at na no- or submicromolar concentrations, and this effect was more evident in piceatannol-treated cells, that significantly increased MnSOD protein level in a concentration dependent manner. Furthermore, since piceatannol, which is far less abundant in natural sources, displayed a higher bioactivity than the parent compound, we hereby report on a very fast synthesis and detailed structure-based design of a focused stilbene library. Finally, taking into account that hypoxia-induced ROS accumulation also increases expression and activity of 5-lipoxygenase (5-LOX) with production of leukotrienes, we have disclosed structural key factors crucial for 5-LOX activity. Among the synthesized analogues ( 3-7), compound 7 was the most effective in improving cardiomyocytes viability and in 5-LOX inhibition. In conclusion, modeling and experimental studies provided the basis for further optimization of stilbene analogues as multi-target inhibitors of the inflammatory and oxidative pathway.
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http://dx.doi.org/10.1016/j.ejmech.2019.07.033DOI Listing
October 2019

Optimisation by Design of Experiment of Benzimidazol-2-One Synthesis under Flow Conditions.

Molecules 2019 Jul 3;24(13). Epub 2019 Jul 3.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06560 Ankara, Turkey.

A novel flow-based approach for the preparation of benzimidazol-2-one () scaffold by the 1,1'-carbonyldiimidazole (CDI)-promoted cyclocarbonylation of -phenylenediamine () is reported. Starting from a preliminary batch screening, the model reaction was successfully translated under flow conditions and optimised by means of design of experiment (DoE). The method allowed the efficient preparation of this privileged scaffold and to set up a general protocol for the multigram-scale preparation in high yield, purity, and productivity, and was successfully applied for the multigram flow synthesis of -(2-chlorobenzyl)-5-cyano-benzimidazol-2-one, which is a key synthon for hit-to-lead explorations in our anti-inflammatory drug discovery program.
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http://dx.doi.org/10.3390/molecules24132447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651037PMC
July 2019

A Multi-step Virtual Screening Protocol for the Identification of Novel Non-acidic Microsomal Prostaglandin E Synthase-1 (mPGES-1) Inhibitors.

ChemMedChem 2019 01 20;14(2):273-281. Epub 2018 Dec 20.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, 06560, Turkey.

Microsomal prostaglandin E synthase-1 (mPGES-1) is a potential therapeutic target for the treatment of inflammatory diseases and certain types of cancer. To identify novel scaffolds for mPGES-1 inhibition, we applied a virtual screening (VS) protocol that comprises molecular docking, fingerprints-based clustering with diversity-based selection, protein-ligand interactions fingerprints, and molecular dynamics (MD) simulations with molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations. The hits identified were carefully analyzed to ensure the selection of novel scaffolds that establish stable interactions with key residues in the mPGES-1 binding pocket and inhibit the catalytic activity of the enzyme. As a result, we discovered two promising chemotypes, 4-(2-chlorophenyl)-N-[(2-{[(propan-2-yl)sulfamoyl]methyl}phenyl)methyl]piperazine-1-carboxamide (6) and N-(4-methoxy-3-{[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]sulfamoyl}phenyl)acetamide (8), as non-acidic mPGES-1 inhibitors with IC values of 1.2 and 1.3 μm, respectively. Minimal structural optimization of 8 resulted in three more compounds with promising improvements in inhibitory activity (IC : 0.3-0.6 μm). The unprecedented chemical structures of 6 and 8, which are amenable to further derivatization, reveal a new and attractive approach for the development of mPGES-1 inhibitors with potential anti-inflammatory and anticancer properties.
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http://dx.doi.org/10.1002/cmdc.201800701DOI Listing
January 2019

Synthesis and cellular bioactivities of novel isoxazole derivatives incorporating an arylpiperazine moiety as anticancer agents.

J Enzyme Inhib Med Chem 2018 Dec;33(1):1352-1361

a Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Gazi University , Ankara , Turkey.

In our endeavour towards the development of effective anticancer therapeutics, a novel series of isoxazole-piperazine hybrids were synthesized and evaluated for their cytotoxic activities against human liver (Huh7 and Mahlavu) and breast (MCF-7) cancer cell lines. Within series, compounds 5l-o showed the most potent cytotoxicity on all cell lines with IC values in the range of 0.3-3.7 μM. To explore the mechanistic aspects fundamental to the observed activity, further biological studies with 5m and 5o in liver cancer cells were carried out. We have demonstrated that 5m and 5o induce oxidative stress in PTEN adequate Huh7 and PTEN deficient Mahlavu human liver cancer cells leading to apoptosis and cell cycle arrest at different phases. Further analysis of the proteins involved in apoptosis and cell cycle revealed that 5m and 5o caused an inhibition of cell survival pathway through Akt hyperphosphorylation and apoptosis and cell cycle arrest through p53 protein activation.
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http://dx.doi.org/10.1080/14756366.2018.1504041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161610PMC
December 2018

Structural insight into the optimization of ethyl 5-hydroxybenzo[g]indol-3-carboxylates and their bioisosteric analogues as 5-LO/m-PGES-1 dual inhibitors able to suppress inflammation.

Eur J Med Chem 2018 Jul 28;155:946-960. Epub 2018 May 28.

Università degli Studi della Campania Luigi Vanvitelli, Department of Experimental Medicine, Naples, Italy; Consorzio Sannio Tech, Appia Str, Apollosa, BN, 82030, Italy; Institute of Food Sciences, National Research Council, Roma Str. 64, Avellino, 83100, Italy. Electronic address:

The release of pro-inflammatory mediators, such as prostaglandines (PGs) and leukotrienes (LTs), arising from the arachidonic acid (AA) cascade, play a crucial role in initiating, maintaining, and regulating inflammatory processes. New dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E synthase-1 (mPGES-1), that block, at the same time, the formation of PGE and LTs, are currently emerged as a highly interesting drug candidates for better pharmacotherapie of inflammation-related disorders. Following our previous studies, we here performed a detailed structure-based design of benzo[g]indol-3-carboxylate derivatives, disclosing several new key factors that affect both enzyme activity. Ethyl 2-(3,4-dichlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (4b, RAF-01) and ethyl 2-(3,4-dichlorophenyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (7h, RAF-02) emerged as the most active compounds of the series. Additionally, together with selected structure based analogues, both derivatives displayed significant in vivo anti-inflammatory properties. In conclusion, modeling and experimental studies lead to the discovery of new candidate compounds prone to further developments as multi-target inhibitors of the inflammatory pathway.
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http://dx.doi.org/10.1016/j.ejmech.2018.05.041DOI Listing
July 2018

Crystal structure and Hirshfeld surface analysis of 1-(2,4-di-chloro-benz-yl)-5-methyl--(thio-phene-2-sulfon-yl)-1-pyrazole-3-carboxamide.

Acta Crystallogr E Crystallogr Commun 2018 May 27;74(Pt 5):747-751. Epub 2018 Apr 27.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey.

In the title compound, CHClNOS, the thio-phene ring is disordered in a 0.762 (3):0.238 (3) ratio by an approximate 180° rotation of the ring around the S-C bond linking the ring to the sulfonyl unit. The di-chloro-benzene group is also disordered over two sets of sites with the same occupancy ratio. The mol-ecular conformation is stabilized by intra-molecular C-H⋯Cl and C-H⋯N hydrogen bonds, forming rings with graph-set notation (5). In the crystal, pairs of mol-ecules are linked by N-H⋯O and C-H⋯O hydrogen bonds, forming inversion dimers with graph-set notation (8) and (11), which are connected by C-H⋯O hydrogen-bonding inter-actions into ribbons parallel to (100). The ribbons are further connected into a three-dimensional network by C-H⋯π inter-actions and π-π stacking inter-actions between benzene and thio-phene rings, with centroid-to-centroid distances of 3.865 (2), 3.867 (7) and 3.853 (2) Å. Hirshfeld surface analysis has been used to confirm and qu-antify the supra-molecular inter-actions.
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http://dx.doi.org/10.1107/S2056989018006242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947501PMC
May 2018

Identification of multi-target inhibitors of leukotriene and prostaglandin E biosynthesis by structural tuning of the FLAP inhibitor BRP-7.

Eur J Med Chem 2018 Apr 17;150:876-899. Epub 2018 Mar 17.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330, Ankara, Turkey. Electronic address:

Leukotrienes (LTs) and prostaglandin (PG)E are enzymatically produced from arachidonic acid and represent highly bioactive lipid mediators with pro-inflammatory functions. Here, we report on novel multi-target inhibitors that potently and dually interfere with 5-lipoxygenase-activating protein (FLAP) and microsomal prostaglandin E synthase (mPGES)-1 in LT and PGE biosynthesis, based on the previously identified selective FLAP inhibitor BRP-7 (8, IC = 0.31 μM). C (5)-substitution of the benzimidazole ring of BRP-7 by carboxylic acid and its bioisosteres provided compounds, exemplified by 57 that potently suppress LT formation (IC = 0.05 μM) by targeting FLAP along with inhibition of mPGES-1 (IC = 0.42 μM). Besides FLAP, also 5-lipoxygenase (5-LO) and LTC synthase activities were inhibited by 57, albeit with lower potency (IC = 0.6 and 6.2 μM) than FLAP. Docking studies and molecular dynamic simulations with FLAP, mPGES-1 and 5-LO provide valuable insights into potential binding interactions of the inhibitors with their targets. Together, these novel benzimidazole derivatives may possess potential as leads for development of effective anti-inflammatory drugs with multi-target properties for dually inhibiting LT and PGE production.
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http://dx.doi.org/10.1016/j.ejmech.2018.03.045DOI Listing
April 2018

The potential role of in silico approaches to identify novel bioactive molecules from natural resources.

Future Med Chem 2017 09 25;9(14):1665-1686. Epub 2017 Aug 25.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey.

In recent years, integration of in silico approaches to natural product (NP) research reawakened the declined interest in NP-based drug discovery efforts. In particular, advancements in cheminformatics enabled comparison of NP databases with contemporary small-molecule libraries in terms of molecular properties and chemical space localizations. Virtual screening and target fishing approaches were successful in recognizing the untold macromolecular targets for NPs to exploit the unmet therapeutic needs. Developments in molecular docking and scoring methods along with molecular dynamics enabled to predict the target-ligand interactions more accurately taking into consideration the remarkable structural complexity of NPs. Hence, innovative in silico strategies have contributed valuably to the NP research in drug discovery processes as reviewed herein. [Formula: see text].
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http://dx.doi.org/10.4155/fmc-2017-0124DOI Listing
September 2017

Drug discovery approaches targeting 5-lipoxygenase-activating protein (FLAP) for inhibition of cellular leukotriene biosynthesis.

Eur J Med Chem 2018 Jun 13;153:34-48. Epub 2017 Jul 13.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey. Electronic address:

Leukotrienes are proinflammatory lipid mediators associated with diverse chronic inflammatory diseases such as asthma, COPD, IBD, arthritis, atherosclerosis, dermatitis and cancer. Cellular leukotrienes are produced from arachidonic acid via the 5-lipoxygenase pathway in which the 5-lipoxygenase activating protein, also named as FLAP, plays a critical role by operating as a regulatory protein for efficient transfer of arachidonic acid to 5-lipoxygenase. By blocking leukotriene production, FLAP inhibitors may behave as broad-spectrum leukotriene modulators, which might be of therapeutic use for chronic inflammatory diseases requiring anti-leukotriene therapy. The early development of FLAP inhibitors (i.e. MK-886, MK-591, BAY-X-1005) mostly concentrated on asthma cure, and resulted in promising readouts in preclinical and clinical studies with asthma patients. Following the recent elucidation of the 3D-structure of FLAP, development of new inhibitor chemotypes is highly accelerated, eventually leading to the evolution of many un-drug-like structures into more drug-like entities such as AZD6642 and BI665915 as development candidates. The most clinically advanced FLAP inhibitor to date is GSK2190918 (formerly AM803) that has successfully completed phase II clinical trials in asthmatics. Concluding, although there are no FLAP inhibitors reached to the drug approval phase yet, due to the rising number of indications for anti-LT therapy such as atherosclerosis, FLAP inhibitor development remains a significant research field. FLAP inhibitors reviewed herein are classified into four sub-classes as the first-generation FLAP inhibitors (indole and quinoline derivatives), the second-generation FLAP inhibitors (diaryl-alkanes and biaryl amino-heteroarenes), the benzimidazole-containing FLAP inhibitors and other FLAP inhibitors with polypharmacology for easiness of the reader. Hence, we meticulously summarize how FLAP inhibitors historically developed from scratch to their current advanced state, and leave the reader with a positive view that a FLAP inhibitor might soon reach to the need of patients who may require anti-LT therapy.
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http://dx.doi.org/10.1016/j.ejmech.2017.07.019DOI Listing
June 2018

Pteryxin - A promising butyrylcholinesterase-inhibiting coumarin derivative from Mutellina purpurea.

Food Chem Toxicol 2017 Nov 9;109(Pt 2):970-974. Epub 2017 Mar 9.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey. Electronic address:

Pteryxin is a dihydropyranocoumarin derivative found in Apiaceae family. In this study, pteryxin, which was previously isolated from the fruits of Mutellina purpurea, was investigated for its inhibitory potential against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which are the key enzymes in the pathology of Alzheimer's disease (AD). The compound was tested in vitro using ELISA microplate reader at 100 μg/ml and found to cause 9.30 ± 1.86% and 91.62 ± 1.53% inhibition against AChE and BChE, respectively. According to our results, pteryxin (IC = 12.96 ± 0.70 μg/ml) was found to be a more active inhibitor of BChE than galanthamine (IC = 22.16 ± 0.91 μg/ml; 81.93± 2.52% of inhibition at 100 μg/ml). Further study on pteryxin using molecular docking experiments revealed different possible binding modes with both polar and hydrophobic interactions inside the binding pocket of BChE. Top docking solution points out to the formation of two hydrogen bonds with the catalytic residues S198 and H438 of BChE as well as a strong π - π stacking with W231. Therefore, pteryxin as a natural coumarin seems to be a strong BChE inhibitor, which could be considered as a lead compound to develop novel BChE inhibitors for AD treatment.
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http://dx.doi.org/10.1016/j.fct.2017.03.016DOI Listing
November 2017

BRP-187: A potent inhibitor of leukotriene biosynthesis that acts through impeding the dynamic 5-lipoxygenase/5-lipoxygenase-activating protein (FLAP) complex assembly.

Biochem Pharmacol 2016 Nov 31;119:17-26. Epub 2016 Aug 31.

Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743 Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany. Electronic address:

The pro-inflammatory leukotrienes (LTs) are formed from arachidonic acid (AA) in activated leukocytes, where 5-lipoxygenase (5-LO) translocates to the nuclear envelope to assemble a functional complex with the integral nuclear membrane protein 5-LO-activating protein (FLAP). FLAP, a MAPEG family member, facilitates AA transfer to 5-LO for efficient conversion, and LT biosynthesis critically depends on FLAP. Here we show that the novel LT biosynthesis inhibitor BRP-187 prevents the 5-LO/FLAP interaction at the nuclear envelope of human leukocytes without blocking 5-LO nuclear redistribution. BRP-187 inhibited 5-LO product formation in human monocytes and polymorphonuclear leukocytes stimulated by lipopolysaccharide plus N-formyl-methionyl-leucyl-phenylalanine (IC=7-10nM), and upon activation by ionophore A23187 (IC=10-60nM). Excess of exogenous AA markedly impaired the potency of BRP-187. Direct 5-LO inhibition in cell-free assays was evident only at >35-fold higher concentrations, which was reversible and not improved under reducing conditions. BRP-187 prevented A23187-induced 5-LO/FLAP complex assembly in leukocytes but failed to block 5-LO nuclear translocation, features that were shared with the FLAP inhibitor MK886. Whereas AA release, cyclooxygenases and related LOs were unaffected, BRP-187 also potently inhibited microsomal prostaglandin E synthase-1 (IC=0.2μM), another MAPEG member. In vivo, BRP-187 (10mg/kg) exhibited significant effectiveness in zymosan-induced murine peritonitis, suppressing LT levels in peritoneal exudates as well as vascular permeability and neutrophil infiltration. Together, BRP-187 potently inhibits LT biosynthesis in vitro and in vivo, which seemingly is caused by preventing the 5-LO/FLAP complex assembly and warrants further preclinical evaluation.
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http://dx.doi.org/10.1016/j.bcp.2016.08.023DOI Listing
November 2016

Synthesis and biological evaluation of C(5)-substituted derivatives of leukotriene biosynthesis inhibitor BRP-7.

Eur J Med Chem 2016 Oct 5;122:510-519. Epub 2016 Jul 5.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330 Ankara, Turkey. Electronic address:

Pharmacological intervention with 5-lipoxygenase (5-LO) pathway leading to suppression of leukotriene (LT) biosynthesis is a clinically validated strategy for treatment of respiratory and cardiovascular diseases such as asthma and atherosclerosis. Here we describe the synthesis of a series of C(5)-substituted analogues of the previously described 5-LO-activating protein (FLAP) inhibitor BRP-7 (IC50 = 0.31 μM) to explore the effects of substitution at the C(5)-benzimidazole (BI) ring as a strategy to increase the potency against FLAP-mediated 5-LO product formation. Incorporation of polar substituents on the C(5) position of the BI core, exemplified by compound 11 with a C(5)-nitrile substituent, significantly enhances the potency for suppression of 5-LO product synthesis in human neutrophils (IC50 = 0.07 μM) and monocytes (IC50 = 0.026 μM).
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http://dx.doi.org/10.1016/j.ejmech.2016.07.004DOI Listing
October 2016

4,5-Diarylisoxazol-3-carboxylic acids: A new class of leukotriene biosynthesis inhibitors potentially targeting 5-lipoxygenase-activating protein (FLAP).

Eur J Med Chem 2016 May 15;113:1-10. Epub 2016 Feb 15.

Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743, Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743, Jena, Germany.

In this article, we report novel leukotriene (LT) biosynthesis inhibitors that may target 5-lipoxygenase-activating protein (FLAP) based on the previously identified isoxazole derivative (8). The design and synthesis was directed towards a subset of 4,5-diaryl-isoxazole-3-carboxylic acid derivatives as LT biosynthesis inhibitors. Biological evaluation disclosed a new skeleton of potential anti-inflammatory agents, exemplified by 39 and 40, which potently inhibit cellular 5-LO product synthesis (IC50 = 0.24 μM, each) seemingly by targeting FLAP with weak inhibition on 5-LO (IC50 ≥ 8 μM). Docking studies and molecular dynamic simulations with 5-LO and FLAP provide valuable insights into potential binding modes of the inhibitors. Together, these diaryl-isoxazol-3-carboxylic acids may possess potential as leads for development of effective anti-inflammatory drugs through inhibition of LT biosynthesis.
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http://dx.doi.org/10.1016/j.ejmech.2016.02.027DOI Listing
May 2016

Synthesis and preliminary mechanistic evaluation of 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3-carboxylic acid amides with potent antiproliferative activity on human cancer cell lines.

Eur J Med Chem 2014 Nov 20;87:140-9. Epub 2014 Sep 20.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06330 Ankara, Turkey. Electronic address:

We synthesized a series of novel amide derivatives of 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3-carboxylic acid and assessed their antiproliferative activities against three human cancer cell lines (Huh7, human liver; MCF7, breast and HCT116, colon carcinoma cell lines) with the sulforhodamine B assay. Compound 4j with 2-chloro-4-pyridinyl group in the amide part exhibited promising cytotoxic activity against all cell lines with IC50 values of 1.6 μM, 3.3 μM and 1.1 μM for Huh7, MCF7 and HCT116 cells, respectively, and produced dramatic cell cycle arrest at SubG1/G1 phase as an indicator of apoptotic cell death induction. On the basis of their high potency in cellular environment, these straightforward pyrazole-3-carboxamide derivatives may possess potential in the design of more potent compounds for intervention with cancer cell proliferation.
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http://dx.doi.org/10.1016/j.ejmech.2014.09.056DOI Listing
November 2014

Crystal structure and DFT calculations of 5-(4-Chlorophenyl)-1-(6-methoxypyridazin-3-yl)-1H-pyrazole-3-carboxylic acid.

Spectrochim Acta A Mol Biomol Spectrosc 2014 Nov 15;132:555-62. Epub 2014 May 15.

Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, TR-06100 Besevler, Ankara, Turkey.

The title compound, 5-(4-Chlorophenyl)-1-(6-methoxypyridazin-3-yl)-1H-pyrazole-3-carboxylic acid, has been characterized by using elemental analysis, MS, FT-IR, 1H NMR and 13C NMR spectroscopic, and crystallographic techniques. The title compound crystallizes in the triclinic space group P-1 with a=9.612(1), b=9.894(1), c=17.380(1)Å, α=90.213(5)°, β=104.99(1)°, γ=111.072(5)°, V=1481.3(2)Å3 and Dx=1.483 g cm(-3) respectively. The structure of the compound has also been examined by using quantum chemical methods. The molecular geometry and vibrational frequencies of monomeric and dimeric form of the title compound in the ground state have been calculated by using the B3LYP/6-31G(d,p) level of the theory. The calculated results show that the optimized geometry and the theoretical vibration frequencies of the dimeric form are good agreement with experimental data. In addition, HOMO-LUMO energy gap, molecular electrostatic potential map, thermodynamic properties of the title compound were performed at B3LYP/6-31G(d,p) level of theory.
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http://dx.doi.org/10.1016/j.saa.2014.05.014DOI Listing
November 2014

Synthesis, biological evaluation and molecular docking studies of trans-indole-3-acrylamide derivatives, a new class of tubulin polymerization inhibitors.

Bioorg Med Chem 2014 Jun 20;22(12):3096-104. Epub 2014 Apr 20.

Department of Women's and Children's Health, Laboratory of Oncohematology, University of Padova, 35128 Padova, Italy.

In this study, we synthesized a series of trans-indole-3-acrylamide derivatives (3a-k) and investigated their activity for inhibition of cell proliferation against five human cancer cell lines (HeLa, MCF7, MDA-MB-231, Raji and HL-60) by MTT assay. Compound 3e showed significant antiproliferative activity against both the Raji and HL-60 cell lines with IC50 values of 9.5 and 5.1 μM, respectively. Compound 3e also exhibited moderate inhibitory activity on tubulin polymerization (IC50=17 μM). Flow cytometric analysis of cultured cells treated with 3e also demonstrated that the compound caused cell cycle arrest at the G2/M phase in HL-60 and HeLa cells. Moreover, 3e, the most active compound, caused an apoptotic cell death through the activation of caspase-3. Docking simulations suggested that 3e binds to the colchicine site of tubulin.
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http://dx.doi.org/10.1016/j.bmc.2014.04.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091680PMC
June 2014

Chromatographic separation and biological evaluation of benzimidazole derivative enantiomers as inhibitors of leukotriene biosynthesis.

J Pharm Biomed Anal 2014 Feb 7;89:88-92. Epub 2013 Nov 7.

Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy. Electronic address:

For an explicit analysis of the chirality on the effectiveness of a recently identified racemic benzimidazole derivative (BRP7) as inhibitor of leukotriene biosynthesis, we optimized a HPLC-based chiral chromatographic method enabling the quantitative isolation of its enantiomers in sufficient amount to carry out biological investigations. The use of a Lux Amylose-2 column revealed especially profitable to fulfil our task. Indeed, the employment of the amylose-based chiral stationary phase (CSP) in combination with a n-hexane/EtOH/DEA - 99/1/02 (v/v/v) mobile phase allowed getting the enantiomeric peaks fully resolved (α=1.80, RS=2.39). Four consecutive injections repeated at 1-min intervals produced overloaded peaks with a very limited level of isomeric contamination. This procedure allowed the isolation of ca. 20mg of each enantiomer, with enantiomeric excess higher than 99% and 95% for the (S)- and the (R)-isomer, respectively. The enantiomeric elution order was established using synthetic reference compounds of lower enantiomeric excess values. The biological evaluation of the purified individual enantiomers revealed no significant difference in terms of their IC50 values with respect to the previously investigated racemic BRP7: 0.18μM for the (R)-enantiomer (R(2)=0.999) and 0.26μM for the (S)-enantiomer (R(2)=0.986).
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http://dx.doi.org/10.1016/j.jpba.2013.10.039DOI Listing
February 2014

Pyrazole derivatives as inhibitors of arachidonic acid-induced platelet aggregation.

Eur J Med Chem 2013 Jun 6;64:42-53. Epub 2013 Apr 6.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Taç Sok. No:3, Etiler, Yenimahalle, Ankara 06330, Turkey.

Antiplatelet drugs are promising therapeutics to intervene with platelet aggregation in arterial thrombosis, most prominently in myocardial infarction and ischemic stroke. Here, we describe the synthesis and structure-activity relationships of potent inhibitors of platelet aggregation based on the 1,5-diarylpyrazol-3-carboxamide scaffold. Analogs from this series demonstrated potent anti-aggregatory activities against arachidonic acid-induced platelet aggregation, as measured by turbidimetric method of Born. 1,5-Diarylpyrazole-3-carboxamides obtained with small-basic amines (7, 8, 50, 51, 61, 62) displayed the strongest activity with IC50 values in low nanomolar range (5.7-83 nM). On the basis of their high potency in cellular environment, these straightforward pyrazole derivatives may possess potential in the design of more potent compounds for intervention with cardiovascular diseases.
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http://dx.doi.org/10.1016/j.ejmech.2013.03.048DOI Listing
June 2013

Overview of recent drug discovery approaches for new generation leukotriene A4 hydrolase inhibitors.

Expert Opin Drug Discov 2013 Jan 25;8(1):49-63. Epub 2012 Oct 25.

Gazi University, Department of Pharmaceutical Chemistry, Taç Sok. No:3 Yenimahalle, Ankara, Turkey.

Introduction: LTA(4)H is a bifunctional enzyme with hydrolase and aminopeptidase activities. The hydrolase function of this enzyme specifically catalyzes the rate-limiting step in the conversion of LTA(4) to LTB(4), one of the most potent chemoattractant and activator of neutrophils. The wealth of in vitro and in vivo data favors in support of LTA(4)H as an appealing target for the discovery and development of anti-inflammatory drugs.

Areas Covered: The authors provide an overview of the recent advances on LTA(4)H inhibitors since 2000. The review details the medicinal chemistry efforts leading to the generation of novel inhibitor chemotypes with desirable drug-like properties as well as the advantages and disadvantages of LTA(4)H as a desirable therapeutic target.

Expert Opinion: Most of the LTA(4)H inhibitors block pro-inflammatory LTB(4) biosynthesis by concomitant inhibition of both the hydrolase and aminopeptidase activities of LTA(4)H. However, the degradation of another endogenous chemoattractant substrate (PGP) by aminopeptidase function of LTA(4)H was shown, introducing a new anti-inflammatory mission for this pro-inflammatory enzyme. LTA(4)H inhibitors were also shown to maintain anti-inflammatory lipoxin formation. Hence, the data on new LTA(4)H inhibitors should be cautiously interpreted with regard to potential repercussions of preventing PGP degradation as well as for the clinical benefits of concomitant lipoxin formation.
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http://dx.doi.org/10.1517/17460441.2013.735228DOI Listing
January 2013

Identification of novel benzimidazole derivatives as inhibitors of leukotriene biosynthesis by virtual screening targeting 5-lipoxygenase-activating protein (FLAP).

Bioorg Med Chem 2012 Jun 1;20(12):3728-41. Epub 2012 May 1.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06330 Yenimahalle, Ankara, Turkey.

Pharmacological suppression of leukotriene biosynthesis by 5-lipoxygenase (5-LO)-activating protein (FLAP) inhibitors is a promising strategy to intervene with inflammatory, allergic and cardiovascular diseases. Virtual screening targeting FLAP based on a combined ligand- and structure-based pharmacophore model led to the identification of 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-1H-benzimidazole (7) as developable candidate. Compound 7 potently suppressed leukotriene formation in intact neutrophils (IC(50)=0.31 μM) but essentially failed to directly inhibit 5-LO suggesting that interaction with FLAP causes inhibition of leukotriene synthesis. For structural optimization, a series of 46 benzimidazole-based derivatives of 7 were synthesized leading to more potent analogues (70-72, 82) with IC(50)=0.12-0.19 μM in intact neutrophils. Together, our results disclose the benzimidazole scaffold bearing an ibuprofen fingerprint as a new chemotype for further development of anti-leukotriene agents.
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http://dx.doi.org/10.1016/j.bmc.2012.04.048DOI Listing
June 2012

Serum interleukin-16 levels in patients with nasal polyposis.

Laryngoscope 2012 May 23;122(5):961-4. Epub 2012 Mar 23.

Department of Otorhinolaryngology, Gazi University School of Medicine, Ankara, Turkey.

Objective/hypothesis: Several inflammatory and allergic disorders have been reported to correlate with interleukin-16 (IL-16). IL-16 is a highly potent chemotactic and chemoattractant molecule for eosinophils. Nasal polyposis (NP) has an inflammatory basis, and eosinophilia is a common finding in polyp tissue. In this study, we aimed to determine serum IL-16 levels in NP patients.

Study Design: Prospective controlled study in a tertiary academic hospital.

Methods: Peripheral blood samples were obtained and used for serologic studies with enzyme-linked immunosorbent assay kits to determine IL-16 levels.

Results: The study and the control groups consisted of 17 and 10 patients, respectively. Mean serum IL-16 levels were significantly higher in the study group when compared to the control group (447.9 pg/mL vs. 260.2 pg/mL) (P < .001).

Conclusions: Serum IL-16 levels are significantly elevated in NP patients. This finding may represent identification of a valuable serum biomarker and potential therapeutic target in NP patients.
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http://dx.doi.org/10.1002/lary.23238DOI Listing
May 2012

From Molecular Docking to 3D-Quantitative Structure-Activity Relationships (3D-QSAR): Insights into the Binding Mode of 5-Lipoxygenase Inhibitors.

Mol Inform 2012 Feb 20;31(2):123-34. Epub 2012 Jan 20.

Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06330 Ankara, Turkey tel.: +90-312-2023236; fax: +90-312-2235018.

Pharmacological intervention with 5-Lipoxygenase (5-LO) is a promising strategy for treatment of inflammatory and allergic ailments, including asthma. With the aim of developing predictive models of 5-LO affinity and gaining insights into the molecular basis of ligand-target interaction, we herein describe QSAR studies of 59 diverse nonredox-competitive 5-LO inhibitors based on the use of molecular shape descriptors and docking experiments. These studies have successfully yielded a predictive model able to explain much of the variance in the activity of the training set compounds while predicting satisfactorily the 5-LO inhibitory activity of an external test set of compounds. The inspection of the selected variables in the QSAR equation unveils the importance of specific interactions which are observed from docking experiments. Collectively, these results may be used to design novel potent and selective nonredox 5-LO inhibitors.
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http://dx.doi.org/10.1002/minf.201100101DOI Listing
February 2012

Synthesis, antioxidant and antimicrobial evaluation of simple aromatic esters of ferulic acid.

Arch Pharm Res 2011 Aug 11;34(8):1251-61. Epub 2011 Sep 11.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Etiler, Ankara, Turkey.

Aromatic ester derivatives of ferulic acid where the phenolic hydroxyl is free (6a-d) or acetylated (5a-d) were evaluated for their antioxidant and antimicrobial properties. The superoxide radical scavenging capacity of compounds 5d and 6d-e (IC(50) of 0.19, 0.27 and 0.20 mM, respectively) was found to be twice as active as α-tocopherol (IC(50) = 0.51 mM). DPPH radical scavenging capacity was moderate and only found in compounds bearing free phenolic hydroxyl groups (6a-e). With regard to antimicrobial properties, compounds 6b and 6c displayed significant activity against Enterococcus faecalis (MICs = 16 μg/mL) and vancomycin-resistant E. faecalis (MIC for 6b, 32 and for 6c, 16 μg/mL). Compound 6c also demonstrated prominent activity against planktonic Staphylococcus aureus with a MIC value of <8 μg/mL and it inhibited bacterial biofilm formation by S. aureus with a MBEC value of <8 μg/mL, which was 64 and 128 times more potent than ofloxacin and vancomycin, respectively.
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http://dx.doi.org/10.1007/s12272-011-0803-yDOI Listing
August 2011