Synthesis and evaluation of new benzoxazole derivatives as potential antiglioma agents

WOS: 000458080300010Gliomas account for the majority of human brain tumors and the incidence of gliomas is expected to rise in upcoming years and therefore extensive efforts have been devoted to the discovery of potent antiglioma agents. Due to the importance of benzoxazoles for anticancer drug discovery, herein new benzoxazole-based hydrazone derivatives (3a-g) were designed and synthesized. The cytotoxic effects of the compounds on C6 rat glioma and NIH/3T3 mouse embryonic fibroblast cell lines were investigated using MTT assay. The apoptotic effects of the most selective anticancer agent were analyzed based on Annexin V-PI binding capacities in flow cytometry. The compounds were also investigated for their acetylcholinesterase (AChE) inhibitory effects using a modification of Ellman's spectrophotometric method. In order to evaluate the compliance of the compounds to Lipinski's rule of five, their physicochemical parameters were determined using Molinspiration software. N'-([1,1'-Biphenyl]-4-ylmethylene)-2-[(5-fluorobenzoxazol-2-yl)thio]acetohydrazide (3g) was found to be more effective on C6 cell line (IC50 = 4.30 +/- 0.28 mu g/mL) than mitoxantrone (IC50 = 4.56 +/- 1.24 mu g/mL). The high SI value of compound 3g indicated that its antiglioma activity was selective. This compound caused late apoptosis in a dose dependent manner. Compound 3g was also found to be the most effective AChE inhibitor in this series. According to in silico studies, compound 3g only violated one parameter of Lipinski's rule of five. On the basis of Lipinski's rule, the compound was expected to have reasonable oral bioavailability. According to in vitro and in silico studies, compound 3g stands out as a promising antiglioma agent for further studies.Anadolu University Scientific Research Projects Commission [1705S175]This study was supported by Anadolu University Scientific Research Projects Commission under the grant no: 1705S175

The effect of metformin and exercise on serum lipids, nitric oxide synthase and liver nitric oxide levels in streptozotocin-nicotinamide induced diabetic rats

WOS: 000303761200010The objective of this study was to determine the effects of metformin treatment and exercise intervention on lipid metabolism, nitric oxide (NO), nitric oxide synthase (NOS) and glucose levels in streptozotocin-nicotinamide (STZ-NA) induced diabetic rats. Male wistar rats were used to conduct the study and they were divided into five groups of 8 rats in each. These groups are: Control group, diabetes group (STZ-NA), diabetes and metformin (DMet) group, diabetes and exercise (DE) group, and diabetes + exercise + metformin (DEMet) group. The STZ-NA induced diabetic rats were used as a model of type 2 diabetes. Metformin was orally administered to rats. For exercise intervention, rats were forced to run in a running wheel for 10 min each day (20 m/min/day). At the end of experimental period, blood glucose, glycated hemoglobin (HbA1c) levels, plasma lecithin: cholesterol acyltransferase (LCAT) levels, serum triglyceride (TG), cholesterol, high density lipoprotein (HDL), Apo A-I, NOS and liver NO levels were determined. Metformin caused beneficial changes in blood glucose, HbA1c levels, and HDL in type 2 diabetic rats. Both administration of metformin and exercise intervention independently caused beneficial changes in blood glucose. However, the surprising result found was that exercise intervention did not optimize the result of metformin treatment. The other finding of this study was that exercise intervention increased cholesterol and NOS level but exercise combined with metformin was not better than exercise alone. Thus, it appears from the present study that metformin and exercise combination has no effect.Eskisehir Osmangazi University Scientific Research Commission [2006-11]This study was supported by Eskisehir Osmangazi University Scientific Research Commission. Contract grants number 2006-11

Synthesis and biological evaluation of some thiazole derivatives as new cholinesterase inhibitors

WOS: 000316419400011PubMed ID: 22299580In the present study, some thiazole derivatives were synthesized via the ring closure reaction of 1-[2-(2-oxobenzo[d] thiazol-3(2H)-yl)acetyl]thiosemicarbazide with various phenacyl bromides. The chemical structures of the compounds were elucidated by H-1 NMR, C-13 NMR and mass spectral data and elemental analyses. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman's spectrophotometric method. The compounds were also investigated for their cytotoxic properties using MTT assay. The most potent AChE inhibitor was found as compound 4e (IC50 = 25.5 +/- 2.12 mu g/mL) followed by compounds 4i (IC50 = 38.50 +/- 2.12 mu g/mL), 4c (IC50 = 58.42 +/- 3.14 mu g/mL) and 4g (IC50 = 68 +/- 2.12 mu g/mL) when compared with eserine (IC50 = 0.025 +/- 0.01 mu g/mL). Effective compounds on AChE exhibited weak inhibition on BuChE (IC50 > 80 mu g/mL). MTT assay indicated that the cytotoxic dose (IC50 = 71.67 +/- 7.63 mu g/mL) of compound 4e was higher than its effective dose

Rhanterium epapposum Oliv. essential oil: Chemical composition and antimicrobial, insect-repellent and anticholinesterase activities

WOS: 000406021100005PubMed ID: 28725142The essential oil (EO) of the aerial parts of Rhanterium epapposum Oliv. (Asteraceae), was obtained by hydrodistillation. The oil was subsequently analyzed by both GC-FID and GC-MS, simultaneously. Forty-five components representing 99.2% of the oil composition were identified. The most abundant compounds were camphene (38.5%), myrcene (17.5%), limonene (10.1%) and alpha-pinene (8.7%). Referring to the ethnobotanical utilization, an insecticidal assay was performed, where the oil repelled the yellow fever mosquito Aedes aegypti L. at a minimum effective dose (MED of 0.035 +/- 0.010 mg/cm(2)) compared to the positive control DEET (MED of 0.015 +/- 0.004 mg/cm(2)). Additionally, the in vitro antimicrobial activity against a panel of pathogens was determined using a microdilution method. The acetyl- and butyrylcholine esterase inhibitory activities were measured using the colorimetric Ellman method. The bioassay results showed that the oil was rather moderate in antimicrobial and cholinesterase inhibitions when compared to the standard compoundsDeployed War-Fighter Protection Research Program - U.S. Department of Defense through Armed Forces Pest Management BoardWe thank Greg Allen (USDA-ARS, Center for Medical, Agricultural, and Veterinary Entomology, Gainesville, FL) for performing the mosquito bioassays. This study was supported partially by the Deployed War-Fighter Protection Research Program Grant funded by the U.S. Department of Defense through the Armed Forces Pest Management Board

NO levels in diabetes mellitus: Effects of l-NAME and insulin on LCAT, Na+/K+ ATPase activity and lipid profile

PubMed: 25572761Objectives: Diabetes mellitus (DM) is a chronic disease and one of the most important health problems. Several factors may be responsible for the complications of diabetes mellitus including alterations in the activities of sodium-potassium adenosine triphosphatase (Na+/K+ ATPase) and lecithin:cholesterol acyltransferase (LCAT) and also levels of nitric oxide (NO). We have investigated the effects of alterations in serum NO levels on activities of erythrocyte membran Na/K ATPase and serum LCAT enzymes. Materials and methods: The experiments were performed on male rats divided into four groups: group 1, control (standart diet); group 2, diabetic control (single dose of 65 mg/kg of streptozotocin (STZ), i.p); group 3, STZ + insulin (8 IU/kg/day s.c.); group 4 (STZ + l-NAME 5 mg/kg/day orally). Result: Streptozotocin-induced diabetic rats, showed a significant increase in blood glucose and serum cholesterol (C) and triglyceride (TG). Compared to the control group with diabetic group plasma LCAT concentrations and erythrocyte membrane Na +/K+ ATPase were found to be decreased. Activities of Na+/K+ ATPase and serum NO level were decreased with the administration of l-NAME. We observed that insulin was ameliorated in all parameters. Conclusions: Serum NO levels is related to erythrocyte membrane Na+/K+ ATPase activity. But serum NO levels did not affect the plasma LCAT activity and serum lipid profile

CYCLOOXYGENASE INHIBITORY ACTIVITY AND COMPOSITION OF ECHINOPHORA TENUIFOLIA L. SUBSP. SIBTHORPIANA (GUSS.) TUTIN L. ESSENTIAL OIL

CYCLOOXYGENASEINHIBITORY ACTIVITY AND COMPOSITION OF ECHINOPHORATENUIFOLIA L. SUBSP. SIBTHORPIANA (GUSS.)TUTIN L. ESSENTIAL OIL&nbsp;Gulsum Yildiz1, HalideEdip Temel2, Betul Demirci3&nbsp;1 Department of Pharmacognosy,Faculty of Pharmacy, Van Yuzuncu Yil University, 65080, Van, Turkey, [email protected] Department of Biochemistry, Faculty of Pharmacy, Anadolu University, 26470, Eskişehir, Turkey, [email protected] Department of Pharmacognosy, Facultyof Pharmacy, Anadolu University, 26470,Eskişehir, Turkey, [email protected]&nbsp;Objective / Purpose: Echinophora tenuifolia L. subsp. sibthorpiana (Guss.)Tutin L. (Apiaceae) is known as ‘çörtük, turşu otu, tarhana otu’ and used bothfood and folk medicine in Turkey [1-3].The aim of this studywas to determine the chemical composition and inhibitory activity of theessential oil on cylooxygenase enzymes of E.tenuifolia subsp. sibthorpiana.&nbsp;Material and Methods: The plant was collected in May 2018, from Tokat province, Turkey. Aerialparts of the plant were subjected to hydrodistillation using Clevengerapparatus. Chemical composition of the oil was analyzed with GC-FID and GC-MStechniques. The effect of inhibition of essentialoil on cyclooxygenase enzymes was investigated using the "COX ColorimetricInhibitor Screening Test Kit" containing both ovine COX-1 and humanrecombinant COX-2 enzymes.&nbsp;Results: Main components of theoil were found as methyl eugenol (45.5%), p-cymene(11.5%) and δ-3-carene (11.2%). Theoil is exhibited inhibitory activity at 100 µg/ml on cyclooxygenase-1 (COX-1);68,89±2,96 %, while no inhibition activity on cyclooxygenase-2 (COX-2).Rofekoksib and SC-560 were used as standard inhibitors for COX-2 and COX-1,respectively.&nbsp;Conclusion / Discussion: The results showed that the essential oil may play an inhibitory role onCOX-1 enzyme and inflammation relation diseases. To the best of our knowledge,this is the first contribution into the COX enzymes inhibition activity of Echinophora tenuifolia L. subsp. sibthorpiana (Guss.) Tutin L. essentialoil.&nbsp;Key Words:. Echinophora tenuifolia subsp. sibthorpiana, essential oil, GC, GC/MS, COX&nbsp;AcknowledgementWe are grateful to Prof. Dr. Yavuz Bulent Kose,Department of Pharmaceutical Botany, Faculty of Pharmacy, Anadolu University,Eskişehir, Turkey, for determination of the plant specimen. &nbsp;References[1] Baytop, T. (1999). Türkiyede bitkiler ile tedavi (geçmişte ve bugün) (No. 40). İstanbul Üniversitesi yay., pp. 166-167.[2] Melikoğlu, G., Kurtoğlu, S., &amp; Kültür, Ş. (2015).Türkiye’de Astım Tedavisinde Geleneksel Olarak Kullanılan Bitkiler. MarmaraPharmaceutical Journal, 19(1), 1-11.[3] Bulut, G., Tuzlaci, E., Dogan, A., &amp; Senkardes,I. (2014). An ethnopharmacological review on the Turkish Apiaceae species. Journalof Faculty Pharmacy of Istanbul University, 44(2), 163-179.</p

<i>In vitro</i> and <i>in silico</i> studies on AChE inhibitory effects of a series of donepezil-like arylidene indanones

Abstract Objective Donepezil is the most potent acetylcholinesterase (AChE) inhibitor currently available on the market for the management of Alzheimer’s disease. In this study, it was aimed to identify potent donepezil analogues. Materials and methods The effects of arylidene indanones (1–10) on AChE inhibition were examined using modified Ellman’s assay. Compound 4, the most potent arylidene indanone in this series, was subjected to molecular docking to anticipate its binding mode in the AChE site (PDB code: 4EY7). The pharmacokinetic profiles of all derivatives were also predicted. Results Compound 4 was found as the most potent AChE inhibitor with an IC50 value of 5.93 ± 0.29 μg/mL. According to molecular docking studies, compound 4 presented favorable interactions such as π–π interactions with Trp286 and Tyr337. In silico studies revealed that the compound did not violate Lipinski’s rule of five and Jorgensen’s rule of three, making it a potential orally bioavailable agent. Conclusion Compound 4 is a feasible candidate for further experiments related to AChE inhibition. </jats:sec

Evaluation of new sulfathiazole derivatives as antiproliferative agents

Abstract Objectives Sulfonamide group is an important scaffold used for generating new building blocks with diverse biological activities. Considering priority of the sulfonamide structure, seven new sulfathiazole derivatives were synthesized and evaluated for their antiproliferative activity, in this study. Materials and methods Compounds 2a–g were synthesized using a two-step synthetic procedure starting from commercially available sulfathiazole. The antiproliferative activity of the compounds was investigated against A549 and NIH/3T3 cell lines by MTT assay, matrix metalloproteinase-9 (MMP-9) and cathepsin inhibition tests. Results Compound 2b bearing triazole ring exhibited highest inhibitory activity (IC50: 12.33 μg/mL) with selective profile which was better than cisplatin and it also inhibited MMP-9 with 53.67% percentage. Compounds 2c and 2e inhibited cathepsin L with percentages of 62.75 and 57.25%, whereas cathepsin D was poorly inhibited by the compounds. Conclusions Target compounds exhibited high to moderate antiproliferative activity and they displayed higher MMP-9 inhibition than cathepsin inhibition activity. 2b and 2e were identified as the most active compounds when evaluated, biologically. </jats:sec

Butrylcholinesterase Activity in Chronic Liver Disease Patients and Correlation with Child-Pugh Classification and MELD Scoring System

WOS: 000353008800027PubMed ID: 25975011Background: After 40 years since establishment of Child-Pugh staging, 14 years since establishment of MELD scoring system, and 25 years since establishment of King's College Criteria, there is still a search for more accurate systems for determination of prognosis in patients with acute liver failure - cirrhosis and prioritization for receipt of a liver transplant - prediction of post transplant mortality. Butrylcholinesterase is an enzyme which is synthesized in the liver. The aim of the study was to evaluate the clinical utility of butrylcholinesterase as a discriminatory and prognostic factor in chronic liver disease patients. Methods: Intergroup diversity for butrylcholinesterase activity was investigated in sixty cirrhotic, 20 chronic hepatitis patients, and 20 healthy subjects. Correlations between butrylcholinesterase activity and Child-Pugh classification and MELD scoring systems were examined. Results: In addition to the statistically significant decrease in butrylcholinesterase activity among Child-Pugh A/B/C stages, the decrease in butrylcholinesterase activity was also statistically significant in control vs. Child-Pugh stage A and chronic hepatitis vs. Child Pugh stage A groups. A statistically significant correlation was determined between butrylcholinesterase activity and Child Pugh/MELD scores. Conclusions: Serum butrylcholinesterase activity might be helpful for discrimination of chronic hepatitis from cirrhosis after determination of reliable cut-off levels and dependent on the reductions of serum levels in acute liver failure and cirrhosis. It might be a useful tool for prioritization of liver transplantation

Apoptosis inducing effects of novel benzimidazole derivatives bearing pyridyl/pyrimidinyl piperazine moieties on A549 lung adenocarcinoma

41st FEBS Congress on Molecular and Systems Biology for a Better Life -- SEP 03-08, 2016 -- Kusadasi, TURKEYWOS: 000383616901091…FEB