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Antypenko O.M.,Zaporizhzhya State Medical University | Kovalenko S.I.,Zaporizhzhya State Medical University | Karpenko O.V.,Enamine Ltd.
Synthetic Communications | Year: 2016

A series of tetrazolo[1,5-c]quinazolines were synthesized by [4 + 1]-cyclocondensation of 4-hydrazinoquinazolines with sodium nitrite with good yields. Peculiarities of this reaction were discussed, namely, the influence of halogen on the reaction yield. Hydrolytic cleavage of tetrazolo[1,5-c]quinozoline cycle was studied in order to obtain 2-(1H-tetrazolo-5-yl)anilines. The structures of the compounds were elucidated by 1H NMR, 13C NMR, infrared, mass spectrometry, and elemental analysis. 2016 Copyright © Taylor & Francis Group, LLC


Hauser R.A.,University of South Florida | Olanow C.W.,Mount Sinai School of Medicine | Kieburtz K.D.,University of Rochester | Pourcher E.,Laval University | And 8 more authors.
The Lancet Neurology | Year: 2014

Background: Many patients with Parkinson's disease have motor fluctuations despite treatment with available drugs. Tozadenant (SYN115) is an oral, selective adenosine A2A receptor antagonist that improves motor function in animal models of Parkinson's disease. We aimed to assess the safety and efficacy of tozadenant as an adjunct to levodopa in patients with Parkinson's disease who have motor fluctuations on levodopa. Methods: We did an international, multicentre, phase 2b, randomised, double-blind, placebo-controlled, parallel-group, dose-finding clinical trial of tozadenant in levodopa-treated patients with Parkinson's disease who had motor fluctuations (at least 2·5 h off-time per day). Eligible patients were randomly assigned via a computer-generated randomisation schedule to receive tozadenant 60, 120, 180, or 240 mg or matching placebo twice daily for 12 weeks. All study management, site personnel, and patients were masked to treatment assignment. The primary outcome was change from baseline to week 12 in hours per day spent in the off-state (assessed from Parkinson's disease diaries completed by patients). This study is registered at ClinicalTrials.gov, number NCT01283594. Findings: Of 420 randomised patients (mean age 63·3 [SD 8·3] years; mean duration of Parkinson's disease 8·7 [4·7] years), 403 provided post-baseline diary data and 337 completed study treatment. Compared with placebo, mean daily off-time was significantly reduced in the combined tozadenant 120 mg twice-daily and 180 mg twice-daily group (-1·1 h, 95% CI -1·8 to -0·5; p=0·0006), the tozadenant 120 mg twice-daily group (-1·1 h, -1·8 to -0·4; p=0.0039), and the tozadenant 180 mg twice-daily group (-1·2 h, -1·9 to -0·4; p=0·0039). The most common adverse events in these groups were dyskinesia (seven [8%] of 84 patients in the placebo group, 13 [16%] of 82 in the 120 mg twice-daily group, and 17 [20%] of 85 in the 180 mg twice-daily group), nausea (three [4%], 9 [11%], and ten [12%]), and dizziness (one [1%], four [5%], and 11 [13%]). Tozadenant 60 mg twice daily was not associated with a significant reduction in off-time, and tozadenant 240 mg twice daily was associated with an increased rate of discontinuation because of adverse events (17 [20%] of 84 patients). Interpretation: Tozadenant at 120 or 180 mg twice daily was generally well tolerated and was effective at reducing off-time. Further investigation of tozadenant treatment in phase 3 trials is warranted. Funding: Biotie Therapies. © 2014 Elsevier Ltd.


Novello S.,University of Turin | Scagliotti G.V.,University of Turin | Sydorenko O.,Zaporizhzhya State Medical University | Vynnychenko I.,Sumy State University | And 6 more authors.
Journal of Thoracic Oncology | Year: 2014

Introduction: The phase 3 MONET1 study evaluated motesanib (a small-molecule inhibitor of vascular endothelial growth factor receptors) plus carboplatin/paclitaxel versus placebo plus carboplatin/ paclitaxel as first-line therapy for advanced non-small-cell lung cancer (NSCLC). Treatment and enrollment of patients with squamous histology were permanently discontinued following higher early mortality and gross hemoptysis in those with squamous NSCLC who received motesanib. Enrollment of patients with nonsquamous histology was temporarily halted, but resumed following a protocol amendment (Scagliotti et al. J Clin Oncol. 2012;30:2829-2836). Herein, we report data from the squamous cohort. Methods: Patients with stage IIIB/IV or recurrent squamous NSCLC (without prior systemic therapy for advanced disease) received up to six 3-week cycles of chemotherapy (carboplatin, area under the curve 6 mg/L•min/paclitaxel, 200 mg2) and were randomized 1:1 to receive motesanib 125 mg (Arm A) or placebo (Arm B) once daily. The primary end point was overall survival. Results: Three-hundred and sixty patients with squamous NSCLC were randomized (Arm A, n = 182; Arm B, n = 178) between July 2007 and November 2008. Twenty-three patients (13%) in Arm A and 10 (6%) in Arm B had fatal adverse events within the first 60 days of treatment. Among these, six patients in Arm A, but none in Arm B, had fatal bleeding events. At final analysis, serious adverse events had occurred in 47% of patients in Arm A and 29% of patients in Arm B. Median overall survival was similar in Arms A and B (11.1 versus 10.7 months). Conclusions: Motesanib plus carboplatin/paclitaxel had unacceptable toxicity compared with carboplatin/paclitaxel alone in patients with advanced squamous NSCLC. Copyright © 2014 by the International Association for the Study of Lung.


PubMed | Zaporizhzhya State Medical University, University of Rochester, University of South Florida, Ovidius University and 4 more.
Type: Clinical Trial, Phase II | Journal: The Lancet. Neurology | Year: 2014

Many patients with Parkinsons disease have motor fluctuations despite treatment with available drugs. Tozadenant (SYN115) is an oral, selective adenosine A2A receptor antagonist that improves motor function in animal models of Parkinsons disease. We aimed to assess the safety and efficacy of tozadenant as an adjunct to levodopa in patients with Parkinsons disease who have motor fluctuations on levodopa.We did an international, multicentre, phase 2b, randomised, double-blind, placebo-controlled, parallel-group, dose-finding clinical trial of tozadenant in levodopa-treated patients with Parkinsons disease who had motor fluctuations (at least 25 h off-time per day). Eligible patients were randomly assigned via a computer-generated randomisation schedule to receive tozadenant 60, 120, 180, or 240 mg or matching placebo twice daily for 12 weeks. All study management, site personnel, and patients were masked to treatment assignment. The primary outcome was change from baseline to week 12 in hours per day spent in the off-state (assessed from Parkinsons disease diaries completed by patients). This study is registered at ClinicalTrials.gov, number NCT01283594.Of 420 randomised patients (mean age 633 [SD 83] years; mean duration of Parkinsons disease 87 [47] years), 403 provided post-baseline diary data and 337 completed study treatment. Compared with placebo, mean daily off-time was significantly reduced in the combined tozadenant 120 mg twice-daily and 180 mg twice-daily group (-11 h, 95% CI -18 to -05; p=00006), the tozadenant 120 mg twice-daily group (-11 h, -18 to -04; p=0.0039), and the tozadenant 180 mg twice-daily group (-12 h, -19 to -04; p=00039). The most common adverse events in these groups were dyskinesia (seven [8%] of 84 patients in the placebo group, 13 [16%] of 82 in the 120 mg twice-daily group, and 17 [20%] of 85 in the 180 mg twice-daily group), nausea (three [4%], 9 [11%], and ten [12%]), and dizziness (one [1%], four [5%], and 11 [13%]). Tozadenant 60 mg twice daily was not associated with a significant reduction in off-time, and tozadenant 240 mg twice daily was associated with an increased rate of discontinuation because of adverse events (17 [20%] of 84 patients).Tozadenant at 120 or 180 mg twice daily was generally well tolerated and was effective at reducing off-time. Further investigation of tozadenant treatment in phase 3 trials is warranted.Biotie Therapies.


Lezhenko G.,Zaporizhzhya State Medical University
Georgian medical news | Year: 2013

The purpose of this investigation is to determine the role of osteopontin and adiponectin in the formation of arterial hypertension in adolescents with obesity. 67 adolescents with obesity have been examined. Two groups were composed taking into account the state of arterial pressure. The first group included adolescents with obesity and arterial hypertension, the second group - adolescents with obesity and without arterial hypertension. Arterial pressure was measured and serum content of osteopontin, insulin, C-peptid and adiponectin in blood has been determined. The result of the investigation has revealed that in adolescents without arterial pressure the growth of insulin and C-peptid in the serum of blood has been observed; in patients with obesity and arterial hypertension the increase of content of osteopontin and hypoadiponectinemia has been occurred. The revealed changes indicated about the pathogenic role of osteopontin and adiponectin in the formation of arterial hypertension in adolescents with obesity.


Antypenko O.,Zaporizhzhya State Medical University | Kovalenko S.,Zaporizhzhya State Medical University | Rasulev B.,North Dakota State University | Rasulev B.,Jackson State University | Leszczynski J.,Jackson State University
Acta Chimica Slovenica | Year: 2016

Chemical compounds with tetrazole ring are very interesting systems that can be valuable in pharmaceutical and clinical applications, especially as anticancer agents. In this work, novel 6-N-R-tetrazolo[1,5-c]quinazolin-5(6H)-ones were synthesized. A large set of IR, LC-, EI-MS, 1H, 13C NMR and elemental analysis data were collected and evaluated for their structures and purity. Details of synthesis, namely the N-alkylation, are discussed, including reactions with secondary and tertiary amides. Four new synthesized compounds (2.7, 3.2, 5.2, 5.3) were tested in vitro for anticancer activity at 10 μM against 60 cell lines of nine different cancer types: leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers. Further synthesis of substances within the series of substituted tetrazolo[1,5-c]quinazoline systems will be attempted to develop improved compounds with better anticancer activity.


Dzyak G.V.,Zaporizhzhya State Medical University | Kolesnyk M.Y.,Zaporizhzhya State Medical University
Kardiologiya | Year: 2014

Purpose: to assess parameters of myocardial deformation and rotation in untreated hypertensive men depending on presence and degree of left ventricular hypertrophy (LVH). Material and methods. We examined 98 hypertensive men aged 51 (46-58) years. Examination included clinical evaluation, conventional transthoracic echocardiography, ambulatory blood pressure monitoring, routine laboratory screening. LV deformation and rotation was studied by two-dimensional speckle tracking echocardiography. Results. In patients without LVH we observed significant decrease of longitudinal strain without changes of rotation. Higher degree of LVH was associated with more pronounced lowering of longitudinal deformation. Severe LVH was characterized by decreased longitudinal, circumferential and radial deformation with compensatory increase of apical LV rotation. Conclusion. Changes of LV deformation are observed in patients with hypertension before LVH formation. This opens new perspectives of early assessment of LV remodeling. Changes of LV deformation are related to degree of LVH.


PubMed | Zaporizhzhya State Medical University
Type: Journal Article | Journal: Current computer-aided drug design | Year: 2016

The increasing mortality due to antibacterial resistance necessitates the search for novel antimicrobial agents. Hence, series of 1-R-2-([1,2,4]triazolo[1,5-c]quinazoline-2-ylthio)etanon(ol)s were synthesized, evaluated by spectral data and studied against St. aureus, M. luteum, E. faecalis, E. aerogenes, P. aeruginosa, C. sakazakii, E. coli, K. pneumonia, hospital Streptococcus spp., C. albicans and A. niger in 100, 500 g/mL and 100 g/disk. Substances exhibited moderate toxicity in 0.025, 0.1 and 0.25 mg/mL in bioluminescence inhibition tests of Photobacterium leiognathi. SAR exposed that introduction of 2,4-(Cl)2C6H3-, 2,5-(OMe)2C6H3-, 4-Me-2-iPr-C6H3O- and 3-iPr-C6H4O- fragments and reduction of the pyrimidine ring of R-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)alcohols were the best modifications to promote antimicrobial activity. Molecular docking showed their good affinity into the active sites of EcPanK-AMPPNP and hDHFR. Hence, reported results will be used for subsequent QSAR model creation and purposeful antimicrobial modification of the strongest compounds.


PubMed | Zaporizhzhya State Medical University
Type: Journal Article | Journal: Scientia pharmaceutica | Year: 2013

The combinatorial library of novel potential anticancer agents, namely, 2-(alkyl-, alkaryl-, aryl-, hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines, was synthesized by the heterocyclization of the alkyl-, alkaryl-, aryl-, hetarylcarboxylic acid (3H-quinazoline-4-ylidene)hydrazides by oxidative heterocyclization of the 4-(arylidenehydrazino)quinazolines using bromine, and by the heterocyclization of N-(2-cyanophenyl)formimidic acid ethyl ester. The optimal method for synthesis of the s-triazolo[1,5-c]quinazolines appeared to be cyclocondensation of the corresponding carboxylic acid (3H-quinazoline-4-ylidene)hydrazides. The compounds structures were established by (1)H, (13)C NMR, LC- and EI-MS analysis. The in vitro screening of anticancer activity determined the most active compound to be 3,4,5-trimethoxy-N-[quinazolin-4(3H)-ylidene]benzohydrazide (3.20) in micromolar concentrations with the GI50 level (MG_MID, GI50 is 2.29). Thus, the cancer cell lines whose growth is greatly inhibited by compound 3.20 are: non-small cell lung cancer (NCI-H522, GI50=0.34), CNS (SF-295, GI50=0.95), ovarian (OVCAR-3, GI50=0.33), prostate (PC-3, GI50=0.56), and breast cancer (MCF7, GI50=0.52), leukemia (K-562, GI50=0.41; SR, GI50=0.29), and melanoma (MDA-MB-435, GI50=0.31; SK-MEL-5, GI50=0.74; UACC-62, GI50=0.32). SAR-analysis is also discussed.


PubMed | Zaporizhzhya State Medical University
Type: | Journal: Current computer-aided drug design | Year: 2016

The increasing mortality due to antibacterial resistance necessitates the search for novel antimicrobial agents. Hence, series of 1-R-2-([1,2,4]triazolo[1,5-c]quinazoline-2-ylthio)etanon(ol)s were synthesized, evaluated by spectral data and studied against St. aureus, M. luteum, E. faecalis, E. aerogenes, P. aeruginosa, C. sakazakii, E.coli, K. pneumonia, hospital Streptococcus spp., C. albicans and A. niger in 100, 500 g/mL and 100 g/disk. Substances exhibited moderate toxicity in 0.025, 0.1 and 0.25 mg/mL in bioluminescence inhibition tests of Photobacterium leiognathi. SAR exposed that introduction of 2,4-(Cl)2C6H3-, 2,5-(OMe)2C6H3-, 4-Me-2-iPr-C6H3O- and 3-iPr-C6H4O- fragments and reduction of the pyrimidine ring of R-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)alcohols were the best modifications to promote antimicrobial activity. Molecular docking showed their good affinity into the active sites of EcPanK-AMPPNP and hDHFR. Hence, reported results will be used for subsequent QSAR model creation and purposeful antimicrobial modification of the strongest compounds.

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