Publications

Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors

Twelve pyridazinones (T1–T12) containing the (2-fluorophenyl) piperazine moiety were designed, synthesized, and evaluated for monoamine oxidase (MAO) -A and -B inhibitory activities. T6 was found to be the most potent MAO-B inhibitor with an IC50 value of 0.013 µM, followed by T3 (IC50 = 0.039 µM). Inhibitory potency for MAO-B was more enhanced by meta bromo substitution (T6) than by para bromo substitution (T7). For para substitution, inhibitory potencies for MAO-B were as follows: -Cl (T3) > -N(CH3)2 (T12) > -OCH3 (T9) > Br (T7) > F (T5) > -CH3 (T11) > -H (T1). T6 and T3 efficiently inhibited MAO-A with IC50 values of 1.57 and 4.19 µM and had the highest selectivity indices (SIs) for MAO-B (120.8 and 107.4, respectively). T3 and T6 were found to be reversible and competitive inhibitors of MAO-B with Ki values of 0.014 and 0.0071, respectively. Moreover, T6 was less toxic to healthy fibroblast cells (L929) than T3. Molecular docking simulations with MAO binding sites returned higher docking scores for T6 and T3 with MAO-B than with MAO-A. These results suggest that T3 and T6 are selective, reversible, and competitive inhibitors of MAO-B and should be considered lead candidates for the treatment of neurodegenerative disorders like Alzheimer’s disease.

Effect of binder dosage and the use of waste rubber fiber on the mechanical and durability performance of geopolymer concrete

Modeling of compressive strength and UPV of high-volume mineral-admixtured concrete using rule-based M5 rule and tree model M5P classifiers

Compressive strength and UPV parameters are the methods that are used to determine high-volume mineral admixture concrete quality. But experiments for all levels of these parameters are expensive, difficult and time consuming. For determination of output values, classifiers with model extraction features can be used. In this study, classifiers, with the rule-based M5 rule and tree model M5P in the area of data mining are used to predict the compressive strength and UPV of concrete mixtures after 3, 7, 28 and 120 days of curing. The M5 rule and tree model M5P are tested using the available test data of 40 different concrete mix-designs gathered from literature [1] . The input of the model is a variable data set corresponding to concrete mixture proportions. The findings of this study indicated that the M5 rule and tree model M5P models are sufficient tools for estimating the compressive strength and UPV of concrete. 97% and 87% success is obtained in predicting compressive strength and UPV results, respectively.

An X-ray and DFT Computational Study on 1-（Naphthalene-2-yl）-2-（1H-pyrazol-1-yl） ethanone O-butyl Oxime

Approaches Based on Cholinergic Hypothesis and Cholinesterase Inhibitors in the Treatment of Alzheimer's Disease

Thermal conductivity of limestone from Gaziantep (Turkey)

Mechanical properties and setting time of geopolymer paste and mortar produced from ferrochrome slag

Many researches have been done to investigate using raw materials in the production of geopolymer cements. The aim of this paper is the effect of dosage of alkali and silica modulus when using sodium metasilicate solution at different curing conditions on the geopolymerisation of ferrochrome slag (FS). As alkali activation for geopolymerization, NaOH and Na <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf> SiO <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</inf> solution were used. Geopolymer cement was produced using FS and 3 different silica modulus (0.50, 0.60, and 0.70) and 4 different Na <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf> O concentrations (4, 7, 10, and 12%). The setting time, heat of hydration and compressive strength of geopolymer paste samples and compressive strength of geopolymer mortar samples were obtained. The setting time varies between 120 and 870 min, it shows variability depending on content of Na <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf> O. As a result of the highest 28 day strength of the geopolymer paste sample was obtained at Na <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf> O concentration of 7% and at silica modulu of 0.70. Geopolymer mortars were prepared for the determination of compressive strength by adding FS:sand:alkali activator ratio 1∶2∶0.30, 0.35 and 0.40. The specimens were cured at 60°C, 80°C kept in 20 hours and the other mortars were stored under laboratory conditions. Compressive strength of the material decreases, when w/b ratio increases. The highest 28 day strength of the geopolymer mortar was obtained at 0.30 w/b ratio and at curing temperature laboratory conditions. The hydration heat of geopolymer paste samples was found to be less than normal Portland cements. Microstructural changes in the specimens were studied with SEM and XRD.

The effect of elevated temperature on the mechanical properties of concrete produced with raw perlite aggregate

Deterioration caused by elevated temperatures in the micro and of concrete can lead to serious decreases in the mechanical properties of the material. In this context, it is important to determine the mechanical properties of the materials constituting the structure to assess the current condition of the reinforced concrete structure after the fire. The present experimental study investigates the effects of elevated temperatures (25 °C, 200 °C, 400 °C, and 600 °C) on cubic and prism samples fabricated with two different aggregate types (raw perlite aggregate and traditional coarse aggregate) by considering four different concrete mixtures (C25, C40, P25, and P40). Additionally, the aim is to reveal the usability of a raw perlite aggregate as an alternative to traditional concrete production in facilities that are likely to be exposed to elevated temperature effects. In line with these aims and objectives, experiments and visual observations were conducted before and after exposure to elevated temperatures using both destructive (e.g., compression test and bending test) and non-destructive (e.g., mass loss, UPV, SEM, color, and crack deterioration) methods. The results show that although they initially have similar mechanical properties (e.g., compressive strength), the deterioration in the P25 and P40 samples is more limited with increasing temperature compared to the C25 and C40 samples. Additionally, although the bending strength of the P25 and P40 samples at 25 °C is lower than that of the C25 and C40 samples due to the more limited stress-strain relationship of the perlite samples, it is observed that the specimens with the same compressive strength show similar flexural behavior under the effect of increasing temperature.

Relationship between compressive strength and UPV for high strength concrete containing expanded Perlite aggregate

Antifungal screening and in silico mechanistic studies of an in‐house azole library

Abstract Systemic Candida infections pose a serious public health problem with high morbidity and mortality. C. albicans is the major pathogen identified in candidiasis; however, non‐ albicans Candida spp. with antifungal resistance are now more prevalent. Azoles are first‐choice antifungal drugs for candidiasis; however, they are ineffective for certain infections caused by the resistant strains. Azoles block ergosterol synthesis by inhibiting fungal CYP 51, which leads to disruption of fungal membrane permeability. In this study, we screened for antifungal activity of an in‐house azole library of 65 compounds to identify hit matter followed by a molecular modeling study for their CYP 51 inhibition mechanism. Antifungal susceptibility tests against standard Candida spp. including C. albicans revealed derivatives 12 and 13 as highly active. Furthermore, they showed potent antibiofilm activity as well as neglectable cytotoxicity in a mouse fibroblast assay. According to molecular docking studies, 12 and 13 have the necessary binding characteristics for effective inhibition of CYP 51. Finally, molecular dynamics simulations of the C. albicans CYP 51 ( CACYP 51) homology model's catalytic site complexed with 13 were stable demonstrating excellent binding.

Abstract 4147504: Efficacy and Safety of Vorapaxar in Patients with Peripheral Arterial Disease: A Meta-Analysis of Randomized Controlled Trials

Introduction: Vorapaxar is an inhibitor of protease-activated receptor-1 (PAR1) and primarily blocks thrombin mediated platelet activation. There are discrepancies in the literature regarding whether vorapaxar alleviates ischemic outcomes and increases bleeding in patients with peripheral arterial disease (PAD). Purpose: The aim of this study is to evaluate the efficacy and safety of Vorapaxar in patients with PAD. Methods: A comprehensive literature search of Cochrane CENTRAL, PubMed, Ovid Medline, and Web of Science databases was conducted. Randomized controlled trials (RCTs) comparing Vorapaxar in patients with PAD were included. Primary efficacy outcome was defined as hospitalization for acute limb ischemia, while primary safety outcome was assessed for severe bleeding events according to GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) trial. Summary effect measures of the primary outcomes were obtained by pooling the data with an inverse variance–weighted random-effects model. Statistical analyses were performed with “meta” package in R (version 4.3.2). Results: Three unique RCTs involving 4825 patients were included in the analysis. Vorapaxar was associated with a significantly less rate of hospitalization for acute limb ischemia (Risk Ratio [RR] 0.57, 95% Confidence Interval (CI) 0.39 to 0.83, I 2 : 0%) and significantly less requirement of peripheral revascularization (RR 0.85, 95% CI 0.76 to 0.97, I 2 : 0%) compared to placebo. Furthermore, no significant differences were observed between Vorapaxar and placebo groups in fatal bleeding (RR 1.00, 95% CI 0.38 to 2.66, I 2 : 0), severe bleeding according to GUSTO trial (RR 1.38, 95% CI 0.84 to 2.27, I 2 : 0%), and lower extremity amputation (RR 0.53, 95% CI 0.17 to 1.67, I 2 : 0%). Conclusion: In patients with PAD, Vorapaxar significantly reduces hospitalizations due to acute limb ischemia and the need for peripheral revascularizations compared to placebo. However, it does not have a significant effect on the need for lower extremity amputations. In terms of safety, Vorapaxar does not lead to fatal or severe bleedings compared to placebo. Therefore, Vorapaxar should remain one of the treatment options for patients with PAD.

Activation of the Mas receptors by AVE0991 and MrgD receptor using alamandine to limit the deleterious effects of Ang II‐induced hypertension

Abstract The MrgD receptor agonist, alamandine (ALA) and Mas receptor agonist, AVE0991 have recently been identified as protective components of the renin‐angiotensin system. We evaluated the effects of ALA and AVE0991 on cardiovascular function and remodeling in angiotensin (Ang) II‐induced hypertension in rats. Sprague Dawley rats were subject to 4‐week subcutaneous infusions of Ang II (80 ng/kg/min) or saline after which they were treated with ALA (50 μg/kg), AVE0991 (576 μg/kg), or ALA+AVE0991 during the last 2 weeks. Systolic blood pressure (SBP) and heart rate (HR) values were recorded with tail‐cuff plethysmography at 1, 15, and 29 days post‐treatment. After euthanization, the heart and thoracic aorta were removed for further analysis and vascular responses. SBP significantly increased in the Ang II group when compared to the control group. Furthermore, Ang II also caused an increase in cardiac and aortic cyclophilin‐A (CYP‐A), monocyte chemoattractant protein‐1 (MCP‐1), and cardiomyocyte degeneration but produced a decrease in vascular relaxation. HR, matrix metalloproteinase‐2 and ‐9, NADPH oxidase‐4, and lysyl oxidase levels were comparable among groups. ALA, AVE0991, and the drug combination produced antihypertensive effects and alleviated vascular responses. The inflammatory and oxidative stress related to cardiac MCP‐1 and CYP‐A levels decreased in the Ang II+ALA+AVE0991 group. Vascular but not cardiac angiotensin‐converting enzyme‐2 levels decreased with Ang II administration but were similar to the Ang II+ALA+AVE0991 group. Our experimental data showed the combination of ALA and AVE0991 was found beneficial in Ang II‐induced hypertension in rats by reducing SBP, oxidative stress, inflammation, and improving vascular responses.

Efficacy and safety of ruxolitinib plus extracorporeal photopheresis in acute and chronic graft versus host disease: A single center experience

Conventional and microwave prompted synthesis of aryl(alkyl)azole oximes, 1H-NMR spectroscopic determination of E/Z isomer ratio and HOMO-LUMO analysis

Thermo-mechanical properties of HSC made with expanded perlite aggregate

Fire resistance of geopolymer concrete produced from Ferrochrome slag by alkali activation method

The effect of high temperatures up to 700°C on compressive strength and water absorption of two alkali-activated aluminosilicate composites (one of them with river sand aggregates, the second crushed sand aggregates) and ordinary Portland cement (OPC) concretes is analyzed in this paper. Binding geopolymer material was obtained after grinding the Elazığ Ferrochrome slag (EFS) as fine as cement and alkaline activating with chemical materials (NaOH-Na <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf> SiO <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</inf> ). Geopolymer concrete samples were produced by using this binding material with aggregates. Produced concrete samples were exposed to temperature for 1 hour, after reaching the maximum temperature. Fire resistance and water absorption of geopolymer and OPC concrete samples was obtained experimentally. Compressive strength of river aggregates and crushed sand aggregates concrete increased at 100 and 300°C temperatures compared to unexposed samples, and the maximum compressive strength for these geopolymer concrete sample was obtained at 300°C. Water absorption of all concrete samples increased at 700°C temperature compared to unexposed samples. But there appeared to be a slight decrease of water absorption in the all concrete samples up to 300°C temperatures compared to unexposed samples. Scanning electron microscopy and XRD tests were also conducted to examine microstructure and mineralogical changes during the thermal exposure.

Inhibition of Monoamine Oxidases by Pyridazinobenzylpiperidine Derivatives

Monoamine oxidase inhibitors (MAOIs) have been crucial in the search for anti-neurodegenerative medications and continued to be a vital source of molecular and mechanistic diversity. Therefore, the search for selective MAOIs is one of the main areas of current drug development. To increase the effectiveness and safety of treating Parkinson’s disease, new scaffolds for reversible MAO-B inhibitors are being developed. A total of 24 pyridazinobenzylpiperidine derivatives were synthesized and evaluated for MAO. Most of the compounds showed a higher inhibition of MAO-B than of MAO-A. Compound S5 most potently inhibited MAO-B with an IC50 value of 0.203 μM, followed by S16 (IC50 = 0.979 μM). In contrast, all compounds showed weak MAO-A inhibition. Among them, S15 most potently inhibited MAO-A with an IC50 value of 3.691 μM, followed by S5 (IC50 = 3.857 μM). Compound S5 had the highest selectivity index (SI) value of 19.04 for MAO-B compared with MAO-A. Compound S5 (3-Cl) showed greater MAO-B inhibition than the other derivatives with substituents of -Cl &gt; -OCH3 &gt; -F &gt; -CN &gt; -CH3 &gt; -Br at the 3-position. However, the 2- and 4-position showed low MAO-B inhibition, except S16 (2-CN). In addition, compounds containing two or more substituents exhibited low MAO-B inhibition. In the kinetic study, the Ki values of S5 and S16 for MAO-B were 0.155 ± 0.050 and 0.721 ± 0.074 μM, respectively, with competitive reversible-type inhibition. Additionally, in the PAMPA, both lead compounds demonstrated blood–brain barrier penetration. Furthermore, stability was demonstrated by the 2V5Z-S5 complex by pi–pi stacking with Tyr398 and Tyr326. These results suggest that S5 and S16 are potent, reversible, selective MAO-B inhibitors that can be used as potential agents for the treatment of neurological disorders.

A new series of pyridazinone derivatives as cholinesterases inhibitors: Synthesis, in vitro activity and molecular modeling studies