Ayla Balkan

Molecular modeling, synthesis and screening of some new 4-thiazolidinone derivatives with promising selective COX-2 inhibitory activity.

In order to develop new selective cyclooxygenase-2 inhibitors, a series of novel 2-aryl-3-(4-sulfamoyl/methylsulfonylphenylamino)-4-thiazolidinones were designed. Molecular modeling studies with COX-2 enzyme were performed by using MOE program. The designed compounds with reasonable binding modes and high docking scores were synthesized. Their COX-1/COX-2 inhibitory activities were evaluated in vitro, using NS-398 and indomethacine as reference compounds. Compounds possessing methyl group (3d and 4d) on the phenyl ring exhibited highly COX-2 inhibitory selectivity and potency.

Synthesis and cyclooxygenase inhibitory activities of some N-acylhydrazone derivatives of isoxazolo[4,5-d]pyridazin-4(5H)-ones

In this study, new isoxazolo[4,5-d]pyridazin-4(5H)-one derivatives having an N-acylhydrazone moiety were synthesized. The compounds were tested for their COX inhibitory activities using NS-398 and indomethacine as reference compounds. Although the compounds had an inhibitory profile against both COX-1 and COX-2, most were found to be more selective against COX-2 by a small percentage of inhibition, at the concentration of 50 microM. Docking studies were done to understand the interactions of the tested compounds with the active site of COX-2. It was observed that the compounds fit into, and interacted with, the hydrophobic parts which are common in the active pocket of COX-1 and COX-2 enzymes but could not fit to the area which is specific for COX-2 enzyme.

Synthesis and antimycobacterial activities of some new thiazolylhydrazone derivatives.

This Letter reports the synthesis and evaluation of some thiazolylhydrazone derivatives for their in vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv. The cytotoxic activities of all compounds were also evaluated. The compounds exhibited promising antimycobacterial activity with MICs of 1.03-72.46 μM and weak cytotoxicity (8.9-36.8% at 50 μg/mL). Among them, 1-(4-(1H-1,2,4-triazol-1-yl)benzylidene)-2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazine 10 was found to be the most active compound (MIC of 1.03 μM) with a good safety profile (16.4% at 50 μg/mL). Molecular modeling studies were done to have an idea for the mechanism of the action of the target compounds. According the docking results it can be claimed that these compounds may bind most likely to TMPK than InhA or CYP121.

Novel multi-targeted agents for Alzheimer's disease: Synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles

The present study describes the synthesis, pharmacological evaluation (BChE/AChE inhibition, Aβ antiaggregation, and neuroprotective effects), and molecular modeling studies of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazole derivatives. The alkyl-substituted derivatives exhibited selective inhibition on BChE with varying efficiency. Compounds 3b and 3d were found to be the most potent inhibitors of BChE with IC50 values of 5.18 and 5.22μM, respectively. The kinetic studies revealed that 3b is a partial non-competitive BChE inhibitor. Molecular modeling studies also showed that the alkyl-substituted derivatives were able to reach the catalytic anionic site of the BChE. The compounds with an inhibitory effect on BChE were subsequently screened for their Aβ antiaggregating and neuroprotective activities. Compounds 3a and 3b exerted a potential neuroprotective effect against H2O2 and Aβ-induced cytotoxicity in SH-SY5Y cells. Collectively, 3b was found as the most promising compound for the development of multi-target directed ligands against Alzheimers disease.

Novel 2-Arylbenzimidazole derivatives as multi-targeting agents to treat Alzheimer’s disease

This study describes the synthesis, pharmacological evaluation, including acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibition, amyloid beta (Aβ) antiaggregation, and neuroprotective effects, as well as molecular modeling of novel 2-(4-substituted phenyl)-1H-benzimidazole derivatives. These derivatives were synthesized by cyclization of o-phenylenediamines with sodium hydroxy(4-substituted phenyl)methanesulfonate salts. In vitro studies indicated that the most of the target compounds showed remarkable inhibitory activity against BChE (IC50: 13.60–95.44 µM). Among them, 3d and 3g-i also exhibited high selectivity (SI ≥ 35.7) for BChE with IC50 values 39.56, 13.60, 14.45, and 15.15 µM, respectively. According to the molecular modeling studies, it may be assumed that the compounds are able to reach the catalytic site of BChE but not that of AChE. The compounds showing BChE inhibitory effects were subsequently examined for their Aβ-antiaggregating and neuroprotective activities. Among the compounds, 3d inhibited the Aβ1–40 aggregation and demonstrated significant neuroprotection against H2O2-induced and Aβ1–40-induced cell death. Collectively, compound 3d showed the best multifunctional activity (BChE; IC50 = 39.56 µM, SI > 126; Aβ self-mediated aggregation; 67.78% at 100 μM; H2O2-induced cytotoxicity with cell viability of 98% and Aβ1-40-induced cytotoxicity with cell viability of 127%). All these results suggested that 2-(4-(4-methylpiperidin-1-yl)phenyl)-1H-benzo[d]imidazole (compound 3d) could be a promising multi-target lead candidate against Alzheimer’s disease.

The in vivo metabolism of 3-oxo-5-benzylidene-6-methyl-(4H)-2-(benzoylmethyl)pyridazine in rats

SummaryThe purpose of the study was to investigate the in vivo metabolic pathway of 3-oxo-5-benzylidene-6-methyl-(4H)-2-(benzoylmethyl)pyridazine (substrate) in rats. Firstly its potential metabolites, i.e. N-dealkylation, ring scission of pyridazine and aromatic hydroxylation products, were synthesized and then the substrate was given orally (100 mg/kg) to male or female Wistar rats at a dose of 100 mg/kg to body weight. Blood samples were collected at 0, 1, 2, 4, 6 and 8 hours after administration of substrate and blood was centrifuged to obtain serum. The substrate and its potential metabolites were separated using a gradient HPLC method on a reverse phase system. This study revealed that 3-oxo-5-benzylidene-6-methyl-(4H)-2-(benzoylmethyl)pyridazine was not metabolized to the proposed metabolites and was present unchanged in the serum.

Functional exercise capacity evaluated by timed walk tests in myasthenia gravis: 6mWT and 2mWT for MG Patients

Introduction: We sought to evaluate the test–retest reliability and construct validity of the 6‐ and 2‐minute walk tests (6mWT and 2mWT, respectively) in patients with myasthenia gravis (MG). Methods: Thirty‐one patients with generalized MG were enrolled in this study. The 6mWT, 2mWT, MG‐specific quality of life questionnaire Turkish version (MG‐QoL15T), quantitative myasthenia gravis test (QMG), and pulmonary function tests were administered. Results: The intraclass correlation coefficients of 2mWT and 6mWT were 0.894 and 0.932, respectively. The 6mWT and 2mWT had moderate correlations with forced vital capacity, maximal inspiratory pressure, QMG score, and MG‐QoL15T score (ρ for 6mWT: 0.579, 0.539, −0.572, and −0.474; ρ for 2mWT: 0.460, 0.446, −0.532, −0.457). Both tests had similar performances for predicting disease severity (area under the curve = 0.761 for 6mWT and 0.759 for 2mWT). Discussion: The 6mWT and 2mWT have excellent test–retest reliability as well as moderate construct validity for the evaluation of functional exercise capacity patients with MG. Muscle Nerve 59:208–212, 2019

Investigating the Dynamic Plantar Pressure Distribution and Loading Pattern in Subjects with Multiple Sclerosis

BACKGROUND Multiple sclerosis (MS) is a complex disorder affecting subjects by multiple system impairments. Gait problems are common in subjects with MS and various factors such as; ataxia, hypertonic muscles or/and seconder musculoskeletal system deformities affect the normal plantigrade contact by disturbing accommodation of foot to the ground while walking. The aim of this study was investigating the dynamic plantar pressure distribution and time of maximum pressure in subjects with MS and determining the differences from healthy subjects (HS). METHODS Fifty-five subjects with MS (110 foot) and 20 HS (40 foot) were the participants of the study. The dynamic pedobarograph was utilized for evaluation of dynamic loading parameters; maximum pressure (N/cm2) and time of maximum pressure (ms) collected from heel medial, heel lateral, midfoot, heads of first, second, third, fourth and fifth metatarsal bones. RESULTS There were differences between the groups in maximum pressure of heel medial (p < .001) and heel lateral (p < .001) was higher in HS. Also, there were differences between the groups the time of maximum pressure of all metatarsal head areas, midfoot, heel medial and heel lateral (p < .001). Subjects with MS spent lesser time to reach maximum pressure for forefoot loading and longer time for hindfoot loading. CONCLUSION The study provided basic data about foot pressure distribution and time of maximum pressure in subjects with MS. Results of the study showed that the hindfoot loading was disrupted and inappropriate timing during load transfer from hindfoot to forefoot is exist in subjects with MS.