Alpha-glucosidase inhibitory and hypoglycemic effects of imidazole-bearing thioquinoline derivatives with different substituents: In silico, in vitro, and in vivo evaluations.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by high blood sugar levels. It was shown that modulating the activity of α-glucosidase, an enzyme involved in carbohydrate digestion and absorption, can improve blood sugar control and overall metabolic health in individuals with T2DM. As a result, in the current study, a series of imidazole bearing different substituted thioquinolines were designed and synthesized as α-glucosidase inhibitors. All derivatives exhibited significantly better potency (IC50 = 12.1 ± 0.2 to 102.1 ± 4.9 µM) compared to the standard drug acarbose (IC50 = 750.0 ± 5.0 µM). 8g as the most potent analog, indicating a competitive inhibition with Ki = 9.66 µM. Also, the most potent derivative was subjected to molecular docking and molecular dynamic simulation against α-glucosidase to determine its mode of action in the enzyme and study the complex's behavior over time. In vivo studies showed that 8g did not cause acute toxicity at 2000 mg/kg doses. Additionally, in a diabetic rat model, treatment with 8g significantly reduced fasting blood glucose levels and decreased blood glucose levels following sucrose loading compared to acarbose, a standard drug used for blood sugar control. The findings suggest that the synthesized compound 8g holds promise as an α-glucosidase inhibitor for improving blood sugar control and metabolic health.

Pyrano[2,3-b]chromone derivatives as novel dual inhibitors of α-glucosidase and α-amylase: Design, synthesis, biological evaluation, and in silico studies.

Inhibition of α-glucosidase and α-amylase is an important target for treatment of type 2 diabetes. In this work, a novel series of pyrano[2,3-b]chromene derivatives 5a-m was designed based on potent α-glucosidase and α-amylase inhibitors and synthesized by simple chemical reactions. These compounds were evaluated against the latter enzymes. Most of the title compounds exhibited high inhibitory activity against α-glucosidase and α-amylase in comparison to standard inhibitor (acarbose). Representatively, the most potent compound, 4-methoxy derivative 5d, was 30.4 fold more potent than acarbose against α-glucosidase and 6.1 fold more potent than this drug against α-amylase. In silico molecular modeling demonstrated that compound 5d attached to the active sites of α-glucosidase and α-amylase with a favorable binding energies and established interactions with important amino acids. Dynamics of compound 5d also showed that this compound formed a stable complex with the α-glucosidase active site. In silicodrug-likeness as well as ADMET prediction of this compound was also performed and satisfactory results were obtained.

New phenylthiosemicarbazide-phenoxy-1,2,3-triazole-N-phenylacetamides as dual inhibitors against α-glucosidase and PTP-1B for the treatment of type 2 diabetes.

This study describes the design, synthesis, and evaluation of a novel series of phenylthiosemicarbazide-phenoxy-1,2,3-triazole-N-phenylacetamide derivatives (7a-l) as dual inhibitors of α-glucosidase and protein tyrosine phosphatase 1-B (PTB-1B). The latter enzymes are two important targets in the treatment of type 2 diabetes. The in vitro obtained data demonstrated that all title compounds 7a-l were more potent than the standard inhibitor acarbose against α-glucosidase while only four derivatives (7a, 7g, 7h, and 7h) were more potent than the standard inhibitor suramin against PTP-1B. Furthermore, these data showed that the most potent α-glucosidase inhibitor was compound 7i, with sixfold higher inhibitory activity than acarbose, and the most potent PTP-1B inhibitor was compound 7a with 3.5-fold higher inhibitory activity than suramin. Kinetic studies of compounds 7i and 7a revealed that they inhibited their target enzymes in a competitive mode. The docking study demonstrated that compounds 7i and 7a well occupied the active site pockets of α-glucosidase and PTP-1B, respectively. In silico pharmacokinetic and toxicity assays of the most potent compounds were performed, and the obtained results were compared with those of the standard inhibitors.

Synthesis and in vitro urease inhibitory activity of 5-nitrofuran-2-yl-thiadiazole linked to different cyclohexyl-2-(phenylamino)acetamides, in silico and kinetic studies.

A series of 5-nitrofuran-2-yl-thiadiazole linked to different cyclohexyl-2-(phenylamino)acetamides were rationally designed and synthesized. All synthetic compounds were evaluated for their urease inhibitory activity and exhibited good inhibitory potential against urease with IC50 values in the range of 0.94 - 6.78 µM as compared to the standard thiourea (IC50 = 22.50 µM). Compound 8g (IC50 = 0.94 µM) with a thiophene substituent at the R2 position was found to be the most active member of the series. Kinetic studies exhibited that the compound 8g was a non-competitive inhibitor. In silicostudy showed the critical interactions of potent inhibitors with the active site of the enzyme. These newly identified inhibitors of the urease enzyme can serve as leads for further research and development.

Acetylsalicylic acid-induced alterations in male reproductive parameters in Wistar rats and the effect of sprint interval training.

The present study investigated the effect of a 5-week ASA treatment on male reproductive parameters in Wistar rats; moreover, the potential benefits of a 4-week sprint interval training (SIT) on these measures following ASA treatment were investigated. A total of 25 male rats were obtained and randomly assigned to the control group (C, n = 10) and the ASA treatment group (EP, n = 15). After 5 weeks, five rats from each group were killed and the effect of ASA treatment on the reproductive parameters was assessed. Then, the ASA treatment terminated and the remaining 10 ASA-treated rats were divided into the non-treatment group (NT, n = 5) and the exercise training group (ET, n = 5), which performed SIT 3 sessions/week for 4 weeks. Five weeks of ASA treatment resulted in a statistically significant decrease in serum testosterone level, Leydig cell number, sperm count, sperm motility, sperm viability, TDI, SI and RI, and it resulted in a significant increase in sperm nucleus maturity and sperm DNA fragmentation (p Ë‚ 0.05). Furthermore, 4 weeks of SIT reversed all the ASA-induced changes in male reproductive parameters (p < 0.05), but not the number of seminiferous tubules and the sperm motility (p > 0.05). A subchronic dose of ASA could lead to adverse alterations in male reproductive parameters and SIT is beneficial in reversing those alterations.

Novel N,N-dimethylbarbituric-pyridinium derivatives as potent urease inhibitors: Synthesis, in vitro, and in silico studies.

A new series of N,N-dimethylbarbituric-pyridinium derivatives 7a-n was synthesized and evaluated as Helicobacter pylori urease inhibitors. All the synthesized compounds (IC50 = 10.37 ± 1.0-77.52 ± 2.7 µM) were more potent than standard inhibitor hydroxyurea against urease (IC50 = 100.00 ± 0.2 µM). Furthermore, comparison of IC50 values of the synthesized compounds with the second standard inhibitor thiourea (IC50 = 22.0 ± 0.03 µM) revealed that compounds 7a-b and 7f-h were more potent than thiourea. Molecular modeling study of the most potent compounds 7a, 7b, 7f, and 7g was also conducted. Additionally, the drug-likeness properties of the synthesized compounds, based on Lipinski rule and other filters, were evaluated.

Synthesis and biological evaluation of new benzimidazole-1,2,3-triazole hybrids as potential α-glucosidase inhibitors.

In this study, a series of benzimidazole-1,2,3-triazole hybrids 8a-n as new α-glucosidase inhibitors were designed and synthesized. In vitro α-glucosidase inhibition activity results indicated that all the synthesized compounds (IC50 values ranging from 25.2 ± 0.9 to 176.5 ± 6.7 µM) exhibited more inhibitory activity in comparison to standard drug acarbose (IC50 = 750.0 ± 12.5 µM). Enzyme kinetic study on the most potent compound 8c revealed that this compound was a competitive inhibitor into α-glucosidase. Moreover, the docking study was performed in order to evaluation of interaction modes of the synthesized compounds in the active site of α-glucosidase and to explain structure-activity relationships of the most potent compounds and their corresponding analogs.

Novel fused 1,2,3-triazolo-benzodiazepine derivatives as potent anticonvulsant agents: design, synthesis, in vivo, and in silico evaluations.

A novel series of 1,2,3-triazolo-benzodiazepine derivatives 6a-o has been synthesized and evaluated in vivo for their anticonvulsant activities using by pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures in mice. The synthetic approach started with diazotizing 2-aminobenzoic acids 1 to produce 2-azidobenzoic acids 2. Next, reaction of the latter compounds with propargylamine 3, benzaldehyde 4, and isocyanides 5 led to the formation of the title compounds 6a-o, in good yields. All the synthesized compounds exhibited high anticonvulsant activity in the PTZ test, comparable to or better than the standard drug diazepam. Among the tested compounds, N-(tert-butyl)-2-(9-chloro-6-oxo-4H-[1,2,3]triazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl)-2-(3-bromophenyl)acetamide 6h was the most potent compound in this assay. Moreover, compounds 6i and 6k showed excellent activity in MES test. Loss of the anticonvulsant effect of compound 6h in the presence of flumazenil in the PTZ test and appropriate interaction of this compound in the active site of benzodiazepine (BZD)-binding site of GABAA receptor confirm involvement of BZD receptors in the anticonvulsant activity of compound 6h. A novel series of 1,2,3-triazolo-benzodiazepine derivatives 6a-o have been synthesized and evaluated in vivo for their anticonvulsant activities using by pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures in mice. All the synthesized compounds exhibited high anticonvulsant activity, comparable to or better than the standard drug diazepam in the PTZ test and compounds 6i and 6k showed excellent activity in MES test. Flumazenil test and in silico docking study confirm involvement of benzodiazepine receptors in the anticonvulsant activity of these compounds.

New 1,2,3-triazole-(thio)barbituric acid hybrids as urease inhibitors: Design, synthesis, in vitro urease inhibition, docking study, and molecular dynamic simulation.

A new series of 1,2,3-triazole-(thio)barbituric acid hybrids 8a-n was designed and synthesized on the basis of potent pharmacophores with urease inhibitory activity. Therefore, these compounds were evaluated against Helicobacter pylori urease. The obtained result demonstrated that all the synthesized compounds, 8a-n, were more potent than the standard urease inhibitor, hydroxyurea. Moreover, among them, compounds 8a, 8c-e, 8g,h, and 8k,l exhibited higher urease inhibitory activities than the other standard inhibitor used: thiourea. Docking studies were performed with the synthesized compounds. Furthermore, molecular dynamic simulation of the most potent compounds, 8e and 8l, showed that these compounds interacted with the conserved residues Cys592 and His593, which belong to the active site flap and are essential for enzymatic activity. These interactions have two consequences: (a) blocking the movement of a flap at the entrance of the active site channel and (b) stabilizing the closed active site flap conformation, which significantly reduces the catalytic activity of urease. Calculation of the physicochemical and topological properties of the synthesized compounds 8a-n predicted that all these compounds can be orally active. The ADME prediction of compounds 8a-n was also performed.

Investigating the prevalence of risk factors of papillary thyroid carcinoma recurrence and disease-free survival after thyroidectomy and central neck dissection in Iranian patients.

Background: Papillary thyroid carcinoma (PTC) is considered the most frequent thyroid malignancy (85-90%) with a good prognosis. However, its frequent recurrence increases mortality and morbidity. In this inquiry we investigated the prevalence of risk factors of PTC recurrence and disease free survival after thyroidectomy and central neck dissection. Method: In this retrospective study, all patients with confirmed PTC who underwent total thyroidectomy and central neck dissection in Imam Reza and Omid hospitals of Mashhad University of Medical Sciences from 2004 to 2011 were included. Total locoregional and distant recurrence rate, 5-year disease free survival rate (DFS) and contributing factors of recurrence were investigated after at least 5 years. Results: In this study 289 patients were included with a mean follow-up of 72.90 ± 11.02 months. 70.6% were female and 29.4% were male. Recurrence occurred in 58 cases from which 10 were distant and 48 were loco-regional. 5-year DFS was 80% and total-survival-rate was 99%. Our analysis showed that primary tumor size, vascular-invasion, extra-thyroid extension, and lymph node ratio (LNR) were significantly related to DFS.

Design, Synthesis, and Cholinesterase Inhibition Assay of Coumarin-3-carboxamide-N-morpholine Hybrids as New Anti-Alzheimer Agents.

A new series of coumarin-3-carboxamide-N-morpholine hybrids 5a-5l was designed and synthesized as cholinesterases inhibitors. The synthetic approach for title compounds was started from the reaction between 2-hydroxybenzaldehyde derivatives and Meldrum's acid to afford corresponding coumarin-3-carboxylic acids. Then, amidation of the latter compounds with 2-morpholinoethylamine or N-(3-aminopropyl)morpholine led to the formation of the compounds 5a-5l. The in vitro inhibition screen against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) revealed that most of the synthesized compounds had potent AChE inhibitory while their BuChE inhibitions are moderate to weak. Among them, propylmorpholine derivative 5g (N-[3-(morpholin-4-yl)propyl]-2-oxo-2H-chromene-3-carboxamide) bearing an unsubstituted coumarin moiety and ethylmorpholine derivative 5d (6-bromo-N-[2-(morpholin-4-yl)ethyl]-2-oxo-2H-chromene-3-carboxamide) bearing a 6-bromocoumarin moiety showed the most activity against AChE and BuChE, respectively. The inhibitory activity of compound 5g against AChE was 1.78 times more than that of rivastigmine and anti-BuChE activity of compound 5d is approximately same as rivastigmine. Kinetic and docking studies confirmed the dual binding site ability of compound 5g to inhibit AChE.

Design, Synthesis, Molecular Docking, and Cholinesterase Inhibitory Potential of Phthalimide-Dithiocarbamate Hybrids as New Agents for Treatment of Alzheimer's Disease.

A novel series of phthalimide-dithiocarbamate hybrids was synthesized and evaluated for in vitro inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The anti-cholinesterase results indicated that among the synthesized compounds, the compounds 7g and 7h showed the most potent anti-AChE and anti-BuChE activities, respectively. Molecular docking and dynamic studies of the compounds 7g and 7h, respectively, in the active site of AChE and BuChE revealed that these compounds as well interacted with studied cholinesterases. These compounds also possessed drug-like properties and were able to cross the BBB.

Design, synthesis, and biological evaluation of selective and potent Carbazole-based butyrylcholinesterase inhibitors.

Alzheimer's disease (AD) is the most common form of dementia. Inhibition of BChE might be a useful therapeutic target for AD. A new series of Carbazole-Benzyl Pyridine derivatives were designed synthesized and evaluated as butyrylcholinesterase (BChE) inhibitors. In vitro assay revealed that all of the derivatives had selective and potent anti- BChE activities. 3-((9H-Carbazol-9-yl)methyl)-1-(4-chlorobenzyl)pyridin-1-ium chloride (compound 8f) had the most potent anti-BChE activity (IC50 value = 0.073 µM), the highest BChE selectivity and mixed-type inhibition. Docking study revealed that 8f interacted with the peripheral site, the choline binding site, catalytic site and the acyl pocket of BChE. Physicochemical properties were accurate to Lipinski's rule. In addition, compound 8f demonstrated neuroprotective activity at 10 µM. This compound could also inhibit AChE-induced and self-induced Aß peptide aggregation at concentration of 100 µM and 10 µM respectively. The in-vivo study showed that compound 8f in 10 mg/kg increased the time spent in target quadrant in the probe day and decreased mean training period scape latency in rats. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.

Efficacy and Safety of Pleurodesis Using Platelet-Rich Plasma and Fibrin Glue in Management of Postoperative Chylothorax After Esophagectomy.

INTRODUCTION: Chylothorax is by definition a collection of lymphatic fluids in the pleural cavity because of leakage from main thoracic duct or its tributaries. It is an uncommon but serious postoperative complication in esophageal cancer patients. There is no standard therapeutic algorithm for chylothorax because no prospective or randomized trials have yet been performed to evaluate the available treatment options. The aim of this study was to evaluate the efficacy of pleurodesis with a combination of platelet-rich plasma (PRP) and fibrin glue to the treatment of chylothorax after trans-hiatal esophagectomy. MATERIALS AND METHODS: We randomly allocated 52 consecutive esophageal cancer patients with postoperative chylothorax who did not respond to conservative management to either PRP fibrin glue pleurodesis or surgical thoracic duct ligation. 26 patients in each group were treated with PRP fibrin glue pleurodesis or surgical thoracic duct ligation in order to control chylothorax. Perioperative data, including success rate and complications of both interventions, were analyzed. RESULTS: Two groups were similar in terms of patients' demographics and tumor characteristics. All 26 patients in pleurodesis group (100%) and 20 patients in surgery group (76.9%) were successfully treated (p = 0.009). Seven patients (26.92%) in pleurodesis group required a second application of PRP fibrin glue after a week. The mean length of hospital stay was 53.50 ± 16.662 days in surgery group and 36.04 ± 8.224 days in pleurodesis group (p < 0.001). Although mortality rate in surgery group was higher than pleurodesis group, it was not statistically significant (p = 0.1621). There was no significant difference in complications between two groups either. No serious side effect occurred with PRP fibrin glue application. CONCLUSION: In conclusion, pleurodesis using PRP and fibrin glue for chylothorax after trans-hiatal esophagectomy was associated with significantly increased success rate, decreased ICU stay, decreased overall hospital stay, and decreased mortality compared with surgical thoracic duct ligation. No patient after PRFG required additional intervention including surgery. Thus, given the improved outcomes with PRFG pleurodesis, this technique may be considered in all patients with postoperative chylothorax after or during conservative management and before proceeding to more invasive interventions.

N-(2-(Piperazin-1-yl)phenyl)arylamide Derivatives as ß-Secretase (BACE1) Inhibitors: Simple Synthesis by Ugi Four-Component Reaction and Biological Evaluation.

A novel series of N-(2-(piperazin-1-yl)phenyl)aryl carboxamide derivatives were simply synthesized by Ugi-multicomponent reaction as ß-secretase (BACE1) inhibitors. The BACE1 inhibitory activity of the synthesized compounds was examined using a Forester resonance energy transfer (FRET)-based assay. Among the tested compounds, the N-(5-bromo-2-(4-phenylpiperazine-1-yl)phenyl)thiophene-carboxamide derivative 14 containing the N-cyclohexyl indole acetamide moiety showed superior BACE1 inhibition at 10 and 40 µM. The results of the molecular docking study indicated that compound 14 establishes favorable hydrogen bonding interactions with the catalytic amino acid residues Asp228 and Thr72 and could be well accommodated in the flap region and P2 and P'2 pockets of the BACE1 active site.

Synthesis and Evaluation of Chroman-4-One Linked to N-Benzyl Pyridinium Derivatives as New Acetylcholinesterase Inhibitors.

A novel series of chroman-4-one derivatives containing the N-benzyl pyridinium moiety were designed, synthesized, and evaluated for their acetylcholinesterase (AChE) inhibitory activities. Among the various synthesized compounds, (E)-1-(2,3-dibromobenzyl)-4-((7-ethoxy-4-oxochroman-3-ylidene)methyl)pyridinium bromide (8l) depicted the most potent anti-AChE activity (IC50 = 0.048 µM). In addition, the molecular modeling study allowed us to detect possible binding modes that are in full compliance with the observed results through in vitro experiments.

Axillary concordance between superficial and deep sentinel node mapping material injections in breast cancer patients: systematic review and meta-analysis of the literature.

It is still unclear whether the deep and superficial lymphatics of the breast always drain into the same nodes and which route best simulates the spread of breast cancer. In the current study, we systematically searched the available literature to find the studies evaluated the sentinel node locations of deep and superficial injections in the same patients simultaneously or serially. We searched SCOPUS, and PUBMED for relevant studies. Patient basis concordance rate was defined as the ratio of patients with at least one identified axillary sentinel node by both deep and superficial injections to all patients with identified axillary sentinel nodes using either methods. Sentinel node basis concordance was defined as the ratio of the number of axillary sentinel nodes identified by both deep and superficial injections to the sum of all identified axillary sentinel nodes using either methods. Pooled sentinel node detection rates were 94 % [92.1-95.5], 91.2 % [87.1-94.1], and 97.2 % [96-98] for superficial, deep, and combined (superficial and deep) injections. Pooled patient basis and sentinel node basis concordance rates were 90 % [86.7-92.4] and 73 % [63.3-80.9]. Pooled false negative rates were 9.1 % [5.9-14], 8.6 % [3.7-18.8], and 6.5 % [3.4-11.9] for superficial, deep, and combined (superficial and deep) injections, respectively. Axillary lymphatic drainage concordance between superficial and deep sentinel node mapping material in breast cancer patients is fairly high and clinically acceptable. However, both injection techniques can complement each other and the combined superficial/deep injection technique seems to be more successful clinically and can decrease the overall false negative rate.

Protective Effect of Low-Volume High-Intensity Interval Training on Aspirin-Induced Reproductive Impairments in Adult Male Wistar Rats.

Lifestyle factors such as sedentary behavior and consumption of certain medications can disturb the function of the male reproductive system. In the present study, we investigated the potential co-treatment effects of low-volume high-intensity interval training (HIIT) on markers of reproductive function in adult male Wistar rats under aspirin (ASA) treatment. Eighteen adult male Wistar rats were randomized into three groups: control (C), aspirin treatment (AT), and aspirin treatment + exercise (ATE). Animals in the AT and ATE groups received an oral subchronic dose of aspirin (12.5 mg/kg body mass). The exercise was performed three times per week for 6 weeks (4-6 reps of 10-s sprints). Serum testosterone level, sperm parameters (sperm count, viability, maturity, and DNA fragmentation), histomorphometric (Leydig cell, tubule diameter, thickness of tubular epithelium, and indices of spermatogenesis and spermiogenesis), and histochemical parameter (testicular fat density) were assessed. Results revealed that compared to the C group, ASA consumption led to a negative alteration in serum testosterone levels, sperm parameters, and histomorphometric and histochemical parameters (P < 0.05). However, there were no significant differences between the C and ATE groups in terms of serum testosterone level, number of Leydig cells, epididymal fat density, tubule diameter, epithelium height, immature-to-mature sperm ratio, and DNA breakage (P > 0.05). These findings suggest that ASA treatment is associated with deleterious changes in male reproductive parameters. However, low-volume HIIT may prevent ASA-induced male reproductive impairments and could be considered a potential prophylactic measure in subjects under ASA treatment.

Modified osprey algorithm for optimizing capsule neural network in leukemia image recognition.

The diagnosis of leukemia is a serious matter that requires immediate and accurate attention. This research presents a revolutionary method for diagnosing leukemia using a Capsule Neural Network (CapsNet) with an optimized design. CapsNet is a cutting-edge neural network that effectively captures complex features and spatial relationships within images. To improve the CapsNet's performance, a Modified Version of Osprey Optimization Algorithm (MOA) has been utilized. Thesuggested approach has been tested on the ALL-IDB database, a widely recognized dataset for leukemia image classification. Comparative analysis with various machine learning techniques, including Combined combine MobilenetV2 and ResNet18 (MBV2/Res) network, Depth-wise convolution model, a hybrid model that combines a genetic algorithm with ResNet-50V2 (ResNet/GA), and SVM/JAYA demonstrated the superiority of our method in different terms. As a result, the proposed method is a robust and powerful tool for diagnosing leukemia from medical images.