Investigation of biological activities of two cultivars of Cicer arietinum proteins mass associated with Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, with some known classical factors. Cicer arietinum (Leguminosae) is a source of protein for humans and contains albumin, globulin, glutelin, and prolamin. The protein content of two cultivars of C. arietinum, Hashem and Mansour, was isolated to evaluate their inhibition activity against acetylcholinesterase (AChE), butyrylcholine esterase (BChE), and ß-amyloid peptide (ßA) aggregation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and molecular docking were also applied to evaluate the content and determine the potential of each chickpea protein to interact with AChE, respectively. Obtained data showed that proteins from both cultivars could inhibit AChE with IC50 of 17.73 (0.03) and 22.20 (0.06) µg/mL, respectively, with no activity on BChE. The 50 µg/mL protein concentration of each cultivar suppressed ßA accumulation (Mansour: 25.66% and Hashem: 21.69%) and showed biometal chelating activity. SDS-PAGE analysis revealed relatively different protein patterns, though the Mansour cultivar contained some protein bands with molecular weights of 18, 24, and 70 kDa were estimated to belong to vicilin and legumin, which were absent in the Hashem protein mass. Molecular docking showed that legumin and especially vicilin have good potential to interact with AChE. The chickpea proteins showed inhibitory activity against AChE, which might be due to the vicilin and legumin fractions. The characterization of the inhibitory effect of each protein band could be promising in finding new therapeutic peptide candidates to treat Alzheimer's in the future, although more experimental work is needed in this issue.

Are women with preterm labour at risk for negative birth experience? a comparative cross-sectional study from Iran.

BACKGROUND: The unpredictable nature of preterm labour can be a stressful experience for the mother. The occurrence of preterm birth can lead to the failure of the mother's previous expectations regarding the process of labour and birth leading to negative perception towards birth. METHODS: This descriptive-analytical cross-sectional study was conducted in Tabriz, Iran. We employed convenience sampling to recruit eligible mothers with term birth (314 women) and preterm birth (157 women). Childbirth Experience Questionnaire 2.0, Preterm Birth Experiences and Satisfaction Scale, and Delivery Fear Scale were used to measure the woman's fear of delivery during labour and birth experience. Data were analysed by general linear model. RESULTS: The prevalence of negative birth experience in the term and preterm birth groups was 31.8% and 14.3%, respectively. The results of the multivariable general linear model, after the adjustment of demographic and obstetric characteristics, showed that there was no statistically significant difference between the two groups of mothers with term and preterm birth [ß (95% CI): -0.06 (-0.22 to 0.09); p = 0.414] in terms of childbirth experience. However, the fear of delivery had a significant relationship with the childbirth experience [-0.02 (-0.03 to -0.01); p < 0.001]. CONCLUSION: There was no statistically significant difference in terms of women's childbirth experience between the mothers with term and preterm births. The fear of delivery during labour was the predictor of childbirth experience. In order to improve women's childbirth experience, interventions should be made to reduce their fear during labour.

Stewardship; The Missing Loop of Rehabilitation in the Health System: A Policy Brief.

Providing optimal rehabilitation services for people with disabilities has always been recognized as a major concern of health systems in all countries. Stewardship is one of the biggest challenges to provide rehabilitation services to people with disabilities in Iran. We advocate the Ministry of Health & Medical Education (MoHME) to take the lead as a steward of rehabilitation services in Iran, while the dedicated sections in the MoHME need to be determined, with a clear list of responsibilities and affiliations.

Novel tacrine-based acetylcholinesterase inhibitors as potential agents for the treatment of Alzheimer's disease: Quinolotacrine hybrids.

A new series of quinolotacrine hybrids including cyclopenta- and cyclohexa-quinolotacrine derivatives were designed, synthesized, and assessed as anti-cholinesterase (ChE) agents. The designed derivatives indicated higher inhibitory effect on the acetylcholinesterase (AChE) with IC50 values of 0.285-100 µM compared to butyrylcholinesterase (BChE) with IC50 values of > 100 µM. Of these compounds, cyclohexa-quinolotacrine hybrids displayed a little better anti-AChE activity than cyclopenta-quinolotacrine hybrids. Compound 8-amino-7-(3-hydroxyphenyl)-5,7,9,10,11,12-hexahydro-6H-pyrano[2,3-b:5,6-c'] diquinolin-6-one (6m) including 3-hydroxyphenyl and cyclohexane ring moieties exhibited the best AChE inhibitory activity with IC50 value of 0.285 µM. The kinetic and molecular docking studies indicated that compound 6m occupied both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE as a mixed inhibitor. Using neuroprotective assay against H2O2-induced cell death in PC12 cells, the compound 6h illustrated significant protection among the assessed compounds. In silico ADME studies estimated good drug-likeness for the designed compounds. As a result, these quinolotacrine hybrids can be very encouraging AChE inhibitors to treat Alzheimer's disease. A novel series of quinolotacrine hybrids were designed, synthesized, and evaluated against AChE and BChE enzymes as potential agents for the treatment of AD. The hybrids showed good to significant inhibitory activity against AChE (0.285-100 µM) compared to butyrylcholinesterase (BChE) with IC50 values of > 100 µM. Among them, compound 8-amino-7-(3-hydroxyphenyl)-5,7,9,10,11,12-hexahydro-6H-pyrano[2,3-b:5,6-c'] diquinolin-6-one (6 m) bearing 3-hydroxyphenyl moiety and cyclohexane ring exhibited the highest anti-AChE activity with IC50 value of 0.285 µM. The kinetic and molecular docking studies illustrated that compound 6 m is a mixed inhibitor and binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE.

Synthesis and evaluation of novel arylisoxazoles linked to tacrine moiety: in vitro and in vivo biological activities against Alzheimer's disease.

Alzheimer's disease (AD) is now ranked as the third leading cause of death after heart disease and cancer. There is no definite cure for AD due to the multi-factorial nature of the disease, hence, multi-target-directed ligands (MTDLs) have attracted lots of attention. In this work, focusing on the efficient cholinesterase inhibitory activity of tacrine, design and synthesis of novel arylisoxazole-tacrine analogues was developed. In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition assay confirmed high potency of the title compounds. Among them, compounds 7l and 7b demonstrated high activity toward AChE and BChE with IC50 values of 0.050 and 0.039 µM, respectively. Both compounds showed very good self-induced Aß aggregation and AChE-induced inhibitory activity (79.4 and 71.4% for compound 7l and 61.8 and 58.6% for compound 7b, respectively). Also, 7l showed good anti-BACE1 activity with IC50 value of 1.65 µM. The metal chelation test indicated the ability of compounds 7l and 7b to chelate biometals (Zn2+, Cu2+, and Fe2+). However, they showed no significant neuroprotectivity against Aß-induced damage in PC12 cells. Evaluation of in vitro hepatotoxicity revealed comparable toxicity of compounds 7l and 7b with tacrine. In vivo studies by Morris water maze (MWM) task demonstrated that compound 7l significantly reversed scopolamine-induced memory deficit in rats. Finally, molecular docking studies of compounds 7l and 7b confirmed establishment of desired interactions with the AChE, BChE, and BACE1 active sites.

Urinary incontinence and related quality of life among elderly women in Tabas, South Khorasan, Iran.

BACKGROUND: Urinary incontinence (UI) is one of the most common problems in old age that is often seen in women, which causes not only physical problems but also psychological, social, economic problems and poor quality of life. The aim of the present study was to evaluate the UI and related quality of life (QoL) in elderly women. METHODS: This cross-sectional study enrolled 369 women over 60 years old and living in Tabas city, Iran who were selected by cluster random sampling method. The instruments included the International Consultation on Incontinence Questionnaire-Short Form, the International Consultation on Incontinence Questionnaire Urinary Incontinence Quality of Life Module, and a demographic questionnaire. Data analysis was carried out using independent t-test, chi-square, and logistic regression in SPSS software. RESULTS: The UI prevalence among participants was 24.9% and stress urinary incontinence was the most common type (40.2% of all elderly patients). The mean UI-related QoL score was 38.04 ± 11.67 from the score range of 22-76. There was a significant positive correlation between UI-related QoL score and UI score (r = 0.585, p < 0.001). Age, body mass index (BMI), constipation, history of cesarean section, hypertension, and the use of angiotensin receptor blockers are factors increasing the odds of having UI in this study population. CONCLUSION: Aging, some chronic diseases, high BMI, and the use of some drugs are related to UI prevalence. Also, it is associated with lower QOL among elderly women. Designing appropriate intervention programs, controlling chronic diseases, training in the proper use of drugs, and also some physical exercises can be effective in controlling and improving this common syndrome of old age and promoting their QoL.

Factors affecting nurses' retention in Iranian hospitals.

AIM: This research was conducted to study the factors affecting nurses' retention in Iranian hospitals. BACKGROUND: Health care systems should pay attention to their human resources' retention to deliver health care services and maintain their organizational values. This issue becomes more significant when we consider the human and financial limitations in place. METHOD: Data were analysed using conventional qualitative content analysis based on the model developed by Elo and Kyngäs. Forty-two managers and nurses were selected by purposive sampling. Data were obtained through 45 semi-structured interviews until data saturation was reached. RESULTS: The data analysis resulted in four main categories and 17 subcategories. The main categories included dignity and respect, ethics and spirituality, empathy, and flourishing. The main theme extracted was 'maternal management'. CONCLUSION: The present study proposes 'maternal management' as a strategy to increase the retention of nurses.

Design, Synthesis, and Molecular Docking of Some Novel Tacrine Based Cyclopentapyranopyridine- and Tetrahydropyranoquinoline-Kojic Acid Derivatives as Anti-Acetylcholinesterase Agents.

A novel series of tacrine based cyclopentapyranopyridine- and tetrahydropyranoquinoline-kojic acid derivatives were designed, synthesized, and evaluated as anti-cholinesterase agents. The chemical structures of all target compounds were characterized by 1 H-NMR, 13 C-NMR, and elemental analyses. The synthesized compounds mostly inhibited acetylcholinesterase enzyme (AChE) with IC50 values of 4.18-48.71 µM rather than butyrylcholinesterase enzyme (BChE) with IC50 values of >100 µM. Among them, cyclopentapyranopyridine-kojic acid derivatives showed slightly better AChE inhibitory activity compared to tetrahydropyranoquinoline-kojic acid. The compound 10-amino-2-(hydroxymethyl)-11-(4-isopropylphenyl)-7,8,9,11-tetrahydro-4H-cyclopenta[b]pyrano[2',3' : 5,6]pyrano[3,2-e]pyridin-4-one (6f) bearing 4-isopropylphenyl moiety and cyclopentane ring exhibited the highest anti-AChE activity with IC50 value of 4.18 µM. The kinetic study indicated that the compound 6f acts as a mixed inhibitor and the molecular docking studies also illustrated that the compound 6f binds to both the catalytic site (CS) and peripheral anionic site (PAS) of AChE. The compound 6f showed moderate neuroprotective properties against H2 O2 -induced cytotoxicity in PC12 cells. The theoretical ADME study also predicted good drug-likeness for the compound 6f. Based on these results, the compound 6f seems to be a very promising AChE inhibitor for the treatment of Alzheimer's disease.

Convention on the rights of persons with disabilities: Qualitative exploration of barriers to the implementation of articles 25 (health) and 26 (rehabilitation) in Iran.

Background: The International Convention on the Rights of Persons with Disabilities (CRPD) is the most important International Document for recognizing the rights of persons with disabilities, including the right to health and rehabilitation. Islamic Republic Iran acceded to the Convention in 2008, but still has a long way to go to achieve its desired status and in line with the objectives of the convention. This study aimed to identify the barriers to the implementation of articles 25 and 26 of the CRPD in Iran. Methods: This study was performed using conventional content analysis. Twenty-one individuals were recruited by purposive sampling with maximum variation and were continued until saturation. Data were gathered through in-depth, semi-structured interviews from June 2018 to May 2019. MAXQDA version 10 was used for analyzing data. Results: The resulting data analysis yielded 860 initial or open codes. The concepts were categorized into 27 subcategories and 7 categories. Main categories were included: "Structure inefficiency", "lack of comprehensive rehabilitation program", "inadequate awareness", "neglected economy of people with disabilities", "weak access to services", "cultural challenges" and "disregard for new technologies". Conclusion: The findings showed that the executive structures in the country have a lot of problems with health and rehabilitation programs for people with disabilities. It seems understanding the barriers to implementation of articles 25 and 26 of the international CRPD empowers officials in the field and improve services by providing a better view of the disabled. Nevertheless, it is recommended for policymakers to consider rehabilitation as a main element of the health system.

DMLR: A toolkit for investigation of deoxyribozyme-mediated ligation based on real time PCR.

Deoxyribozymes or DNAzyme are identified as catalytic DNA sequences which catalyze different chemical reactions. Ligating deoxyribozymes catalyze the formation of branched and linear products. Due to the lack of efficient read-out systems, there is no report on in vivo application of ligating deoxyribozymes. To expand the biological application of branched-RNA forming deoxyribozymes, we performed our study in order to suggest a practical toolkit for measurement of in vivo real-time activity of ligating deoxyribozymes. Further in vitro studies were designed to analyze the effects of the location of branch site on reverse transcriptase (RT) interference. With this toolkit even the activity of RT was measured precisely. Our results indicate that the activity of RT enzyme significantly affected by a 17 nt branched adaptor synthesized by 10DM24 ligating deoxyribozyme. The RT stalls at or near the RNA branch point during both initiation and elongation phases. The DNA synthesis is decreased 4.3 and 2.7 fold during initiation and elongation phases respectively. In conclusion, we introduce a general and practical toolkit called "DMLR" which is based on Real-time PCR method. The use of DMLR precisely determines RT behavior when encountered with any backbone modification with the ability of stopping the enzyme activity.

Design, synthesis, biological evaluation, and docking study of novel dual-acting thiazole-pyridiniums inhibiting acetylcholinesterase and ß-amyloid aggregation for Alzheimer's disease.

New compounds containing thiazole and pyridinium moieties were designed and synthesized. The potency of the synthesized compounds as selective inhibitors of acetylcholinesterase (AChE), and ß-amyloid aggregation (Aß) was evaluated. Compounds 7d and 7j showed the best AChE inhibitory activities at the submicromolar concentration range (IC50 values of 0.40 and 0.69 µM, respectively). Most of the novel compounds showed moderate to low inhibition of butyrylcholinesterase (BChE), which is indicative of their selective inhibitory effects towards AChE. Kinetic studies using the most potent compounds 7d and 7j confirmed a mixed-type of AChE inhibition mechanism in accordance with the docking results, which shows their interactions with both catalytic active (CAS) and peripheral anionic (PAS) sites. The specific binding of 7a, 7j, and 7m to PAS domain of AChE was also confirmed experimentally. In addition, 7d and 7j were able to show ß-amyloid self-aggregation inhibitory effects (20.38 and 42.66% respectively) stronger than donepezil (14.70%) assayed at 10 µM concentration. Moreover, compounds 7j and 7m were shown to be effective neuroprotective agents in H2O2-induced oxidative stress on PC12 cells almost similar to those observed for donepezil. The ability of 7j to pass blood-brain barrier was demonstrated using the PAMPA method. The results presented in this work provide useful information about designing novel anti-Alzheimer agents.

The Effect of Complementary and Alternative Medicines on Quality of Life in Patients with Breast Cancer: A Systematic Review.

BACKGROUND: Breast cancer disease and its classic treatment lead to decrease in patients' quality of life (QOL). This systematic review aimed to compare the effectiveness of complementary and alternative medicines (CAMs) categories on the QOL of women with breast cancer. METHODS: English clinical trials from PubMed, Emabase, Scupos, and Google Scholar databases were searched electronically by the end of 2018 with the Cochrane Collaboration protocol. Two researchers independently extracted data such as participants' characteristics, CAM methods, QOL assessment tools. CAMs were classified into three categories of dietary supplements, herbal medicine, and mind-body techniques. RESULTS: During the initial search, 1186 articles were found. After reviewing titles, abstracts, and full texts based on inclusion and exclusion criteria, 28 clinical trials were included in the systematic review, 18 of which was randomized controlled trial (RCT). Participants included women with breast cancer who were undergoing the first three phases of breast cancer or postcancer rehabilitation. Among CAM interventions, one article used a dietary supplement, and the other 27 articles included a variety of mind-body techniques. Twenty-seven studies showed improved QOL (P > 0.05). CONCLUSION: The findings may indicate the potential benefits of CAMs, especially mind-body techniques on QOL in breast cancer patients. Further RCTs or long-term follow-up studies are recommended. Moreover, the use of similar QOL assessment tools allows for more meta-analysis and generalizability of results, especially for the development of clinical guidelines.

New benzyl pyridinium derivatives bearing 2,4-dioxochroman moiety as potent agents for treatment of Alzheimer's disease: Design, synthesis, biological evaluation, and docking study.

A new series of benzyl pyridinium-2,4-dioxochroman derivatives 7a-o was synthesized and evaluated as new anti-Alzheimer agents. Among the synthesized compounds, the compounds 7f and 7i exhibited the most potent anti-AChE and anti-BuChE activities, respectively. The kinetic study of the compound 7f revealed that this compound inhibited AChE in a mixed-type inhibition mode. Furthermore, the docking study of the compounds 7f and 7i showed that these compounds bound to both the catalytic site (CS) and peripheral anionic site (PAS) of AChE and BuChE, respectively. The compound 7f also exhibited a greater self-induced Aß peptide aggregation inhibitory activity in compare to donepezil. Furthermore, the neuroprotective activity of this compound at 20 µM was comparable to that of the standard neuroprotective agent (quercetin).

Novel tacrine-coumarin hybrids linked to 1,2,3-triazole as anti-Alzheimer's compounds: In vitro and in vivo biological evaluation and docking study.

A new series of tacrine-coumarin hybrids linked to 1,2,3-triazole were designed, synthesized, and tested as potent dual binding site cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer's disease (AD). Among them, compound 8e was the most potent anti-AChE derivative (IC50 = 27 nM) and compound 8m displayed the best anti-BChE activity (IC50 = 6 nM) much more active than tacrine and donepezil as the reference drugs. Compound 8e was also evaluated for its BACE1 inhibitory activity and neuroprotectivity against PC12 cells exposed to Aß25-35 which indicated low activity. Finally, in vivo studies by Morris water maze task showed that compound 8e significantly reversed scopolamine-induced memory deficit in rats.

Novel cinnamic acid-tryptamine hybrids as potent butyrylcholinesterase inhibitors: Synthesis, biological evaluation, and docking study.

A novel series of cinnamic acid-tryptamine hybrids was designed, synthesized, and evaluated as cholinesterase inhibitors. Anticholinesterase assays showed that all of the synthesized compounds displayed a clearly selective inhibition of butyrylcholinesterase (BChE), but only a moderate inhibitory effect toward acetylcholinesterase (AChE) was detected. Among these cinnamic acid-tryptamine hybrids, compound 7d was found to be the most potent inhibitor of BChE with an IC50 value of 0.55 ± 0.04 µM. This compound showed a 14-fold higher inhibitory potency than the standard drug donepezil (IC50 = 7.79 ± 0.81 µM) and inhibited BChE through a mixed-type inhibition mode. Moreover, a docking study revealed that compound 7d binds to both the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of BChE. Also, compound 7d was evaluated against ß-secretase, which exhibited low activity (inhibition percentage: 38%).

Design and synthesis of novel anti-Alzheimer's agents: Acridine-chromenone and quinoline-chromenone hybrids.

A novel series of acridine-chromenone and quinoline-chromenone hybrids were designed, synthesized, and evaluated as anti-Alzheimer's agents. All synthesized compounds were evaluated as cholinesterases (ChEs) inhibitors and among them, 7-(4-(6-chloro-2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)phenoxy)-4-methyl-2H-chromen-2-one (8e) exhibited the most potent anti-acetylcholinesterase (AChE) inhibitory activity (IC50=16.17µM) comparing with rivastigmine (IC50=11.07µM) as the reference drug. Also, compound 8e was assessed for its ß-secretase (BACE1) inhibitory and neuroprotective activities which demonstrated satisfactory results. It should be noted that both kinetic study on the inhibition of AChE and molecular modeling revealed that compound 8e interacted simultaneously with both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE.

Three-Dimensional Numerical Simulations of Peristaltic Contractions in Obstructed Ureter Flows.

Ureteral peristalsis can be considered as a series of waves on the ureteral wall, which transfers the urine along the ureter toward the bladder. The stones that form in the kidney and migrate to the ureter can create a substantial health problem due to the pain caused by interaction of the ureteral walls and stones during the peristaltic motion. Three-dimensional (3D) computational fluid dynamics (CFD) simulations were carried out using the commercial code ansys fluent to solve for the peristaltic movement of the ureter, with and without stones. The effect of stone size was considered through the investigation of varying obstructions of 5%, 15%, and 35% for fixed spherical stone shape. Also, an understanding of the effect of stone shape was obtained through separate CFD calculations of the peristaltic ureter with three different types of stones, a sphere, a cube, and a star, all at a fixed obstruction percentage of 15%. Velocity vectors, mass flow rates, pressure gradients, and wall shear stresses were analyzed along one bolus of urine during peristalsis of the ureteral wall to study the various effects. It was found that the increase in obstruction increased the backflow, pressure gradients, and wall shear stresses proximal to the stone. On the other hand, with regard to the stone shape study, while the cube-shaped stones resulted in the largest backflow, the star-shaped stone showed highest pressure gradient magnitudes. Interestingly, the change in stone shape did not have a significant effect on the wall shear stress at the obstruction level studied here.

Novel Tacrine-Based Pyrano[3',4':5,6]pyrano[2,3-b]quinolinones: Synthesis and Cholinesterase Inhibitory Activity.

In order to develop effective anti-cholinesterase compounds, a novel series of pyrano[3',4':5,6]pyrano[2,3-b]quinolinones were designed, synthesized, and evaluated in vitro against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). All derivatives showed very good AChE inhibitory (AChEI) activity (IC50 = 0.37-5.62 µM) compared with rivastigmine (IC50 = 11.07 µM). Among them, 11-amino-12-(2,3-dichlorophenyl)-3-methyl-7,8,9,10-tetrahydropyrano[3',4':5,6]pyrano[2,3-b]quinolin-1(12H)-one (6f) displayed the best inhibitory activity. However, most of the synthesized compounds showed no anti-BChE activity and compounds 6b and 6f were found to be only moderate inhibitors. The most potent anti-AChE compound 6f had low and moderate inhibitory activity and neuroprotective effects against beta-secretase (BACE1) and oxidative stress-induced cell death, respectively. Also, kinetic and molecular docking studies of binding interactions elucidated that compound 6f bound to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE.

Design, synthesis, and molecular dynamics simulation studies of some novel kojic acid fused 2-amino-3-cyano-4H-pyran derivatives as tyrosinase inhibitors.

A novel series of kojic acid fused 2-amino-3-cyano-4H-pyran derivatives were synthesized via a multicomponent reaction involving kojic acid, benzyloxy benzaldehyde, and malonitrile as tyrosinase inhibitors. Subsequently, the structures of the compounds were characterized using FT-IR, 1H-, and 13C-NMR spectroscopic analyses. The designed compounds fall into three series: (1) 4-benzyloxy-phenyl kojopyran 6a-e, (2) 3-benzyloxy- phenyl kojopyran derivatives 6f-j, and (3) 4-benzyloxy-3-methoxy-phenyl kojopyran derivative 6 k-o. The assessment of tyrosinase inhibition activity was conducted using L-Dopa as the substrate. Among synthesized compounds, 2-amino-4-(4-((4-fluorobenzyl)oxy)phenyl)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6b) demonstrated the highest antityrosinase activity with a competitive inhibition pattern (IC50 = 7.69 ± 1.99 µM) as compared to the control agent kojic acid (IC50 = 23.64 ± 2.56 µM). Since compound 6b was synthesized as a racemic mixture, in silico studies were performed for both R and S enantiomers. The R- enantiomer showed critical interactions compared with the S-enantiomer. Specifically, it established hydrogen bonds and hydrophobic interactions with crucial and highly conserved amino acids within the enzyme's binding site in the target protein. Moreover, the molecular dynamics simulations revealed that compound 6b demonstrated significant interactions with essential residues of the binding site, resulting in a stable complex throughout the entire simulation run. The drug-like and ADMET properties predictions showed an acceptable profile for compound 6b. Thus, it can serve as a drug candidate to develop more potent antityrosinase agents due to its low toxicity and its high inhibition activity.

Novel Pyrano[3,2-c]quinoline-1,2,3-triazole Hybrids as Potential Anti-Diabetic Agents: In Vitro α-Glucosidase Inhibition, Kinetic, and Molecular Dynamics Simulation.

In this study, a novel series of pyrano[3,2-c]quinoline-1,2,3-triazole hybrids 8a-o were synthesized and evaluated against the α-glucosidase enzyme. All compounds showed significant in vitro inhibitory activity (IC50 values of 1.19 ± 0.05 to 20.01 ± 0.02 µM) compared to the standard drug acarbose (IC50 = 750.0 µM). Among them, 2-amino-4-(3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-5-oxo-5,6-dihydro-4H-pyrano[3,2-c]quinoline-3-carbonitrile (compound 8k) demonstrated the best inhibitory effect toward α-glucosidase (IC50 = 1.19 ± 0.05 µM) with a competitive pattern of inhibition. Since compound 8k was synthesized as a racemic mixture, molecular docking and dynamics simulations were performed on R- and S-enantiomers of compound 8k. Based on the molecular docking results, both R- and S-enantiomers of compound 8k displayed significant interactions with key residues including catalytic triad (Asp214, Glu276, and Asp349) in the enzyme active site. However, an in silico study indicated that S- and R-enantiomers were inversely located in the enzyme active site. The R-enantiomer formed a more stable complex with a higher binding affinity to the active site of α-glucosidase than that of the S- enantiomer. The benzyl ring in the most stable complex ((R)-compound 8k) was located in the bottom of the binding site and interacted with the enzyme active site, while the pyrano[3,2-c]quinoline moiety occupied the high solvent accessible entrance of the active site. Thus, the synthesized pyrano[3,2-c]quinoline-1,2,3-triazole hybrids seem to be promising scaffolds for the development of novel α-glucosidase inhibitors.