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.

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.

Design and synthesis of vancomycin-functionalized ZnFe2 O4 nanoparticles as an effective antibacterial agent against methicillin-resistant Staphylococcus aureus.

The emergence of antibiotic-resistant bacterial infections is a principal threat to global health. Functionalization of nanomaterial with antibiotics is known as a useful method for increasing the effectiveness of existing antibiotics. In this study, vancomycin-functionalized ZnFe2 O4 nanocomposite (ZnFe2 O4 @Cell@APTES@Van) was synthesized, and its functional groups and particle size were characterized using Fourier-transform infrared spectroscopy, thermogravimetric analysis, dynamic light scattering, scanning electron microscope, and transmission electron microscopy. The antibacteria activity of the synthesized nanocomposite was evaluated using minimum inhibitory concentration and minimum bactericidal concentration against Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus (MRSA). Cytotoxicity assay was done by 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide method. Characterization analyses of synthesized nanocomposite confirmed the binding of vancomysin on the surface of ZnFe2 O4 @Cell@APTES. Nanocomposite exhibited an aggregated semi-spherical structure with hydrodynamic radii of ∼382 nm. In vitro antibacterial activity test showed that vancomycin and vancomycin functionalized ZnFe2 O4 have no antibacterial effect against E. coli. S. aureus was sensitive to vancomycin and ZnFe2 O4 @Cell@APTES@Van NPs and ZnFe2 O4 NPs did not improve vancomycin antibacterial activity against these bacteria. MRSA is resistant to vancomycin while ZnFe2 O4 @Cell@APTES@Van NPs was efficient in inhibiting MRSA growth. In summary, this study showed that attachment of vancomycin to ZnFe2 O4 NPs was increased its antibacterial activity against MRSA.

Electrospun Fibers Loaded with Probiotics: Fundamentals, Characterization, and Applications.

Increasing demand for safe, efficient, and eco-friendly solutions for pharmaceutical and food industries has led researchers to explore new approaches to bacterial storage. Several advantages make electrospinning (ES) a promising technique for food systems, including simple manufacturing equipment, a relatively low spinning cost, a wide variety of spinnable materials, and a mild process that is easily controlled, which allows continuous fabrication of ultrafine polymeric fibers at submicron or nanoscales without high temperatures or high pressures. This review briefly describes recent advances in the development of electrospun fibers for loading probiotics (PRB) by focusing on ES technology, its efficiency for loading PRB into fibers (viability, digestive stability, growth rate, release, thermal stability, and interactions of fibers with PRB), and the application of PRB-loaded fibers as active packaging (spoilage/microbial control, antioxidant effect, shelf life). Based on the literature reviewed, the incorporation of PRB into electrospun fibers is both feasible and functional. However, several studies have been limited to proof-of-principle experiments and the use of model biological products. It is necessary to conduct further research to establish the industrial applicability of PRB-loaded fibers, particularly in the fields of food and medicine.

Phenyl-quinoline derivatives as lead structure of cholinesterase inhibitors with potency to reduce the GSK-3ß level targeting Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to cognitive decline and memory loss. Unfortunately, there is no effective treatment for this condition, so there is a growing interest in developing new anti-AD agents. In this research project, a series of phenyl-quinoline derivatives were designed as potential anti-AD agents. These derivatives were substituted at two different positions on benzyl and phenyl rings. The structures of the derivatives were characterized using techniques such as IR spectroscopy, 1H NMR, 13C NMR, and elemental analysis. During the in vitro screening, the derivatives were tested against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). It was observed that most of the derivatives showed higher selectivity against BChE compared to AChE. Among the derivatives, analog 7n (with a methoxy group at R1 and a 4-bromine substituent at R2 exhibited the highest potency, with a 75-fold improvement in the activity compared to the positive control. Importantly, this potent analog demonstrated no toxicity at the tested concentration on SH-SY5Y cells, indicating its potential as a safe anti-AD agent. The level of GSK-3ß was also reduced after treatments with 7n at 50 µM. Overall, this study highlights the design and evaluation of phenyl-quinoline derivatives as promising candidates for developing novel anti-AD agents.

Design, synthesis, in vitro, and in silico biological evaluations of coumarin-indole hybrids as new anti-α-glucosidase agents.

BACKGROUND: A series of coumarin-indole hybrids was synthesized as the new α-glucosidase inhibitors. The title hybrids were considered as α-glucosidase inhibitors because had two active pharmacophores against α-glucosidase: coumarin and indole. METHODS: The thirteen various derivatives 4a-m were synthesized, purified, and fully characterized. These compounds were evaluated against α-glucosidase in vitro and in silico. In silico pharmacokinetic studies of the most potent compounds were also performed. RESULTS: Most of the title compounds exhibited high anti-α-glucosidase activity in comparison to standard drug acarbose. In particular, the phenoxy derivative 4d namely 3-((1H-indol-3-yl)(3-phenoxyphenyl)methyl)-4-hydroxy-2H-chromen-2-one showed promising activity. This compound is a competitive inhibitor against α-glucosidase and showed the lowest binding energy at the α-glucosidase active site in comparison to other potent synthesized compounds and acarbose. CONCLUSION: Compound 4d can be a lead compound for further structural development to obtain effective and potent α-glucosidase inhibitors.

Docking study, molecular dynamic, synthesis, anti-α-glucosidase assessment, and ADMET prediction of new benzimidazole-Schiff base derivatives.

The control of postprandial hyperglycemia is an important target in the treatment of type 2 diabetes mellitus (T2DM). As a result, targeting α-glucosidase as the most important enzyme in the breakdown of carbohydrates to glucose that leads to an increase in postprandial hyperglycemia is one of the treatment processes of T2DM. In the present work, a new class of benzimidazole-Schiff base hybrids 8a-p has been developed based on the potent reported α-glucosidase inhibitors. These compounds were synthesized by sample recantations, characterized by 1H-NMR, 13C-NMR, FT-IR, and CHNS elemental analysis, and evaluated against α-glucosidase. All new compounds, with the exception of inactive compound 8g, showed excellent inhibitory activities (60.1 ± 3.6-287.1 ± 7.4 µM) in comparison to acarbose as the positive control (750.0 ± 10.5). Kinetic study of the most potent compound 8p showed a competitive type of inhibition (Ki value = 60 µM). In silico induced fit docking and molecular dynamics studies were performed to further investigate the interaction, orientation, and conformation of the title new compounds over the active site of α-glucosidase. In silico druglikeness analysis and ADMET prediction of the most potent compounds demonstrated that these compounds were druglikeness and had satisfactory ADMET profile.

Design, synthesis, and molecular docking studies of diphenylquinoxaline-6-carbohydrazide hybrids as potent α-glucosidase inhibitors.

A novel series of diphenylquinoxaline-6-carbohydrazide hybrids 7a-o were rationally designed and synthesized as anti-diabetic agents. All synthesized compounds 7a-o were screened as possible α-glucosidase inhibitors and exhibited good inhibitory activity with IC50 values in the range of 110.6 ± 6.0 to 453.0 ± 4.7 µM in comparison with acarbose as the positive control (750.0 ± 10.5 µM). An exception in this trend came back to a compound 7k with IC50 value > 750 µM. Furthermore, the most potent derivative 7e bearing 3-fluorophenyl moiety was further explored by kinetic studies and showed the competitive type of inhibition. Additionally, the molecular docking of all derivatives was performed to get an insight into the binding mode of these derivatives within the active site of the enzyme. In silico assessments exhibited that 7e was well occupied in the binding pocket of the enzyme through favorable interactions with residues, correlating to the experimental results.

Rational Design, Synthesis, in Vitro, and in Silico Studies of Chlorophenylquinazolin-4(3H)-One Containing Different Aryl Acetohydrazides as Tyrosinase Inhibitors.

Tyrosinase plays a pivotal role in the hyperpigmentation and enzymatic browning of fruit and vegetable. Therefore, tyrosinase inhibitors can be of interest in industries as depigmentation compounds as well as anti-browning agents. In the present study, a series of chlorophenylquinazolin-4(3H)-one derivative were rationally designed and synthesized. The formation of target compounds was confirmed by spectral characterization techniques such as IR, 1 H-NMR, 13 C-NMR, and elemental analysis. Among the synthesized derivatives, compound 8l was proved to be the most potent inhibitor with an IC50 value of 25.48±1.19 µM. Furthermore, the results of the molecular docking study showed that this compound fitted well in the active site of tyrosinase with the binding score of -10.72.

Evaluating the effects of disubstituted 3-hydroxy-1H-pyrrol-2(5H)-one analog as novel tyrosinase inhibitors.

In the present study, a series of 3-hydroxy-1H-pyrrol-2(5H)-one derivative were rationally designed and synthesized. The structure of targeted compounds was confirmed by IR, 1H NMR, 13C NMR, and elemental analysis. Next, all derivatives were evaluated as tyrosinase inhibitors, and among the synthesized derivatives, compound 6a was proved to be the most potent inhibitor with an IC50 value of 6.98 ± 1.05 µM. Kinetic study of compound 6a confirmed the mixed type of inhibitory activity towards tyrosinase. Furthermore, the results of the molecular docking study showed that this compound fitted well in the active site of tyrosinase and exhibited interaction with important residues of the binding site.

Design, synthesis, and α-glucosidase-inhibitory activity of phenoxy-biscoumarin-N-phenylacetamide hybrids.

Thirteen new phenoxy-biscoumarin-N-phenylacetamide derivatives (7a-m) were designed based on a molecular hybridization approach as new α-glucosidase inhibitors. These compounds were synthesized with high yields and evaluated in vitro for their inhibitory activity against yeast α-glucosidase. The obtained results revealed that a significant proportion of the synthesized compounds showed considerable α-glucosidase-inhibitory activity in comparison to acarbose as a positive control. Representatively, 2-(4-(bis(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenoxy)-N-(4-bromophenyl)acetamide (7f), with IC50 = 41.73 ± 0.38 µM against α-glucosidase, was around 18 times more potent than acarbose (IC50 = 750.0 ± 10.0 µM). This compound was a competitive α-glucosidase inhibitor. Molecular modeling and dynamic simulation of these compounds confirmed the obtained results through in vitro experiments. Prediction of the druglikeness/ADME/toxicity of the compound 7f and comparison with the standard drug acarbose showed that the new compound 7f was probably better than the standard drug in terms of toxicity.

New quinoxalin-1,3,4-oxadiazole derivatives: Synthesis, characterization, in vitro biological evaluations, and molecular modeling studies.

A new series of quinoxalin-1,3,4-oxadiazole (10a-l) derivatives was synthesized and evaluated against some metabolic enzymes including human carbonic anhydrase (hCA) isoenzymes I and II (carbonic anhydrases I and II), cholinesterase (acetylcholinesterase and butyrylcholinesterase), and α-glucosidase. Obtained data revealed that all the synthesized compounds were more potent as compared with the used standard inhibitors against studied target enzymes. Among the synthesized compounds, 4-fluoro derivative (10f) against hCA I, 4-chloro derivative (10i) against hCA II, 3-fluoro derivative (10e) against acetylcholinesterase and butyrylcholinesterase, and 3-bromo derivative (10k) against α-glucosidase were the most potent compounds with inhibitory activity around 1.8- to 7.37-fold better than standard inhibitors. Furthermore, docking studies of these compounds were performed at the active site of their target enzymes.

Arylmethylene hydrazine derivatives containing 1,3-dimethylbarbituric moiety as novel urease inhibitors.

A new series of arylmethylene hydrazine derivatives bearing 1,3-dimethylbarbituric moiety 7a-o were designed, synthesized, and evaluated for their in vitro urease inhibitory activity. All the title compounds displayed high anti-urease activity, with IC50 values in the range of 0.61 ± 0.06-4.56 ± 0.18 µM as compared to the two standard inhibitors hydroxyurea (IC50 = 100 ± 0.15 µM) and thiourea (IC50 = 23 ± 1.7 µM). Among the synthesized compounds, compound 7h with 2-nitro benzylidene group was found to be the most potent compound. Kinetic study of this compound revealed that it is a mix-mode inhibitor against urease. Evaluation of the interaction modes of the synthesized compounds in urease active site by molecular modeling revealed that that compounds with higher urease inhibitor activity (7h, 7m, 7c, 7l, 7i, and 7o, with IC50 of 0.61, 0.86, 1.2, 1.34, 1.33, 1.94 µM, respectively) could interact with higher number of residues, specially Arg609, Cys592 (as part of urease active site flap) and showed higher computed free energy, while compounds with lower urease activity (7f, 7n, 7g, and 7a with IC50 of 3.56, 4.56, 3.62 and 4.43 µM, respectively) and could not provide the proper interaction with Arg609, and Cys592 as the key interacting residues along with lower free binding energy. MD investigation revealed compound 7h interacted with Arg609 and Cys592 which are of the key residues at the root part of mobile flap covering the active site. Interacting with the mentioned residue for a significant amount of time, affects the flexibility of the mobile flap covering the active site and causes inhibition of the ureolytic activity. Furthermore, in silico physico-chemical study of compounds 7a-o predicted that all these compounds are drug-likeness with considerable orally availability.

Quinazolinone-dihydropyrano[3,2-b]pyran hybrids as new α-glucosidase inhibitors: Design, synthesis, enzymatic inhibition, docking study and prediction of pharmacokinetic.

A series of new quinazolinone-dihydropyrano[3,2-b]pyran derivatives 10A-L were synthesized by simple chemical reactions and were investigated for inhibitory activities against α-glucosidase and α-amylase. New synthesized compounds showed high α-glucosidase inhibition effects in comparison to the standard drug acarbose and were inactive against α-amylase. Among them, the most potent compound was compound 10L (IC50 value = 40.1 ± 0.6 µM) with inhibitory activity around 18.75-fold more than acarboase (IC50 value = 750.0 ± 12.5 µM). This compound was a competitive inhibitor into α-glucosidase. Our obtained experimental results were confirmed by docking studies. Furthermore, the cytotoxicity of the most potent compounds 10L, 10G, and 10N against normal fibroblast cells and in silico druglikeness, ADME, and toxicity prediction of these compounds were also evaluated.

Design and synthesis of 4,5-diphenyl-imidazol-1,2,3-triazole hybrids as new anti-diabetic agents: in vitro α-glucosidase inhibition, kinetic and docking studies.

Fourteen novel 4,5-diphenyl-imidazol-1,2,3-triazole hybrids 8a-n were synthesized with good yields by performing click reaction between the 4,5-diphenyl-2-(prop-2-yn-1-ylthio)-1H-imidazole and various benzyl azides. The synthesized compounds 8a-n were evaluated against yeast α-glucosidase, and all these compounds exhibited excellent inhibitory activity (IC50 values in the range of 85.6 ± 0.4-231.4 ± 1.0 µM), even much more potent than standard drug acarbose (IC50 = 750.0 µM). Among them, 4,5-diphenyl-imidazol-1,2,3-triazoles possessing 2-chloro and 2-bromo-benzyl moieties (compounds 8g and 8i) demonstrated the most potent inhibitory activities toward α-glucosidase. The kinetic study of the compound 8g revealed that this compound inhibited α-glucosidase in a competitive mode. Furthermore, docking calculations of these compounds were performed to predict the interaction mode of the synthesized compounds in the active site of α-glucosidase. A novel series of 4,5-diphenyl-imidazol-1,2,3-triazole hybrids 8a-n was synthesized with good yields by performing click reaction between the 4,5-diphenyl-2-(prop-2-yn-1-ylthio)-1Himidazole and various benzyl azides. The synthesized compounds 8a-n were evaluated against yeast α-glucosidase and all these compounds exhibited excellent inhibitory activity (IC50 values in the range of 85.6 ± 0.4-231.4 ± 1.0 µM), even much more potent than standard drug acarbose (IC50 = 750.0 µM).

Design, synthesis, characterization, enzymatic inhibition evaluations, and docking study of novel quinazolinone derivatives.

In this study, novel quinazolinone derivatives 7a-n were synthesized and evaluated against metabolic enzymes including α-glycosidase, acetylcholinesterase, butyrylcholinesterase, human carbonic anhydrase I, and II. These compounds exhibited high inhibitory activities in comparison to used standard inhibitors with Ki values in the range of 19.28-135.88 nM for α-glycosidase (Ki value for standard inhibitor = 187.71 nM), 0.68-23.01 nM for acetylcholinesterase (Ki value for standard inhibitor = 53.31 nM), 1.01-29.56 nM for butyrylcholinesterase (Ki value for standard inhibitor = 58.16 nM), 10.25-126.05 nM for human carbonic anhydrase I (Ki value for standard inhibitor = 248.18 nM), and 13.46-178.35 nM for human carbonic anhydrase II (Ki value for standard inhibitor = 323.72). Furthermore, the most potent compounds against each enzyme were selected in order to evaluate interaction modes of these compounds in the active site of the target enzyme. Cytotoxicity assay of the title compounds 7a-n against cancer cell lines MCF-7 and LNCaP demonstrated that these compounds do not show significant cytotoxic effects.

Survey of protein-based sport supplements for illegally added anabolic steroids methyltestosterone and 4-androstenedione by UPLC-MS/MS.

There is some evidence that marketable supplements contain hormones not declared on the product label. The presence of these androgenic anabolic steroids (AAS) in sports supplements can be considered an adulteration and affect the health of consumers, who are predominantly athletes. This study aimed to measure anabolic hormones (methyltestosterone and 4-androstenedione) in sport supplements. Ultra Performance Liquid chromatography coupled mass spectrometry (UPLC-MS/MS) with electrospray ionization (ESI) in positive mode was employed under the Multiple Reaction Monitoring (MRM) ion program. To overcome matrix effects and quantify the selected analyte, the calibration curve was made using Matrix Match method. The LOQ and LOD were 1 ng/g and 0.3 ng/g for both analytes. The recovery of 4-androstenedione and methyltestosterone was in the range of 86.87-107.35 and 77.31-113.98, respectively. In terms of reproducibility, CV % for 4-androstenedione and methyltestosterone ranged from 6.56 to 16.87% and 1.45-15.12%, respectively. 4-androstenedione was found in 11 samples including 9 whey as 1.578 ±â€¯0.154 ng/g and 2 whey albumin samples with an amount of 1.134 ng/g and 1.474 ng/g. Consequently, continuous controlling of sport supplements comprising intentionally or unintentionally added androgens could be important for health and discuss in the context of compliance with anti-doping.

Comparison of UVA Protection Factor Measurement Protocols.

BACKGROUND: In the past, it was taught that UVA wavelengths (320- 400nm) only plays a major role in skin aging but recently the scientific researches also show that UVA cause cancerous keratinocyte cells in deep layer of the epidermis. Therefore, the protective ability of the product against UVA is important in addition to protection against UVB rays. The UVA protective factor (UVA-PF) is used to evaluate the effectiveness of sunscreen products against UVA rays. This study aims to review and compare all outstanding protocols in the field of UVA-PF measurement and finally the introduction of the best method of measuring UVA-PF based on the further benefits. MATERIALS AND METHODS: Four standards including ISO 24443 (AS/NZS 2604: 2012 recommended approach), CEN 2006, FDA 2007 and FDA 2011 are selected. RESULTS: In order to measure UVA-PF with in vivo method, two standards of CEN 2006 and FDA 2007 recommended persistent pigment darkening (PPD) method. Although the general principle of both is similar, there are some differences in detail. For in vitro measurement of UVA-PF, CEN and FDA 2011 standards use critical wavelengths. FDA 2007 introduces the modified Diffey fraction, and ISO 24443 standard meets the UVA-PF measurement in a manner that is consistent with PPD. CONCLUSION: Finally, this review discussed the comparison of all in vitro and in vivo UVA-PF measurement standards and provided information in the form of texts and tables to move towards the creation of an integrated standard. Since in vitro methods of UVA-PF measurement are not reproducible due to differences in test conditions, it may be concluded that the in vivo PPD method is a more suitable option.

Design and synthesis of new imidazo[1,2-b]pyrazole derivatives, in vitro α-glucosidase inhibition, kinetic and docking studies.

A new series of imidazo[1,2-b]pyrazole derivatives 4a-o was designed, synthesized, and screened for in vitro α-glucosidase inhibitory activity. All compounds showed high inhibitory activity in the range of IC50 = 95.0 ± 0.5-372.8 ± 1.0 µM as compared to standard drug acarbose (IC50 = 750 ± 1.5 µM) and were also found to be non-cytotoxic. Among the synthesized compounds, the most potent compound was compound 4j with eightfold higher inhibitory activity compared to acarbose. Like acarbose, compound 4j inhibited α-glucosidase in a competitive mode. Molecular modeling studies of the most potent compounds 4j, 4f, 4o, and 4c were also conducted.

Lovastatin alters neurotrophin expression in rat hippocampus­derived neural stem cells in vitro.

Neural stem/progenitor cells hold valuable potential for the treatment of neurodegenerative disorders. The modulation of intrinsic growth factor expression, such as neurotrophins and their receptors, is a necessary step in achieving neural stem cells (NSCs) therapy. The statins have recently been reported to provide both anti­inflammatory and neuroprotective effects. In the developing and mature nervous systems, neurotrophic factors are known to impact neuronal growth and survival. In this study, we investigated for a positive effect of lovastatin on the expression of neurotrophins in the neonatal rat hippocampus­derived NSCs. NSCs were isolated and cultured up to passage three. To confirm cellular identity, immunocytochemical evaluation and flow cytometry analysis were performed using specific antibodies. To determine the optimum concentration of lovastatin, the MTT assay was used. Neurotrophin expression was evaluated using quantitative real­time reverse transcription­polymerase chain reaction (RT­qPCR). Flow cytometry results demonstrated that NSCs were positive for nestin, a marker for neural progenitor cells. An increase in cellular viability was observed with a 24 h exposure of lovastatin. Moreover, results showed an increase in mRNA expression for all neurotrophins compared to the control group. Taken together, the results of this study add to the growing body of literature on the neuroprotective effects of statins in neurological disorders. Lovastatin is a promising therapeutic agent for the treatment of neurodegenerative disorders.