Cardiovascular diseases are one of the primary causes of deaths worldwide, and the development of atherosclerosis is closely related to hypercholesterolemia. As the reduction of the low‐density ...lipoprotein cholesterol level is critical for treating these diseases, the inhibition of 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A (HMG‐CoA) reductase, which is essentially responsible for cholesterol biosynthesis, stands out as a key solution to lower plasma cholesterol levels. In this study, we synthesized several dihydroxycoumarins and investigated their antioxidant and in vitro HMG‐CoA reductase inhibitory effects. Furthermore, we carried out in silico studies and examined the quantum‐chemical properties of the coumarin derivatives. We also performed molecular docking experiments and analyzed the binding strength of each coumarin derivative. Our results revealed that compound IV displayed the highest HMG‐CoA reductase inhibitory activity (IC50 = 42.0 µM) in vitro. Cupric‐reducing antioxidant capacity and ferric‐reducing antioxidant power assays demonstrated that coumarin derivatives exhibit potent antioxidant activities. Additionally, a close relationship was found between the lowest unoccupied molecular orbital energy levels and the antioxidant activities.
Five dihydroxycoumarins were synthesized and investigated for their antioxidant and in vitro 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A (HMG‐CoA) reductase inhibitory effects. The quantum‐chemical properties of the coumarin derivatives were explored and molecular docking was performed to determine the binding strength of each coumarin derivative. Compound IV displayed the highest HMG‐CoA reductase inhibitory activity, with IC50 = 42.0 µM.
A series of 3-aryl coumarin derivatives and 3-phenylazo-4-hydroxycoumarin were evaluated for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity by fluorometric enzymological ...assays. Among 21 coumarin derivatives, compound
21
(3-phenylazo-4-hydroxycoumarin) displayed a good inhibitory activity (0.12 ± 0.02 µM) and very high selectivity for MAO-B (SI > 833.33). The inhibition was determined as mixed-type and not time-dependent. Docking studies, molecular dynamics and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) calculations were performed to elucidate
in vitro
results. Our results reveal that the insertion of an azo linker between coumarin and phenyl rings in 3-arylcoumarins enhances MAO-B selectivity enormously since such a linker leads to the perfect alignment of the coumarin ring in the aromatic cage and the phenyl ring in the entrance cavity of MAO-B active site. Hydrogen bond interactions with Cys172 in the active site entrance of MAO-B also contributes to the remarkably higher inhibitory activity and selectivity for MAO-B.
The ability of Archaea to adapt their membrane lipid compositions to extreme environments has brought in archaeosomes into consideration for the development of drug delivery systems overcoming the ...physical, biological blockades that the body exhibits against drug therapies. In this study, we prepared unilamellar archaeosomes, from the polar lipid fraction extracted from Haloarcula 2TK2 strain, and explored its potential as a drug delivery vehicle. Rifampicin and isoniazid which are conventional drugs in tuberculosis medication were loaded separately and together in the same archaeosome formulation for the benefits of the combined therapy. Particle size and zeta potential of archaeosomes were measured by photon correlation spectroscopy, and the morphology was assessed by with an atomic force microscope. Encapsulation efficiency and loading capacities of the drugs were determined, and in vitro drug releases were monitored spectrophotometrically. Our study demonstrates that rifampicin and isoniazid could be successfully loaded separately and together in archaeosomes with reasonable drug‐loading and desired vesicle‐specific characters. Both of the drugs had greater affinity for archaeosomes than a conventional liposome formulation. The results imply that archaeosomes prepared from extremely halophilic archaeon were compatible with the liposomes for the development of stable and sustained release of antituberculosis drugs.
Unilamellar archaeosomes were prepared from the polar lipid fraction extracted from Haloarcula 2TK2 strain, and its potential as a drug delivery vehicle was explored using rifampicin and isoniazid. Particle size, zeta potential, morphology, encapsulation efficiency, and loading capacities of the archaeosomes were analyzed. The results demonstrated that rifampicin and isoniazid were successfully loaded in archaeosomes prepared from extremely halophilic archaeon, and the results were compatible with the liposomes for the development of stable and sustained release of antituberculosis drugs.
In this study, the inhibition potential of 3- and 4-arylcoumarin derivatives on
Theileria annulata
enolase (
Ta
ENO) was assessed for the first time in the literature. Firstly, protein stabilization ...analyses of
Ta
ENO were performed and it was found that the enzyme remains stable with the addition of 6 M ethylene glycol at + 4 °C. Inhibitor screening analyses were carried out using 25 coumarin derivatives on highly purified
Ta
ENO (> 95%), and four coumarin derivatives 4-(3,4-dimethoxyphenyl)-6,7-dihydroxy-2H-chromen-2-one (C8); 4-(3,4-dihydroxyphenyl)-7,8 dihydroxy-2H-chromen-2-one (C9); 4-(3,4-dihydroxyphenyl)-6,7-dihydroxy-2H-chromen-2 one (C21); and 3-(3,4-dihydroxyphenyl)-7,8-dihydroxy-2H-chromen-2-one (C23) showed the highest inhibitory effects with the IC
50
values of 10.450, 13.170, 8.871 and 10.863 µM, respectively. The kinetic results indicated that these compounds inhibited the enzyme by uncompetitive inhibition. In addition, the successful binding of the most potent inhibitor (C21) into
Ta
ENO was confirmed by using MALDI-TOF mass spectrophotometry. Molecular docking analyses have predicted that C8 and C21 coumarin derivatives which showed high inhibitory effects on
Ta
ENO were interacted with high affinity to the potential regions out of the active site. Taken together, these coumarin derivatives (C8, C9, C21 and C23) are first known potent, nonsubstrate, uncompetitive inhibitors of
Ta
ENO and these results will facilitate further in vitro and in vivo analysis toward structure-based drug design studies.
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Single enantiomers of the new 5-methyl-3-aryloxazolidine-2,4-diones have been obtained either by an asymmetric synthesis using the chiral pool strategy or by a semipreparative ...resolution of the racemic compound by HPLC on an optically active stationary phase. The single enantiomers were assayed for their in vitro monoamine oxidase (hMAO) inhibitory activity and selectivity. The most potent inhibitor among the studied compounds has been found as (5R)-3-phenyl-5-methyl-2,4-oxazolidinedione (compound 1-R) which appeared to be a good antidepressant drug candidate since it inhibited hMAO-A selectively, competitively and reversibly with Ki values in the micromolar range (0.16 ± 0.01 μM). To better understand the enzyme-inhibitor interaction and to explain the efficiency and selectivity of the compounds toward hMAOs, molecular modeling studies were carried out on new, high resolution hMAO-A and hMAO-B crystallographic structures. According to binding energies and inhibition constants obtained from molecular docking calculations, compound 1-R has been found as the most selective MAO-A inhibitor and its weak binding affinities to MAO-B (large Ki values) led to the enhancement in MAO-A selectivity. It bounded in close proximity to FAD in the active site of MAO-A and situated near the aromatic cage by means of π-alkyl interactions with Tyr407 and Phe352 whereas its position in MAO-B was 10 Å far from FAD and it was situated outside the Ile199 gate of the active site. None of the studied compounds showed any cytototoxicity on HepG2 cells at 1 and 5 µM concentrations.
The use of biopolymers has gained priority in tissue engineering and biotechnology, both as dressing material and for enhancing treatment efficiency. There is a demand for new biopolymers designed ...with protease inhibitors and antimicrobials. LL‐37 is an important antimicrobial peptide in human skin and exhibits a broad spectrum of antimicrobial activity against bacteria, fungi, and viral pathogens. Using lignin which is an abundant carbohydrate polymer in nature and a polyacrylic acid, we prepared a lignin/caprolactone biodegradable film by plastifying caprolactone and polyacyrlic acid. Lignin/caprolactone biodegradable film was activated with CDI and then immobilized LL‐37 peptide. The structure was elucidated in terms of its functional groups by attenuated total reflectance‐fourier transform infrared spectroscopy (ATR‐FTIR), and the morphology of the lignin/caprolactone biodegradable film was characterized by scanning electron microscopy (SEM) before and after the immobilization process. The amount of LL‐37 immobilized was determined by ELISA method. It was found that 97% of LL‐37 peptide was successfully immobilized onto the lignin/caprolactone biodegradable film. Antimicrobial activity was determined in the lignin/caprolactone biodegradable film samples by quantitative antimicrobial activity method. According to the results, LL‐37 immobilized lignin/caprolactone biodegradable film samples were effective on test organisms; Gram‐positive Staphylococcus aureus and Gram‐negative Escherichia coli. In bio‐compatibility assays, the ability to support tissue cell integration was detected by using 3 T3 mouse fibroblasts. Samples were examined under transverse microscope, non‐immobilized sample showed a huge cellular death, whereas LL‐37 immobilized lignin/caprolactone biodegradable film had identical cellular growth with the control group. This dual functional lignin/caprolactone biodegradable film with enhanced antibacterial properties and increased tissue cell compatibility may be used to design new materials for various types of biological applications.
The purpose of this study was to determine the antioxidant, radical‐scavenging, and acetylcholinesterase inhibitory capabilities of water and methanol extracts of Rhus coriaria L., Ocimum basilicum ...L., Rosmarinus officinalis L., Salvia officinalis L. and Thymbra spicata L., which are grown in the Hatay province of Turkey. Total antioxidant activities were evaluated using 2,2‐diphenyl‐1‐picrylhydrazyl (22–782.6 μg/mL EC50),·OH scavenging (3.93–33.43 μg/mL EC50), ferric (0.143–3.083 mmol trolox equivalent (TE)/g), and cupric‐reducing antioxidant power (0.143–3.083 mmol TE/g) assays. The phenolic composition of the methanolic extract of R. coriaria leaves was also investigated, and the active compound was identified as 4‐O‐methylgallic acid. The highest IC50 value of acetylcholinesterase inhibitory activity (1.17 ± 0.04 mg/mL) was observed in R. coriaria leaves. Principal component analysis showed that R. coriaria leaves possessed greater antioxidant and anti‐acetylcholinesterase potential as compared with the other evaluated plants.
Practical Applications
Antioxidants are widely used in the food industry to prevent the formation of toxic oxidation products and prolong shelf life. Because of increasing concern among consumers about the use of synthetic antioxidants, there has been a great interest in the identification and use of natural antioxidants. The present study reveals that Rhus coriaria leaves, which are not commonly used in Mediterranean cuisine, are a promising source of natural antioxidants and could be considered as a potential source of anti‐acetylcholinesterase agents and food preservatives.
Both the antioxidant and anti‐acetylcholinesterase effects of R. coriaria leaves may be beneficial in the treatment of Alzheimer's disease.
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•Quaternary metallophthalocyanines bind to DNA with good docking scores.•Attractive charge and π-anion interactions largely account for the strong affinity.•Molegro appears to be more ...capable than Autodock Vina in distinguishing metals.•Incorporation of metal to phthalocyanines enhances DNA-binding.•Quaternary substituents improve DNA-binding ability of MPcs.
Phthalocyanines are considered as good DNA binders, which makes them promising anti-tumor drug leads. The purpose of this study is to investigate the interactions between DNA and quaternary metallophthalocyanine derivatives (Q-MPc) possessing varying metals (M = Zn, Ni, Cu, Fe, Mg and Ca) by molecular docking since there seems to be a lack of information in the literature regarding this issue. In this direction, Autodock Vina and Molegro Virtual Docker programs were employed. Autodock Vina results reveal that each Q-MPc derivative binds to DNA strongly with similar binding energies and almost identical binding modes. They bind to the grooves of DNA by constituting favorable interactions between phosphate groups of DNA and Q-MPcs. Although changing the metal has no significant effect on binding, presence of quaternary amine substituents increases the binding constant Kb by about 2-fold comparing to the core Pc (ZnPc). Contrary to Autodock Vina, the calculated Molegro Virtual Docker binding scores have been more diverse indicating that the scoring function of Molegro is better in differentiating these metals. Despite the fact that Molegro is superior to Autodock Vina in terms of metal characterization, Autodock Vina and Molegro exhibit similar binding sites for the studied metallophthalocyanines. We propose that Q-MPc derivatives designed in this study are promising anti-tumor lead compounds since they tightly bind to DNA with considerably high Kb values. Cationic substituents and presence of metal have both positive effects on DNA binding which is critical for designing DNA-active drugs. Additional calculations employing molecular dynamics (MD) simulations verified the stability of Q-MPc-DNA complexes which remained in contact after 20 ns via attractive interactions mainly between DNA backbone and the Pc metal center.
Combination of Off-Stoichiometry Thiol-Ene (OSTE) polymers with thiol-ene “Click” reaction is a versatile method for the development of advanced functional materials. In this study OSTE based ...photocurable coating materials with excess thiol groups on the surface were prepared and functionalized with maleic anhydride via thiol-ene “Click” reaction. Xylanase enzyme was then covalently immobilized onto these coatings. Maleic anhydride functionalization of the prepared OSTE coatings was proved by FTIR and contact angle measurements. The developed functional support was found to have high affinity for xylanase enzyme and the immobilization capacity was determined as 212mgg−1. Almost 100% of immobilization yield was achieved. Immobilization significantly improved the stability of the xylanase at pH values over 6.5 and temperatures exceeding 60°C. Moreover the immobilized xylanase exhibited superior reusability and storage stability compared to free xylanase.
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•UV-curable hybrid epoxy-silica polymer films were prepared via sol–gel method.•Lipase from Candida rugosa was immobilized on polymer through covalent binding.•The hydrolytic and ...synthetic activities of lipase were investigated.•Kinetic properties of immobilized and free lipase were characterized.•Immobilization improved the thermal stability, storage stability and reusability.
In this study UV-curable hybrid epoxy-silica polymer films were prepared via sol–gel method. Lipase (EC 3.1.1.3) from Candida rugosa was covalently immobilized onto hybrid epoxy-silica polymer films and immobilization capacity of polymer films was found 7.22mgg−1. The morphology of the polymeric support was characterized by scanning electron microscopy (SEM) and Fourier Transform Infrared Spectroscopy (FTIR). Immobilized and free enzymes were used in two different reaction systems: hydrolysis of p-nitrophenyl palmitate in aqueous medium and synthesis of p-nitrophenyl linoleate (from p-nitrophenol and linoleic acid) in n-hexane medium. The effect of temperature on hydrolytic and synthetic activities was investigated and observed maximum activities at 50°C and 45°C for immobilized enzyme, orderly. Km values for free enzyme were determined 0.71 and 1.12mM by hydrolytic and synthetic activity assays, respectively, while these values were observed as 0.91mM and 1.19mM for immobilized enzyme.
At the end of 30 repeated cycles, 56% and 59% of initial activities remained for hydrolytic and synthetic assays, respectively. Native enzyme lost its activity completely within 20 days, whereas the immobilized enzyme retained for hydrolytic and synthetic activities was approximately 82% and 72%, respectively, under the same storage time.
