scholarly journals Biophysical Evaluation and In Vitro Controlled Release of Two Isomeric Adamantane Phenylalkylamines with Antiproliferative/Anticancer and Analgesic Activity

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 7
Author(s):  
Marilena Vlachou ◽  
Angeliki-Sofia Foscolos ◽  
Angeliki Siamidi ◽  
Angeliki Syriopoulou ◽  
Nikitas Georgiou ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Minimum Energy ◽  
Md Simulations ◽  
2D Nmr ◽  
Dissolution Profile ◽  
Plasma Stability ◽  
Aromatic Rings ◽  
Compound I ◽  
Compound Ii

The aqueous dissolution profile of the isomeric synthetic adamantane phenylalkylamine hydrochlorides I and II was probed. These adducts have shown significant antiproliferative/anticancer activity associated with an analgesic profile against neuropathic pain. They are both devoid of toxic effects and show appreciable enzymatic human plasma stability. The structures of these two compounds have been elucidated using 2D NMR experiments, which were used to study their predominant conformations. Compound II’s scaffold appeared more flexible, as shown by the NOE spatial interactions between the alkyl bridge chain, the aromatic rings, and the adamantane nucleus. Conversely, compound I appeared very rigid, as it did not share significant NOEs between the aforementioned structural segments. MD simulations confirmed the NOE results. The aqueous dissolution profile of both molecules fits well with their minimum energy conformers’ features, which stem from the NOE data; this was nicely demonstrated, especially in the case of compound II.

Transformations of the Herbicide N-(1,1-dimethylpropynyl)-3,5-dichlorobenzamide in Soil

Weed Science ◽  
1970 ◽  
Vol 18 (5) ◽  
pp. 604-607 ◽  
Author(s):  
Roy Y. Yih ◽  
Colin Swithenbank ◽  
D. Harold McRae
Keyword(s):  
Soil Moisture ◽  
High Temperature ◽  
Soil Moisture Content ◽  
Chemical Change ◽  
Herbicidal Activity ◽  
Compound I ◽  
Subsequent Hydrolysis ◽  
Compound Ii ◽  
Hydrolysis Of

Transformation of N-(1,1-dimethylpropynyl)-3,5-dichlorobenzamide (compound I) in soil occurs readily and two products are produced, initial cyclization giving 2-(3,5-dichlorophenyl)-4,4-dimethyl-5-methyleneoxazoline (compound II) followed by subsequent hydrolysis to N-(1,1-dimethylacetonyl)-3,5-dichlorobenzamide (compound III). These transformations can be brought aboutin vitro, the first step by means of acid or base, and the second by extended treatment with acid. The rate of cyclization and hydrolysis of compound I varies directly with soil temperature, being rapid at high temperature (37 C) and very slow at low temperature (5 C). The rate of chemical change of compound I in soil is influenced to a much greater degree by temperature than by soil moisture content. The effect of soil type on transformation of compound I was studied and compounds II and III were present in five of the six soils examined. The herbicidal activity of compounds II and III was negligible in comparison to compound I.

scholarly journals Co-crystallization of quercetin and isonicotinamide using solvent evaporation method

2021 ◽  
Vol 18 (4) ◽  
pp. 697-702
Author(s):  
Budipratiwi Wisudyaningsih ◽  
Dwi Setyawan ◽  
Siswandono
Keyword(s):  
Minimum Energy ◽  
Solvent Evaporation ◽  
Crystal Habit ◽  
In Vitro Dissolution ◽  
Molar Ratio ◽  
Dissolution Profile ◽  
Solvent Evaporation Method ◽  
Scanning Calorimetry ◽  
Evaporation Method

Purpose: To obtain quercetin-isonicotinamide co-crystal (CQINA) with improved physicochemical and in-vitro dissolution characteristics. Methods: Co-crystallization of quercetin (Q) and isonicotinamide (INA) in molar ratio of 1:1 was performed using solvent evaporation method with the addition of 50 mL of ethanol (99.9%, v/v). The resultant solution was thoroughly mixed and stirred at room temperature for 48 h to slowly evaporate the solvent until CQINA was obtained. The co-crystal phase was characterized using differential scanning calorimetry (DSC), powder x-ray diffractometry (PXRD), scanning electron microscopy (SEM), and fourier transform infrared (FTIR) spectroscopy. In-vitro dissolution was performed by USP method II in 900 mL citrate buffer (pH 5.0 ± 0.05), with stirring at 100 rpm and at 37 ± 0.5 °C. Results: Computational approach predicted the formation of hydrogen bonds between Q and coformers used, and the interaction involved minimum energy. In CQINA thermogram, a new endothermic peak was formed with a melting point of 255.26 °C, while Q (314.85 °C) and INA (156.62 °C). Images from DSC, PXRD, SEM and FTIR showed that the crystal habits and morphologies of the CQINA differed from those of the original components. There was an improvement in the dissolution profile of CQINA, when compared with those of the original components. Conclusion: Q and INA subjected to solvent evaporation result in the formation of a CQINA with different crystal habit, which possess physicochemical characteristics different from those of its constituents. Modification of Q crystals in CQINA increases its in vitro dissolution, making it a potential pharmaceutical agent.

scholarly journals Mechanism of Brain Targeting by Dexibuprofen Prodrugs Modified with Ethanolamine-Related Structures

2015 ◽  
Vol 35 (12) ◽  
pp. 1985-1994 ◽  
Author(s):  
Yanping Li ◽  
Yangyang Zhou ◽  
Jiayu Jiang ◽  
Xinyi Wang ◽  
Yao Fu ◽  
...  
Keyword(s):  
Passive Diffusion ◽  
Brain Targeting ◽  
Active Process ◽  
Compound I ◽  
In Situ Perfusion ◽  
Capillary Endothelial Cells ◽  
In Vitro Bbb Model ◽  
Compound Ii ◽  
The Brain

The first molecular insights into how prodrugs modified with ethanolamine-related structures target the brain were generated using an in vitro BBB model and in situ perfusion technique. Prodrugs were delivered safely and efficiently to the brain through tight interaction with the anionic membrane of brain capillary endothelial cells, observed as a shift in zeta potential, followed by uptake into the cells. Prodrugs III and IV carrying primary and secondary amine modifications appeared to enter the brain via energy-independent passive diffusion. In contrast, besides the passive diffusion, prodrugs I and II carrying tertiary amine modifications also appeared to enter via an active process that was energy and pH dependent but was independent of sodium or membrane potential. This active process involved, at least in part, the pyrilamine-sensitive H+/OC antiporter, for which the N,N-diethyl-based compound II showed a much lower affinity than the N,N-dimethyl-based compound I, likely due to steric hindrance. These new insights into brain-targeting mechanisms may help guide efforts to design new prodrugs.

scholarly journals 1,2,4-triazole derivatives with morpholine; DFT study and antileishmanial activity

2018 ◽  
Vol 96 (7) ◽  
pp. 719-723
Author(s):  
Nevin Süleymanoğlu ◽  
Reşat Ustabaş ◽  
Şahin Direkel ◽  
Yelda Bingöl Alpaslan ◽  
Yasemin Ünver
Keyword(s):  
Density Functional ◽  
Antileishmanial Activity ◽  
Basis Set ◽  
Blue Dye ◽  
Compound I ◽  
Spectral Parameters ◽  
Standard Drug ◽  
Triazole Derivatives ◽  
Compound Ii

1,2,4-triazole derivatives with morpholine; 4-((3-methylthiophene–2-yl)methylenamino)-1-((4-(3-methylthiophene–2-yl)methylene amino)-1-(morpholinomethyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)methyl)-3-(thiophene–2-ylmethyl)-1H-1,2,4-triazole-5(4H)-one (compound I) and 1-((1-(morpholinomethyl)–4-(5-nitrothiophene–2-yl)methyleneamino)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)methyl)-4-((5-nitrothiophene–2-yl)methyleneamino)-3-(thiophene–2-ylmethyl)-1H-1,2,4-triazole-5(4H)-one (compound II), were optimized using a density functional theory (DFT) method with 6-311G(d,p) basis set and structural and spectral parameters were determined. In vitro antileishmanial activities of compounds were performed against Leishmania infantum promastigots by microdilution broth assay with Alamar Blue dye. Amphotericin B was used as standard drug. The results show that both compounds are antiparasitic and especially compound II has considerable antileishmanial activity due to the minimal inhibitory concentration value of 312 μg/mL.

PERILAKU DISOLUSI KETOPROFEN DAN INDOMETASIN FARNESIL TERSALUT GEL KITOSAN-GOM GUAR

2012 ◽  
Vol 12 (1) ◽  
Author(s):  
Purwantiningsih Sugita ◽  
Bambang Srijanto ◽  
Budi Arifin ◽  
Fithri Amelia ◽  
Mahdi Mubarok
Keyword(s):  
Room Temperature ◽  
Guar Gum ◽  
Tween 80 ◽  
Chitosan Solution ◽  
In Vitro Dissolution ◽  
Dissolution Profile ◽  
Magnetic Stirrer ◽  
Dissolution Behaviour ◽  
Shrimp Shell Waste

Chitosan, a modification of shrimp-shell waste, has been utilized as microcapsule. However, it’s fragile gel property needs to be strengthened by adding glutaraldehyde (glu) and natural hydrocolloid guar gum (gg). This research’s purposes were to study dissolution behaviour of ketoprofen and infar through optimum chitosan-guar gum microcapsule. Into 228.6 mL of 1.75% (w/v) chitosan solution in 1% (v/v) acetic acid,38.1 mL of gg solution was added with concentration variation of 0.35, 0.55, and 0.75% (w/v) for ketoprofen microcapsules and 0.05, 0.19, and 0.33% (w/v) for infar microcapsules, and stirred with magnetic stirrer until homogenous. Afterwards, 7.62mL of glu was added slowly under stirring, with concentrations varied: 3, 3.5, and 4% (v/v) for ketoprofen microcapsules, and 4, 4.5, and 5% (v/v) for infar microcapsules. All mixtures were shaked for 20 minutes for homogenization. All mixtures wereshaked for 20 minutes for homogenization. Into each  microcapsule mixture for ketoprofen, a solution of 2 g of ketoprofen in 250 mL of 96% ethanol was added, whereas solution of 100 mg of in 250 mL of 96% ethanol was added into each microcapsule mixture for infar. Every mixture was then added with 5 mL of 2% Tween-80 and stirred with magnetic stirrer for an hour at room temperature. Everymixture was then added with 5 mL of 2% Tween-80 and stirred with magnetic stirrer for an hour at room temperature. Conversion of suspension into fine powders/granules (microcapsules) was done by using spray dryer. The data of [gg], [glu], and medicine’s content from each microcapsule were treated with Minitab 14 software to obtain optimum [gg] and [glu] for microencapsulation. The dissolution behaviour of optimum ketoprofen and infar microcapsules were investigated. The result of optimization by using Minitab Release 14 software showed that among the microcapsule compositions of [gg] and [glu] were 0.35% (w/v) and 3.75% (v/v), respectively, optimum to coat ketoprofen, whereas [gg] and [glu] of 0.05% (w/v) and4.00% (v/v), respectively, optimum to coat infar, at constant chitosan concentration (1.75% [w/v]). In vitro dissolution profile showed that chitosan-guar gum gel microcapsule was more resistant in intestinal pH condition (rather basic) compared with that in gastric pH (very acidic).

Formulation and Evaluation of Immediate Release Bilayer Tablets of Telmisartan and Hydrochlorothiazide

2011 ◽  
Vol 4 (3) ◽  
pp. 1477-1483
Author(s):  
Natarajan R ◽  
N Patel ◽  
Rajendran N N ◽  
M Rangapriya
Keyword(s):  
Antihypertensive Drugs ◽  
In Vitro Release ◽  
Immediate Release ◽  
Wet Granulation ◽  
Physical Parameters ◽  
Dissolution Profile ◽  
Formulation Development ◽  
Sodium Starch Glycolate ◽  
Bilayer Tablets

The main goal of this study was to develop a stable formulation of antihypertensive drugs telmisartan and hydrochlorothiazide as an immediate-release bilayer tablet and to evaluate the dissolution profile in comparison with a reference product. The formulation development work was initiated with wet granulation. Telmisartan was converted to its sodium salt by dissolving in aqueous solution of sodium hydroxide to improve solubility and drug release. Lactose monohydrate and microcrystalline cellulose were used as diluents. Starch paste is prepared in purified water and was used as the binder. Sodium starch glycolate is added as a disintegrating agent. Magnesium stearate was used as the lubricant. The prepared granules were compressed into a double-layer compression machine. The tablets thus formulated with higher proportion of sodium starch glycolate showed satisfactory physical parameters, and it was found to be stable and in vitro release studies are showed that formulation (F-T5H5) was 101.11% and 99.89% respectively. The formulation T5H5 is further selected and compared with the release profile of the innovator product, and was found to be similar (f2 factor) to that of the marketed product. The results suggest the feasibility of developing bilayer tablets consisting of telmisartan and hydrochlorothiazide for the convenience of patients with hypertension.  

In Silico and in Vitro Evaluation of Deamidation Effects on the Stability of the Fusion Toxin DAB389IL-2

2019 ◽  
Vol 16 (4) ◽  
pp. 307-313 ◽  
Author(s):  
Nasrin Zarkar ◽  
Mohammad Ali Nasiri Khalili ◽  
Fathollah Ahmadpour ◽  
Sirus Khodadadi ◽  
Mehdi Zeinoddini
Keyword(s):  
In Silico ◽  
Catalytic Domain ◽  
Md Simulations ◽  
Special Importance ◽  
Native Form ◽  
Vitro Experiment ◽  
In Vitro Experiment ◽  
Pharmaceutical Protein ◽  
The Stability

Background: DAB389IL-2 (Denileukin diftitox) as an immunotoxin is a targeted pharmaceutical protein and is the first immunotoxin approved by FDA. It is used for the treatment of various kinds of cancer such as CTCL lymphoma, melanoma, and Leukemia but among all of these, treatment of CTCL has special importance. DAB389IL-2 consists of two distinct parts; the catalytic domain of Diphtheria Toxin (DT) that genetically fused to the whole IL-2. Deamidation is the most important reaction for chemical instability of proteins occurs during manufacture and storage. Deamidation of asparagine residues occurs at a higher rate than glutamine residues. The structure of proteins, temperature and pH are the most important factors that influence the rate of deamidation. Methods: Since there is not any information about deamidation of DAB389IL-2, we studied in silico deamidation by Molecular Dynamic (MD) simulations using GROMACS software. The 3D model of fusion protein DAB389IL-2 was used as a template for deamidation. Then, the stability of deamidated and native form of the drug was calculated. Results: The results of MD simulations were showed that the deamidated form of DAB389IL-2 is more unstable than the normal form. Also, deamidation was carried by incubating DAB389IL-2, 0.3 mg/ml in ammonium hydrogen carbonate for 24 h at 37o C in order to in vitro experiment. Conclusion: The results of in vitro experiment were confirmed outcomes of in silico study. In silico and in vitro experiments were demonstrated that DAB389IL-2 is unstable in deamidated form.

Assessing the Antimalarial Potentials of Phytochemicals: Virtual Screening, Molecular Dynamics and In-Vitro Investigations

2019 ◽  
Vol 16 (3) ◽  
pp. 291-300
Author(s):  
Saumya K. Patel ◽  
Mohd Athar ◽  
Prakash C. Jha ◽  
Vijay M. Khedkar ◽  
Yogesh Jasrai ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Structural Integrity ◽  
Md Simulations ◽  
Tylophora Indica ◽  
Multidrug Resistance Protein 1 ◽  
Receptor Complexes ◽  
Resistance Protein ◽  
Dynamics Simulations ◽  
Stable Trajectory

Background: Combined in-silico and in-vitro approaches were adopted to investigate the antiplasmodial activity of Catharanthus roseus and Tylophora indica plant extracts as well as their isolated components (vinblastine, vincristine and tylophorine). </P><P> Methods: We employed molecular docking to prioritize phytochemicals from a library of 26 compounds against Plasmodium falciparum multidrug-resistance protein 1 (PfMDR1). Furthermore, Molecular Dynamics (MD) simulations were performed for a duration of 10 ns to estimate the dynamical structural integrity of ligand-receptor complexes. </P><P> Results: The retrieved bioactive compounds viz. tylophorine, vinblastin and vincristine were found to exhibit significant interacting behaviour; as validated by in-vitro studies on chloroquine sensitive (3D7) as well as chloroquine resistant (RKL9) strain. Moreover, they also displayed stable trajectory (RMSD, RMSF) and molecular properties with consistent interaction profile in molecular dynamics simulations. </P><P> Conclusion: We anticipate that the retrieved phytochemicals can serve as the potential hits and presented findings would be helpful for the designing of malarial therapeutics.

DPP-IV Inhibitory Phenanthridines: Ligand, Structure-Based Design and Synthesis

2020 ◽  
Vol 16 (3) ◽  
pp. 295-307
Author(s):  
Reema A. Khalaf ◽  
Dalal Masalha ◽  
Dima Sabbah
Keyword(s):  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Ligand Docking ◽  
Health Concern ◽  
Aromatic Rings ◽  
Oral Antidiabetic Agents ◽  
Design And Synthesis ◽  
Dpp Iv ◽  
Novel Scaffold

Background: Lately, diabetes has become the main health concern for millions of people around the world. Dipeptidyl peptidase-IV (DPP-IV) inhibitors have emerged as a new class of oral antidiabetic agents. Formerly, acridines, N4-sulfonamido-succinamic, phthalamic, acrylic and benzoyl acetic acid derivatives, and sulfamoyl-phenyl acid esters were designed and developed as new DPP-IV inhibitors. Objective: This study aims to develop a pharmacophore model of DPP-IV inhibitors and to evaluate phenanthridines as a novel scaffold for inhibiting DPP-IV enzyme. In addition, to assess their binding interactions with the enzyme through docking in the binding site of 4A5S (PDB). Methods: Herein, Quantum–Polarized Ligand Docking (QPLD) and ligand-based pharmacophore modeling investigations were performed. Three novel 3,8-disubstituted-6-phenyl phenanthridine derivatives 3-5 have been designed, synthesized and characterized. In vitro biological testing against DPP-IV was carried out using fluorometric assay kit. Results: QPLD study demonstrates that compounds 3-5 forms H-bond with Lys554, Trp629, and Tyr631, besides charge transfer interaction between their aromatic rings and the aromatic rings of Tyr547 and Tyr666. Moreover, they fit the three pharmacophoric point features of DPP-IV inhibitors and were proven to have in vitro DPP-IV inhibitory activity where compound 5 displayed a % inhibition of 45.4 at 100 μM concentration. Conclusion: Phenanthridines may serve as a potential lead compound for developing new DPP-IV inhibitors as a promising antidiabetic agent. Computational results suggest future structural simplification.

Targeting Breast Cancer Cells with G4 PAMAM Dendrimers and Valproic Acid Derivative Complexes

2020 ◽  
Vol 20 (15) ◽  
pp. 1857-1872
Author(s):  
Alberto M. Muñoz ◽  
Manuel J. Fragoso-Vázquez ◽  
Berenice P. Martel ◽  
Alma Chávez-Blanco ◽  
Alfonso Dueñas-González ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Cell Lines ◽  
Water Solubility ◽  
Md Simulations ◽  
Pamam Dendrimer ◽  
Pamam Dendrimers ◽  
Force Microscopy ◽  
Micromolar Concentration ◽  
Atomic Force

Background: Our research group has developed some Valproic Acid (VPA) derivatives employed as anti-proliferative compounds targeting the HDAC8 enzyme. However, some of these compounds are poorly soluble in water. Objective: Employed the four generations of Polyamidoamine (G4 PAMAM) dendrimers as drug carriers of these compounds to increase their water solubility for further in vitro evaluation. Methods: VPA derivatives were subjected to Docking and Molecular Dynamics (MD) simulations to evaluate their affinity on G4 PAMAM. Then, HPLC-UV/VIS, 1H NMR, MALDI-TOF and atomic force microscopy were employed to establish the formation of the drug-G4 PAMAM complexes. Results: The docking results showed that the amide groups of VPA derivatives make polar interactions with G4 PAMAM, whereas MD simulations corroborated the stability of the complexes. HPLC UV/VIS experiments showed an increase in the drug water solubility which was found to be directly proportional to the amount of G4 PAMAM. 1H NMR showed a disappearance of the proton amine group signals, correlating with docking results. MALDI-TOF and atomic force microscopy suggested the drug-G4 PAMAM dendrimer complexes formation. Discussion: In vitro studies showed that G4 PAMAM has toxicity in the micromolar concentration in MDAMB- 231, MCF7, and 3T3-L1 cell lines. VPA CF-G4 PAMAM dendrimer complex showed anti-proliferative properties in the micromolar concentration in MCF-7 and 3T3-L1, and in the milimolar concentration in MDAMB- 231, whereas VPA MF-G4 PAMAM dendrimer complex didn’t show effects on the three cell lines employed. Conclusion: These results demonstrate that G4 PAMAM dendrimers are capableof transporting poorly watersoluble aryl-VPA derivate compounds to increase its cytotoxic activity against neoplastic cell lines.

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