scholarly journals Evaluation of pharmacokinetic properties of isobornylphenols in silico

2020 ◽  
Vol 35 (4) ◽  
pp. 79-86
Author(s):  
O. I. Ostrikova ◽  
O. E. Vaizova ◽  
O. I. Aliev ◽  
E. V. Buravlev ◽  
I. Yu. Chukicheva ◽  
...  
Keyword(s):  
Toxicity Assessment ◽  
Pharmacokinetic Parameters ◽  
Structure Property ◽  
Solubility In Water ◽  
Virtual Tools ◽  
Internet Resources ◽  
P Glycoprotein ◽  
Pharmacokinetic Properties ◽  
Low Toxicity ◽  
Low Solubility

Introduction. The potential of a new compound in the ongoing drugs discovery process is initially explored using virtual instruments, where its activity is predicted based on its molecular structure.Aim. This study aimed to evaluate the pharmacokinetic parameters and possible toxicity of isobornyl compounds based on virtual tools.Material and Methods. Several free Internet resources were used to assess the absorption, distribution, metabolism, excretion (ADME), and toxicity (T) of 2,6-diisobornyl-4-methylphenol (1, Dibornol), 2-hydroxy-3-isobornyl-5-methylbenzaldehyde (2), and 2-((di-n-butylamino) methyl)-6-isobornyl-4-methylphenol (3). Pharmacokinetic properties were calculated on ADMETlab platform. Toxicity and physical properties were evaluated using TEST software based on the structure-property quantification models of organic substances according to structure–property principle. Web server ProTox_II was used for acute toxicity assessment.Results. Plasma protein binding degrees were 76,9% for (1), 85,9% for (2), and 91,8% for (3). All three compounds were capable of penetrating the blood-brain barrier. Dibornol was identified neither as a substrate nor as an inhibitor of P-glycoprotein unlike (2) and (3). The half-life of all compounds was short (about 2 hours); the clearance was slow (about 2 mL/min*kg). The study showed that (2) and (3) potentially exert the toxic effects during the developmental stage of the organism, while ADMETlab showed potential cardio- and hepatotoxicity for (2) and (3), respectively. All compounds had extremely low solubility in water, which affected the assessments of other indicators by TEST software. The ProTox_II server showed the extremely low toxicity LD50 for all compounds (toxicity class 5).

scholarly journals New Active Pharmaceutical Ingredient-Ionic Liquids (API-ILs) Derived from Indomethacin and Mebendazole

Proceedings ◽  
2018 ◽  
Vol 9 (1) ◽  
pp. 48 ◽  
Author(s):  
◽  
Emilia Tojo
Keyword(s):  
Ionic Liquids ◽  
Water Solubility ◽  
Methanesulfonic Acid ◽  
Active Pharmaceutical Ingredient ◽  
High Water ◽  
Solubility In Water ◽  
Pharmaceutical Ingredients ◽  
Low Toxicity ◽  
Low Solubility ◽  
High Water Solubility

The transformation of two solid Active Pharmaceutical Ingredients (APIs) into new ionic liquids (IL)s that incorporate APIs (API-ILs) is reported. The structures of the APIs (indomethacin and mebendazole) were selected by their susceptibility to being transformed into API-ILs (either to form the cation or the anion) and their limited bioavailability due to their low solubility in water. The counterions, such as those derived from 2-dimethylaminoethanol (DMEA), tetramethylguanidine (TMG), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2] (TED), <i>p</i>-toluensulfonic acid, glycolic acid, methanesulfonic acid, and saccharin, were carefully chosen, aiming for high biocompatibility, low toxicity, and high water solubility. The synthesis was carried out by direct treatment of the API with the corresponding selected acid or base. Finally, the solubility in water of all the synthesized salts was determined.

TOXICITY OF DIOCTYLTEREPHTHALATE

2018 ◽  
pp. 47-49 ◽  
Author(s):  
R. A. Mamonov ◽  
L. A. Fedotova ◽  
I. A. Pechnikova ◽  
T. D. Potapchenko
Keyword(s):  
Ambient Air ◽  
General Purpose ◽  
Threshold Concentration ◽  
Intragastric Administration ◽  
Exposure Level ◽  
Rural Settlements ◽  
Solubility In Water ◽  
Low Toxicity ◽  
Low Solubility ◽  
Biochemical Oxygen Consumption

Dioctylterephthalate is a general-purpose plasticizer, has low toxicity, and does not irritate the mucous membranes of the eye and the skin; the maximum nonlethal dose (DL0) for dioctylterephthalate after intragastric administration is set at 10,000 mg/kg. Indicative safe exposure level for dioctylterephthalate in ambient air in urban and rural settlements is recommended at 0.5 mg/m3. Substance has low acute toxicity; the maximum inactive dose is set at 4 mg/kg. The substance has low solubility in water (0.4 μg/l), does not affect the dynamics of biochemical oxygen consumption. Threshold concentration in water on organoleptic characteristic is set at 0.25 mg/l as for low hazard substances.

A Review on Camptothecin Analogs with Promising Cytotoxic Profile

2019 ◽  
Vol 18 (13) ◽  
pp. 1796-1814 ◽  
Author(s):  
Sk. Abdul Amin ◽  
Nilanjan Adhikari ◽  
Tarun Jha ◽  
Shovanlal Gayen
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Structure Property ◽  
Cytotoxic Potential ◽  
Structure Property Relationships ◽  
Structure Activity ◽  
Camptothecin Analogs ◽  
Pharmacokinetic Properties ◽  
Quantitative Structure Activity Relationships

Camptothecin (CPT), obtained from Camptotheca acuminata (Nyssaceae), is a quinoline type of alkaloid. Apart from various traditional uses, it is mainly used as a potential cytotoxic agent acting against a variety of cancer cell lines. Though searches have been continued for last six decades, still it is a demanding task to design potent and cytotoxic CPTs. Different CPT analogs are synthesized to enhance the cytotoxic potential as well as to increase the pharmacokinetic properties of these analogs. Some of these analogs were proven to be clinically effective in different cancer cell lines. In this article, different CPT analogs have been highlighted extensively to get a detail insight about the structure-property relationships as well as different quantitative structure-activity relationships (QSARs) modeling of these analogs are also discussed. This study may be beneficial for designing newer CPT analogs in future.

scholarly journals Peptide drugs for photopharmacology: how much of a safety advantage can be gained by photocontrol?

2020 ◽  
Vol 2 (1) ◽  
pp. FDD28 ◽  
Author(s):  
Oleg Babii ◽  
Sergii Afonin ◽  
Tim Schober ◽  
Liudmyla V Garmanchuk ◽  
Liudmyla I Ostapchenko ◽  
...  
Keyword(s):  
Chemotherapeutic Agent ◽  
In Vitro Cytotoxicity ◽  
Pharmacokinetic Parameters ◽  
Cancer Model ◽  
Pharmacokinetic Properties ◽  
Insight Into ◽  
Safety Advantage ◽  
Murine Cancer Model

Aim: To verify whether photocontrol of biological activity could augment safety of a chemotherapeutic agent. Materials & methods: LD50 values for gramicidin S and photoisomeric forms of its photoswitchable diarylethene-containing analogs were determined using mice. The results were compared with data obtained from cell viability measurements taken for the same compounds. Absorption, Distribution, Metabolism, and Elimination (ADME) tests using a murine cancer model were conducted to get insight into the underlying reasons for the observed in vivo toxicity. Results: While in vitro cytotoxicity values of the photoisomers differed substantially, the differences in the observed LD50 values were less pronounced due to unfavorable pharmacokinetic parameters. Conclusion: Despite unfavorable pharmacokinetic properties as in the representative case studied here, there is an overall advantage to be gained in the safety profile of a chemotherapeutic agent via photocontrol. Nevertheless, optimization of the pharmacokinetic parameters of photoisomers is an important issue to be addressed during the development of photopharmacological drugs.

S16020 pyridocarbazole derivatives display high activity to lung cancer cells

2021 ◽  
Vol 21 ◽  
Author(s):  
Gabriela Chabowska ◽  
Helena Moreira ◽  
Beata Tylińska ◽  
Ewa Barg
Keyword(s):  
Cell Viability ◽  
Anticancer Agents ◽  
Topoisomerase Ii ◽  
Wide Spectrum ◽  
A549 Cells ◽  
Biological Evaluation ◽  
Dna Intercalation ◽  
P Glycoprotein ◽  
Low Toxicity ◽  
And Migration

Background: Despite the dynamic development of medicine, globally cancer diseases remain the second leading cause of death. Therefore, there is a strong necessity to improve chemotherapy regimens and search for new anticancer agents. Pyridocarbazoles are compounds with confirmed antitumor properties based on multimodal mechanisms, i.a. DNA intercalation and topoisomerase II-DNA complex inhibition. One of them, S16020, displayed a wide spectrum of activity. Objective: The aim of the study was to investigate the antitumor potency of six S16020 derivatives, synthesized according to the SAR (structure-activity relationship) method. Methods: The biological evaluation included influence on cancer cell viability, proliferation, and migration, as well as P-glycoprotein activity. NHDF, A549, MCF-7, LoVo, and LoVo/DX cell lines were used in the study. Results: All derivatives displayed low toxicity to normal (NHDF) cells at 1 and 2 µM (≤ 20% of cell growth inhibition). The highest reduction in cell viability was noted in A549 cells which was accompanied by significant disruption of cells proliferation and motility. Compound 1 exhibited the strongest cytotoxic, antiproliferative, and antimigratory effects, higher than the reference olivacine. A significant reduction in P-glycoprotein activity was found for derivatives 6 and 1. Conclusion: S16020 derivatives could be considered as potential candidates for new anticancer drugs.

scholarly journals Study of fabomotizole belonging to p-glycoprotein substrates

2017 ◽  
Vol 25 (4) ◽  
pp. 538-550
Author(s):  
I. V. Chernykh ◽  
A. V. Shchulkin ◽  
E. N. Yakusheva ◽  
M. V. Gatsanoga ◽  
N. V Popova
Keyword(s):  
Neuroprotective Activity ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Test Substance ◽  
P Glycoprotein ◽  
Wide Range ◽  
Model Independent ◽  
Clinically Significant ◽  
Potential Substrate

P-glycoprotein (Pgp) is a membrane efflux protein transporter with numerous drug-substrates. In addition, a lot of drugs alter the activity of the transporter. It can lead to drug-drug interactions during polypharmacy. Fabomotizole (afobazol) is a Russian anxiolytic drug with neuroprotective activity, applied over a wide range of indications. The drug belongs to a potential substrate of Pgp according to its chemical structure. Aim. The aim of the study was to assess belonging of fabomotizole to Pgp substrates. Materials and Methods. The work was performed on 12 male Chinchilla rabbits. The belonging of fabomotizole to Pgp substrates was evaluated by comparing pharmacokinetic parameters of the test-substance after course administration of known transporter inducers and inhibitors – rifampicin and verapamil respectively. Fabomotizole was administered orally as a single dose of 3.8 mg/kg b.w. and blood was taken from the ear vein after 5, 10, 15, 20, 30, 60, 90, 120 and 240 min followed by it's pharmacokinetic analysis by HPLC. Pharmacokinetic parameters of fabomotizole were manually calculated by a model-independent method. The animals were then divided into 2 groups of 6 rabbits each: the 1st group received verapamil at a dose 20 mg/kg b.w. 3 times a day for 14 days, the 2nd – rifampicin in a similar course and dose. After the administration of Pgp modulators the pharmacokinetics of fabomotizole were re-analyzed. Results. It was found that only the absorption coefficient of fabomotizole in the rifampicin series was significantly reduced by 1.27 times as compared to the parameter of intact animals (90% CI 0.66-0.94, p=0.04322). However, this change was not clinically significant, because 90% CI overlapped the range of 0.80-1.25, noted by FDA. The remaining pharmacokinetic parameters of Pgp marker substrate were not significantly changed in any series. This is evidence that fabomotizole is not a Pgp substrate. The insignificant participation of Pgp in fabomotizole pharmacokinetics testifies that the drug can be administered together with drug-modulators of transporter activity without dose correction. Conclusion. In vivo experiment on Chinchilla rabbits showed that fabomotizole is not a substrate of P-glycoprotein.

scholarly journals Ruthenacarborane–Phenanthroline Derivatives as Potential Metallodrugs

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2322
Author(s):  
Martin Kellert ◽  
Imola Sárosi ◽  
Rajathees Rajaratnam ◽  
Eric Meggers ◽  
Peter Lönnecke ◽  
...  
Keyword(s):  
Single Crystal ◽  
Diffraction Analysis ◽  
Organic Solvents ◽  
Side Product ◽  
Ambient Conditions ◽  
Carbonyl Ligand ◽  
Single Crystal Diffraction ◽  
Solubility In Water ◽  
Low Solubility

Ruthenium-based complexes have received much interest as potential metallodrugs. In this work, four RuII complexes bearing a dicarbollide moiety, a carbonyl ligand, and a phenanthroline-based ligand were synthesized and characterized, including single crystal diffraction analysis of compounds 2, 4, and 5 and an observed side product SP1. Complexes 2–5 are air and moisture stable under ambient conditions. They show excellent solubility in organic solvents, but low solubility in water.

scholarly journals Quantitative Structure–Activity Relationships for the Flavonoid-Mediated Inhibition of P-Glycoprotein in KB/MDR1 Cells

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1661 ◽  
Author(s):  
Mengmeng Xia ◽  
Yajing Fang ◽  
Weiwei Cao ◽  
Fuqiang Liang ◽  
Siyi Pan ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Quantitative Structure ◽  
Glycoprotein P ◽  
Chemotherapy Drugs ◽  
Structure Activity ◽  
P Glycoprotein ◽  
Daily Diet ◽  
Low Toxicity

P-glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance (MDR) in cancer cells. In order to enhance the uptake of chemotherapy drugs, larger amounts of P-gp inhibitors are required. Besides several chemically synthesized P-gp inhibitors, flavonoids as P-gp inhibitors are being investigated, with their advantages including abundance in our daily diet and a low toxicity. The cytotoxicity of daunorubicin (as a substrate of P-gp) to KB/MDR1 cells and the parental KB cells was measured in the presence or absence of flavonoids. A two-dimensional quantitative structure–activity relationship (2D-QSAR) model was built with a high cross-validation coefficient (Q2) value of 0.829. Descriptors including vsurf_DW23, E_sol, Dipole and vsurf_G were determined to be related to the inhibitory activity of flavonoids. The lack of 2,3-double bond, 3′-OH, 4′-OH and the increased number of methoxylated substitutions were shown to be beneficial for the inhibition of P-gp. These results are important for the screening of flavonoids for inhibitory activity on P-gp.

scholarly journals Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

Science ◽  
2020 ◽  
Vol 368 (6497) ◽  
pp. 1331-1335 ◽  
Author(s):  
Wenhao Dai ◽  
Bing Zhang ◽  
Xia-Ming Jiang ◽  
Haixia Su ◽  
Jian Li ◽  
...  
Keyword(s):  
Antiviral Drug ◽  
X Ray ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Main Protease ◽  
Pharmacokinetic Properties ◽  
Key Enzyme ◽  
Low Toxicity ◽  
Aldehyde Groups

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.

Uptake and Excretion of Chemicals by Aquatic Fauna

1983 ◽  
Vol 15 (S1) ◽  
pp. 67-78
Author(s):  
V Zitko
Keyword(s):  
Molecular Weight ◽  
Flame Retardants ◽  
Physiological State ◽  
Compartment Model ◽  
Solubility In Water ◽  
Aquatic Fauna ◽  
Chlorinated Paraffins ◽  
A Minor ◽  
Low Solubility

Factors influencing the movement of chemicals across biological membranes are: solubility in lipids and in water, chemical stability, ionization, and molecular weight of the chemical. On the part of aquatic fauna, the transport of chemicals is affected by metabolic activity and by the physiological state of the animals. Additional factors include water temperature, hardness or salinity, and presence of other chemicals. The effects of these factors will be discussed and illustrated by examples. The uptake of highly lipid-soluble compounds by fish appears to be determined by their solubility in water, and compounds with extremely low solubility in water are not taken up in spite of their high solubility in lipids. Examples are hexabromo-benzene, highly brominated biphenyls, C24 chlorinated paraffins, and some flame retardants of the Dechlorane series. In addition to solubility in water, there may be a high molecular weight threshold, beyond which compounds are not taken up, and factors based on the chemical structure of the compounds may play a role as well. For example, Dechlorane 604, a tetrabromophenyl norbornene, is accumulated by fish to a much lesser degree than a tribromophenyl norbornene, present as a minor impurity in Dechlorane 604. Chemical and biochemical stability of compounds are additional factors determining the extent of environmental contamination. Examples are the widespread contamination of aquatic biota by two nonachlors, present originally as relatively minor components in technical chlordane, and the contamination by some components of toxaphene. The use of a one compartment model in studies of accumulation and excretion of chemicals by aquatic fauna, and its extension to the determination of lethality curves, will be mentioned.

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