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Introduction: We developed and produced a new series of 4,6-diaryl-pyrimidines 9–29 as antiproliferative agents targeting EGFR/VEGFR-2. Methods: The antiproliferative efficacy of the novel targets was assessed against a panel of 60 NCI cancer cell lines and four cancer cell lines in vitro. Results and Discussion: Compounds 14 , 17 , 19 , 22 , 25 , and 29 demonstrated the greatest potency among the derivatives, with GI50 values between 22 and 33 nM; compounds 22 and 29 exhibited the highest potency, with GI50 values of 22 and 24 nM, respectively. We subsequently examined the most efficient derivatives as dual EGFR/VEGFR-2 inhibitors, finding that compounds 22 and 29 functioned as dual inhibitors. Moreover, 22 and 29 can act as apoptotic inducers by increasing Bax levels and decreasing levels of the anti-apoptotic protein Bcl2. At both 24- and 48-h intervals, the cell migration rates of compounds 22 and 29 were lower than those of untreated cells, according to the migration rate and wound closure percentage assessment. The wound closure rate reached 100% after 72 h of therapy with compound 22 but only 80% with compound 29. The docking study showed that compounds 22 and 29 had docking scores similar to those of Erlotinib and Sorafenib, co-crystallized ligands, for the EGFR and VEGFR-2 proteins. The experiments on lipophilicity showed that the new pyrimidines had a consistent result. This group of compounds has better biological activity in all the biological systems studied with low lipophilicity. [ABSTRACT FROM AUTHOR]

Background: The triazole ring is an attractive structural unit in medicinal chemistry, and chemical compounds containing this type of system in their structure exhibit a wide spectrum of biological activity. They are used in the development of new pharmaceuticals. One of the basic parameters considered in the initial phase of designing potential drugs is lipophilicity, which affects the bioavailability and pharmacokinetics of drugs. Methods: The study aimed to assess the lipophilicity of fifteen new triazole derivatives of aniline using reversed phase thin layer chromatography (RP-TLC) and free web servers. Based on in silico methods, the drug similarity and pharmacokinetic profile (ADMET) of synthesized molecules were assessed. Results: A relationship was observed between the structure of the title compound, including the position of substitution in the aniline ring, and the experimental values of lipophilicity parameters (logPTLC). Most of the algorithms used to determine theoretical logP values showed less sensitivity to structural differences of the tested molecules. All obtained derivatives satisfy the drug similarity rules formulated by Lipinski, Ghose and Veber. Moreover, in silico analysis of the ADME profile showed favorable values of parameters related to absorption. [ABSTRACT FROM AUTHOR]

The use of ligand conjugation onto nanoparticle surfaces as an active targeting strategy has gained significant attention in the pursuit of improving tumor‐specific delivery and retention. However, the chemical conjugation of targeting moieties often induces alterations in the physicochemical properties of nanoparticles, including size, conformation, charge‐to‐mass ratio, and hydrophilicity/lipophilicity, resulting in unexpected biodistribution and pharmacokinetic profiles. Here, the enhanced active targeting efficiency achieved by integrating cyclic arginine–glycine–aspartic acid (cRGD) peptides onto ultrasmall nanocarrier H‐dot while preserving its essential physicochemical and pharmacokinetic attributes is investigated. The resulting cRGD/H‐dots demonstrate improved cellular uptake via integrin αvβ3 receptors, accompanied by negligible cytotoxicity. Notably, the active targeting efficacy of cRGD/H‐dots compared to unmodified H‐dots (1.2%ID/g, two‐fold increase) is quantitatively evaluated, validated through fluorescence imaging and histological analysis. The findings highlight that cRGD/H‐dots offer enhanced tumor targetability and prolonged tumoral retention while maintaining active renal clearance of unbound molecules. [ABSTRACT FROM AUTHOR]

Betulin and α-lipoic acid are naturally occurring substances with different biological properties. Combining two phytochemical units into a conjugate is a frequently used method to obtain new compounds with better pharmacokinetic parameters. This research concerned the preparation of lipoate derivatives of betulin using the Steglich method. Experimental lipophilicity values were determined for target compounds 6–10 by reversed-phase thin-layer chromatography. In silico methods were used to calculate the physicochemical parameters and lipophilicity of new derivatives and to determine the probable directions of biological activity. α-Lipoic acid, betulin, and lipoate derivatives 6–10 were tested for antiproliferative activity against MV4-11, A549, MCF-7, PC-3, HCT116, MiaPaca-2, and Hs294T cancer cells. 3-(5-(1,2-Dithiolan-3-yl)pentanoyl))betulin 10 showed moderate anticancer activity against MV4-11, PC-3, and HCT116, with IC50 values in the range of 39.8–76.7 µM. The introduction of a dithiolate substituent at the C3 position in 28-acetylbetulin gave compound 9 the highest activity (IC50 = 37.9 µM), in the ratio of biphenotypic B myelomonocytic leukemia cells (MV4-11). All lipoate derivatives were inactive towards normal cells. [ABSTRACT FROM AUTHOR]

Introduction: One of the primary tenets in pharmacotherapy is that the applied drug must reach the target tissue at therapeutic concentration. For many therapies intended to treat hearing disorders it has become apparent that we have failed to achieve this goal, contributing to poor outcomes in several important clinical trials. The crux of the delivery problem is that small lipophilic molecules pass with relative ease through membranous boundaries of the body. This initially seems advantageous when the drug is applied intratympanically, enabling entry into perilymph through the round window membrane. Unfortunately, the same property also allows the drug to pass through endothelial cells of blood capillaries, allowing it to be eliminated from perilymph. Drugs that are eliminated rapidly as they diffuse along the cochlear scalae will only treat basal high-frequency cochlear regions and will not reach therapeutic concentrations in the apical regions of the human cochlea. Methods: We have used the FluidSim program, a computer model of the inner ear fluids, to derive perilymph elimination properties for 15 molecules from published and archival data sets, which are compared with calculated molecular properties. Results: Smaller, lipophilic drugs are shown to be eliminated from perilymph more rapidly, with half-times as fast as 17 min, compared to larger, polar ones, with half-times as long as 1,304 min (21.7 h). Discussion: Based on their molecular properties’ drugs can be identified that distribute well along the cochlea when applied intratympanically. This excludes many drugs that have been used for, or are currently in development for, inner ear therapy. On the other hand, it opens a vast array of less-studied, larger molecules, many of which would be unsuitable for oral delivery (characterized as “not druglike”) but representing promising candidates for local inner ear therapy. In the earliest stages of consideration, drugs need to be selected based on the properties which govern their ability to reach the appropriate target site and not whether they are efficacious in small animals or have high potency in vitro. Confirmation that the selected drug is reaching the target site(s) in a large animal model should ideally precede expensive clinical trials. [ABSTRACT FROM AUTHOR]

Despite the numerous published syntheses and applications of sulfoximines, very few studies describe their physico‐chemical properties and in particular their acidic, basic and lipophilic or hydrophilic characters. We report for the first time the acidity values (pKa) of fluorinated sulfoximines in water and in acetonitrile, as well as the basicity (pKaH) measurements of fluorinated and non‐fluorinated sulfoximines in acetonitrile. The same sulfoximine library was also studied in terms of lipophilicity with measurement of the Hansch parameters of the sulfoximine moieties. Finally, these new data allowed us to optimize the N‐alkylation reaction of fluorinated sulfoximines. [ABSTRACT FROM AUTHOR]

Trifluoromethyl heterocyclic compounds have high lipophilicity, metabolic stability and binding selectivity, so it is very important to develop their synthetic methods. This review provides an overview of synthesis of trifluoromethyl substituted heterocyclic compounds from β-trifluoromethylated acrylates over the period from 2018 to the present. [ABSTRACT FROM AUTHOR]

Polyhalogenated molecules are often found as bioactive compounds in nature and are used as synthetic building blocks. Fluoroalkyl compounds hold promise for the development of novel pharmaceuticals and agrochemicals, as the introduction of fluoroalkyl groups is known to improve lipophilicity, membrane permeability, and metabolic stability. Three‐component 1,2‐halo‐halodifluoromethylation reactions of alkenes are useful for their synthesis. However, general methods enabling the introduction of halodifluoromethyl (CF2X) and halogen (X') groups in the desired combination of X and X' are lacking. To address this gap, for the first time, we report a three‐component halo‐halodifluoromethylation of alkenes and alkynes using combinations of commercially available fluorinated carboxylic anhydrides ((CF2XCO)2O, X=Cl and Br) and alkali metal halides (X'=Cl and Br). In situ prepared fluorinated diacyl peroxides were identified as important intermediates, and the use of appropriate bipyridyl‐based ligands and a copper catalyst was essential for achieving high product selectivity. The synthetic utility of the polyhalogenated products was demonstrated by exploiting differences in the reactivities of their C−X and C−X' bonds to achieve selective derivatization. Finally, the reaction mechanism and ligand effect were investigated using experimental and theoretical methods to provide important insights for the further development of catalytic reactions. [ABSTRACT FROM AUTHOR]

In addition to the solubilization of poorly water-soluble, highly lipophilic drugs, lipid nanoemulsions bear potential for drug targeting approaches. This requires that the drug remains within the emulsion droplets until they reach the site of action. Since drug release is rather controlled by the lipophilicity of the drug than by the formulation, this study systematically investigated the influence of drug lipophilicity on the course of drug transfer in (physiological) acceptor media. An increase in drug lipophilicity, according to ClogD/P values, was achieved by the formation of lipophilic prodrugs of 5-phenylanthranilic acid – a potential pathoblocker. The range of substances was supplemented by orlistat, lumefantrine and cholesteryl acetate as model drugs. Drug transfer from supercooled trimyristin nanodroplets was determined via differential scanning calorimetry by monitoring their onset crystallization temperature, which decreases linearly with increasing drug content. Release of the model (pro)drugs ranged from burst to hardly any release in the order of the ClogD/P values. Except for cholesteryl acetate, the results were in line with the lipophilicity of the model (pro)drugs estimated by their retention times on a reversed-phase HPLC column under isocratic conditions. An approximate prediction of drug release kinetics was, thus, possible by logP calculations and, to a limited extent, also by reversed-phase HPLC. A further finding was the increased drug loading capacity of the lipid nanoemulsion for lipophilic prodrugs, if the structural changes of the parent compound were accompanied by a lower melting point. [Display omitted] [ABSTRACT FROM AUTHOR]

The paper presents a physicochemical study of the water-soluble adduct of C60 with l-arginine, including a quantum chemical determination of the stability of isomers, measurement of antiradical activity towards the ABTS radical, determination of the lipophilicity coefficient, particle size distribution in aqueous solutions and calculation of ζ-potentials. A separate part of the article is devoted to the study of the effect of the C60 adduct with l-arginine on DNA in in vitro experiments (determination of the binding constant using isothermal titration calorimetry, study of genotoxicity, DNA melting temperature, effect on DNA circular dichroism spectra). Data are also presented on the biodistribution of the C60 adduct with l-arginine in the organs and tissues of animals and its effect on clinical and biochemical blood parameters. The mutagenic effect of the C60 adduct with l-arginine was determined in vivo on a model of mice abnormal sperm heads. It was shown that the adduct is in a neutral state in physiological solution, has an affinity to both aqueous and lipid phases (logPow = 0.23), and forms a complex with DNA (Ka = 4.59 106 M −1), while it does not have cyto- and genotoxicity in vitro and mutagenicity in vivo. [ABSTRACT FROM AUTHOR]

There are scientific studies indicating that the attachment of an indole moiety to the triterpene scaffold can lead to increased anticancer potential. Lipophilicity is one of the factors that may influence biological properties and is therefore an important parameter to determine for newly obtained compounds as drug candidates. In the present study, previously synthesized 3 and/or 28-indole-betulin derivatives were evaluated for lipophilicity by reversed-phase thin-layer chromatography. The experimental values of lipophilicity (logPTLC) were then subjected to correlation analysis with theoretical values of logP, as well as for selected physicochemical and pharmacokinetic parameters and anticancer activity. A toxicity test using zebrafish embryos and larvae was also conducted. High correlation was observed between the experimental and theoretical values of lipophilicity. We presented correlation equations and statistical parameters describing the relationships between logPTLC and several physicochemical and ADME parameters. We also revealed the lack of correlation between the experimental values of lipophilicity and anticancer activity. Moreover, experiments on zebrafish have confirmed no toxicity of the tested compounds, which was consistent with the results of the in silico toxicity analysis. The results demonstrated, using the example of indole derivatives of betulin, the utility of lipophilicity values in the context of predicting the biological activity of new compounds. [ABSTRACT FROM AUTHOR]

The incorporation of difluoromethylene (CF2) group into chemical molecules often imparts desirable properties such as lipophilicity, binding affinity, and thermal stability. Consequently, the increasing demand for gem-difluoroalkylated compounds in drug discovery and materials science has continued to drive the development of practical methods for their synthesis. However, traditional synthetic methods such as deoxofluorination often confront challenges including complicated substrate synthesis sequences and poor functional group compatibility. In this context, we herein report a metal electron-shuttle catalyzed, modular synthetic methodology for difluoroalkylated compounds by assembling two C(sp3) fragments across CF2 unit in a single step. The approach harnesses a difluoromethylene synthon as a biradical linchpin, achieving the construction of two C(sp3)-CF2 bonds through radical addition to two different π-unsaturated molecules. This catalytic protocol is compatible with broad range of coupling partners including diverse olefins, iminiums, and hydrazones, supporting endeavors in the efficient construction of C(sp3)-rich difluoroalkylated molecules. The difluoromethylene subunit can confer advantageous biological properties to compounds of interest, and the incorporation of this moiety in mild and selective conditions is an active pursuit in synthetic organic chemistry. Here, the authors append a CF2 biradical synthon to two carbon units via cobalt catalysis. [ABSTRACT FROM AUTHOR]

Considering the broad use of the trifluoromethyl functional group (−CF3) in medicinal chemistry and taking into account the recent concerns on the negative environmental effects of CF3 containing compounds, we are searching for "greener" alternatives. Thus, different chemical groups (i. e. iodide, fluoride, cyclopropyl, isopropyl, cyclobutyl, 3‐oxetyl, 2‐oxetyl, methylsulfide, pentafluorosulfide, methylsulfonyl and sulfonamide) have been considered as potential bioequivalents of −CF3 aiming to use them in compounds with therapeutic interest instead of the polyfluoride functionality. Different structural (molecular surface and volume) and physicochemical (electronic and lipophilic) aspects of the bioequivalent functionalities proposed have been theoretically calculated and compared to those of −CF3. Additionally, the corresponding phenyl derivatives carrying these functionalities have been purchased or prepared and their experimental lipophilicity (i. e. LogP) measured using shake‐flask experiments and UV‐vis spectroscopy. [ABSTRACT FROM AUTHOR]

Lipophilicity is an essential parameter of a compound that determines the solubility and pharmacokinetic properties that determine the transport of the drug to the molecular target. Dimers of dipyridothiazines are diazaphenothiazine derivatives exhibiting diverse anticancer potential in vitro, which is related to their affinity for histone deacetylase. In this study, the lipophilicity of 16 isomeric dipyridothiazine dimers was investigated theoretically and experimentally by reversed-phase thin-layer chromatography (RP-TLC) in an acetone–TRIS buffer (pH = 7.4). The relative lipophilicity parameter RM0 and specific hydrophobic surface area b were significantly intercorrelated, showing congeneric classes of dimers. The parameter RM0 was transformed into parameter logPTLC by use of the calibration curve. Molecular descriptors, ADMET parameters and probable molecular targets were determined in silico for analysis of the pharmacokinetic profile of the tested compounds showing anticancer activity. The analyzed compounds were tested in the context of Lipinski's rule of five, Ghose's rule and Veber's rule, confirming their bioavailability. [ABSTRACT FROM AUTHOR]

Treatment of schizophrenia with currently available drugs is often ineffective or results in several adverse reactions. In previous studies focusing on the search for new antipsychotic drugs, we designed and obtained a series of dopamine D2 and serotonin 5-HT1A and 5-HT2A receptor ligands that were pharmacologically evaluated and showed promising antipsychotic activity. Evaluation of ADMET parameters is an important issue in drug development and should be performed at its early stage to avoid developing molecules with poor pharmacokinetics, that are unlikely to enter the market. For this reason, in this work we focused on the assessment of physicochemical parameters of selected compounds from the series we obtained to assess their drug-like potential. The results of thermal analysis showed that most of the tested compounds are thermally stable above 200 °C, with one compound stable up to 190 °C. Permeability through biological membranes assessed in the parallel artificial membrane permeability assay indicated that all tested compounds effectively migrate through biological membranes by means of passive diffusion. The solubility of the tested compounds was determined in PBS, reflecting physiological pH, and 0.01 M HCl, indicating their low to moderate solubility in PBS, which was significantly improved in acidic environment. The lipophilicity of the studied compounds expressed as LogD falls within the range of 1.84–2.80, what suggest that they would show good oral absorption and the ability to cross lipid barriers. The studies were supplemented with in silico prediction of ADMET parameters, which also indicate the probable high drug-likeness of the tested compounds. [ABSTRACT FROM AUTHOR]

Compared to traditional lithium metal batteries, anode-free lithium metal batteries use bare current collectors as an anode instead of Li metal, making them highly promising for mass production and achieving high-energy density. The current collector, as the sole component of the anode, is crucial in lithium deposition-stripping behavior and greatly impacts the rate of Li depletion from the cathode. In this study, to investigate the lithiophilicity effect of the current collector on the solid electrolyte interface (SEI) film construction and cycling performance of anode-free lithium batteries, various lightweight paper-based current collectors were prepared by electroless plating Cu and lipophilic Ag on low-dust paper (LDP). The areal densities of the as-prepared LDP@Cu, LDP@Cu-Ag, and LDP@Ag were approximately 0.33 mg cm−2. The use of lipophilic Ag-coated collectors with varying loadings allowed for the regulation of lipophilicity. The impacts of these collectors on the distribution of SEI components and Li depletion rate in common electrolytes were investigated. The findings suggest that higher loadings of lipophilic materials, such as Ag, on the current collector increase its lipophilicity but also lead to significant Li depletion during the cycling process in full-cell anode-free Li metal batteries. Thus, moderately lithiophilic current collectors, such as LDP@Cu-Ag, show more potential for Li deposition and striping and stable SEI with a low speed of Li depletion. [ABSTRACT FROM AUTHOR]

Iron(III) complexes based on N,N´-bis(salicylidene)ethylenediamine (salene) scaffolds have demonstrated promising anticancer features like induction of ferroptosis, an iron dependent cell death. Since poor cellular uptake limits their therapeutical potential, this study aimed to enhance the lipophilic character of chlorido[N,N′-bis(salicylidene)-1,2-bis(3-methoxyphenyl)ethylenediamine]iron(III) complexes by introducing lipophilicity improving ligands such as fluorine (X1), chlorine (X2) and bromine (X3) in 5-position in the salicylidene moieties. After detailed characterization the binding to nucleophiles, logP values and cellular uptake were determined. The complexes were further evaluated regarding their biological activity on MDA-MB 231 mammary carcinoma, the non-tumorous SV-80 fibroblast, HS-5 stroma and MCF-10A mammary gland cell lines. Stability of the complexes in aqueous and biological environments was proven by the lack of interactions with amino acids and glutathione. Cellular uptake was positively correlated with the logP values, indicating that higher lipophilicity enhanced cellular uptake. The complexes induced strong antiproliferative and antimetabolic effects on MDA-MB 231 cells, but were inactive on all non-malignant cells tested. Generation of mitochondrial reactive oxygen species, increase of lipid peroxidation and induction of both ferroptosis and necroptosis were identified as mechanisms of action. In conclusion, halogenation of chlorido[N,N′-bis(salicylidene)-1,2-bis(3-methoxyphenyl)ethylenediamine]iron(III) complexes raises their lipophilic character resulting in improved cellular uptake. [ABSTRACT FROM AUTHOR]

Direct installation of key functionalities in a molecule through C−H bond activation is one of the thrust areas as well as challenging task in organic synthesis. Particularly, introduction of chlorine in a molecule imparts additional benefits for further functionalizations as well as improves the electronic behaviour such as lipophilicity and polarity towards drug development process. The chlorinated molecules have also been established as efficient biologically relevant scaffolds. Current manuscript has been focused on the direct installation of the chlorine atom at various aromatic and aliphatic positions to produce functional molecules. The key highlight of the manuscript belongs to the site selectivity (regioselectivity) for the installation of chlorine functionality. Manuscript describes the advanced methods developed for the direct C−H chlorination reactions and further simplified for the chlorination reactions at various positions including aromatic (o‐, m‐, and p‐), benzylic, heteroaromatic, and aliphatic positions. Directing groups (DGs) and the coordination with the catalyst is the key for the enhancement of regioselectivities during direct C−H chlorination reactions. [ABSTRACT FROM AUTHOR]

Matrix effects are a major concern in liquid chromatography coupled to tandem mass spectrometry for the determination of pesticide residues. In this work, a novel and efficient lipophilicity-matched chromatographic separation strategy was developed to improve the separation efficiency on an alkyl bonded phase chromatographic column and reduce matrix effects. An ultra-high performance liquid chromatography-tandem mass spectrometry method based on this strategy was established to minimize matrix effects for the determination of triazole fungicides. The samples were cleaned-up with dispersive solid phase extraction and separated on a chromatographic column with similar lipophilicity to the fungicides. The results showed that the proposed method effectively minimized the matrix effects and improved the separation. The matrix effects of 21 fungicides ranged from −8.3% to 4.7%. Moreover, the average recoveries were between 91.4% and 108.1% using solvent calibration for quantification, and the limits of quantitation were between 0.5 and 3.5 μg/kg. These results demonstrate the effectiveness of the proposed strategy in improving the chromatographic efficiency. This work provides a practical strategy and reference for the liquid chromatography-tandem mass spectrometry determination of pesticide residues. [ABSTRACT FROM AUTHOR]

The emerging sub−1 nm nanowires (SNWs) have received tremendous attention given their intriguing properties and broad applications attributable to their ultrasmall feature size. However, applying SNWs in microstructure‐preserving macroscopic functional materials (e.g., aerogels) remains challenging because the solvents used for preparing SNWs are not compatible with conventional supercritical drying or freeze‐drying techniques. In this study, the fabrication of SNW aerogels (SNWAs) is pioneered by developing a nonpolar solvent‐based freeze‐casting strategy. Cyclohexane, a nonpolar solvent with a freezing point (6.5 °C) comparable to that of water, is selected as a reaction and drying medium to assemble various SNWs. The resulting self‐standing SNWAs display low density, excellent hydrophobicity and lipophilicity, and tunable luminescent color. This strategy not only introduces a new aggregation form of SNWs but also provides a creative perspective on synthesizing aerogel structures from sub−1 nm building blocks. [ABSTRACT FROM AUTHOR]

The emergence of new synthetic cannabinoid receptor agonists (SCRAs) onto the illicit drugs market continues to cause harm, and the overall availability of physicochemical and pharmacokinetic data for new psychoactive substances is lacking. The lipophilicity of 23 SCRAs and the plasma protein binding (PPB) of 11 SCRAs was determined. Lipophilicity was determined using a validated chromatographic hydrophobicity index (CHI) log D method; tested SCRAs showed moderate to high lipophilicity, with experimental log D7.4 ranging from 2.48 (AB‐FUBINACA) to 4.95 (4F‐ABUTINACA). These results were also compared to in silico predictions generated using seven commercially available software packages and online tools (Canvas; ChemDraw; Gastroplus; MoKa; PreADMET; SwissADME; and XlogP). Licenced, dedicated software packages provided more accurate lipophilicity predictions than those which were free or had prediction as a secondary function; however, the latter still provided competitive estimates in most cases. PPB of tested SCRAs, as determined by equilibrium dialysis, was in the upper range of the lipophilicity scale, ranging from 90.8% (ADB‐BUTINACA) to 99.9% (BZO‐HEXOXIZID). The high PPB of these drugs may contribute to reduced rate of clearance and extended durations of pharmacological effects compared to lesser‐bound SCRAs. The presented data improve understanding of the behaviour of these drugs in the body. Ultimately, similar data and predictions may be used in the prediction of the structure and properties of drugs yet to emerge on the illicit market. [ABSTRACT FROM AUTHOR]

Multigram synthesis of 3‐fluorinated cyclobutane building blocks has been disclosed. The proposed synthetic schemes were based on nucleophilic fluorination and eventually led to 3‐fluorocyclocutanecarboxylic acid as a key target compound and intermediate. Further functional group transformations provided monofluorinated cyclobutane‐derived alcohols, amines, bromides, thiols, sulfonyl chlorides, etc. Furthermore, the synthesis of diastereopure cis‐ and trans‐isomeric 2‐ and 3‐fluorocyclobutanecarboxylic acids and amines was also performed. In both cases, diastereomer separation was used to obtain pure stereoisomers. The effect of the fluorine position and relative spatial orientation on the physicochemical properties of the corresponding monoflurinated derivatives was studied by measurements of pKa and logP values. [ABSTRACT FROM AUTHOR]

A novel 12-step procedure was developed for preparing methyl 14-isocyano-3-methyltetradecanoate. "2+1B" tricarbonyl complexes [99mTc(CO)3(N^N)CN(CH2)11CH(CH3)CH2COOMe]+, where N^N = 2,2'-bipyridine (bipy) or 1,10-phenanthroline (phen), were prepared by the reaction of [99mTc(CO)3(N^N)(H2O,EtOH)]+ with methyl 14-isocyano-3-methyltetradecanoate in aqueous ethanol. The formation of technetium-99m complexes was confirmed by HPLC, and the partition coefficient (n-octanol/water) of these complexes was measured. [ABSTRACT FROM AUTHOR]

The lipophilicity of a substance is an important physicochemical parameter for the pharmacological activity of a drug. In the current study, high-performance thin-layer chromatography was applied to determine the LogP values of the following anticoagulant drugs: warfarin, acenocoumarol, clopidogrel, and prasugrel. The mobile phase was a mixture of acetonitrile and water in mixed proportions. The content of acetonitrile varied from 50% to 80% in 5% increments. The partition coefficients were calculated with the regression curve Rm0 = f(LogP) based on the compounds with known lipophilicity. The highest LogP was observed for warfarin and the lowest for prasugrel. [ABSTRACT FROM AUTHOR]

Pulmonary Mycobacterium avium-intracellulare complex (MAC) disease is a typical non-tuberculous mycobacterial infection. The incidence of pulmonary MAC is increasing worldwide. This study aimed to clarify the pharmacokinetic parameters of anti-pulmonary MAC disease drugs in silkworms. The pharmacokinetic parameters investigated included maximum concentration, area under the concentration–time curve, total clearance, and volume of distribution at steady-state. In addition, protein-binding rates, fat body transferability, and drug-drug interactions were examined. Antibiotic concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Among the antibiotics investigated, amikacin was not eliminated from silkworms during the 48-h observation period. In contrast, dose-proportional pharmacokinetics were observed in silkworms for all antibiotics tested, except for amikacin. Protein-binding rates in hemolymph for clarithromycin, azithromycin, rifampicin, ethambutol, and amikacin were 39.6 ± 3.0%, 39.5 ± 4.3%, 76.3 ± 3.2%, 20.9 ± 4.2%, and 73.1 ± 4.7%, respectively (mean ± standard deviation). The distribution of antibiotics in the fat bodies of silkworms was related to drug lipophilicity. No drug-drug interactions were observed in the silkworms. The pharmacokinetics of these drugs in silkworms differed significantly from those in humans. Therefore, while it is challenging to predict the pharmacokinetics of these drugs in humans based on silkworm data, the silkworm infection model has facilitated a comprehensive assessment of the relationship between antibiotic exposure and efficacy. [ABSTRACT FROM AUTHOR]

The search for new metal-based anticancer drug candidates is a fundamental task in medicinal inorganic chemistry. In this work, we assessed the potential of two new Ru(II)–phosphine–mercapto complexes as potential anticancer agents. The complexes, with the formula [Ru(bipy)(dppen)(Lx)]PF6 [(1), HL1 = 2-mercapto–pyridine and (2), HL2 = 2-mercapto–pyrimidine, bipy = 2,2′-bipyridine, dppen = cis-1,2-bis(diphenylphosphino)-ethylene] were synthesized and characterized by nuclear magnetic resonance (NMR) [1H, 31P(1H), and 13C], high resolution mass spectrometry (HR-MS), cyclic voltammetry, infrared and UV-Vis spectroscopies. Complex 2 was obtained as a mixture of two isomers, 2a and 2b, respectively. The composition of these metal complexes was confirmed by elemental analysis and liquid chromatography-mass spectrometry (LC-MS). To obtain insights into their lipophilicity, their distribution coefficients between n-octanol/PBS were determined. Both complexes showed affinity mainly for the organic phase, presenting positive log P values. Also, their stability was confirmed over 48 h in different media (i.e., DMSO, PBS and cell culture medium) via HPLC, UV-Vis and 31P{1H} NMR spectroscopies. Since enzymes from the P-450 system play a crucial role in cellular detoxification and metabolism, the microsomal stability of 1, which was found to be the most interesting compound of this study, was investigated using human microsomes to verify its potential oxidation in the liver. The analyses by LC-MS and ESI-MS reveal three main metabolites, obtained by oxidation in the dppen and bipy moieties. Moreover, 1 was able to interact with human serum albumin (HSA). The cytotoxicity of the metal complexes was tested in different cancerous and non-cancerous cell lines. Complex 1 was found to be more selective than cisplatin against MDA-MB-231 breast cancer cells when compared to MCF-10A non-cancerous cells. In addition, complex 1 affects cell morphology and migration, and inhibits colony formation in MDA-MB-231 cells, making it a promising cytotoxic agent against breast cancer. [ABSTRACT FROM AUTHOR]

Silver(I) complexes with proline and hydroxyproline were synthesized and structurally characterized and crystal structure analysis shows that the formulas of the compounds are {[Ag2(Pro)2(NO3)]NO3}n (AgPro) (Pro = L -proline) and {[Ag2(Hyp)2(NO3)]NO3}n (AgHyp) (Hyp = trans-4-hydroxy- L -proline). Both complexes crystallize in the monoclinic lattice with space group P21 with a carboxylate bidentate-bridging coordination mode of the organic ligands Pro and Hyp (with NH2+ and COO− groups in zwitterionic form). Both complexes have a distorted seesaw (C2v) geometry around one silver(I) ion with τ4 values of 58% (AgPro) and 51% (AgHyp). Moreover, the results of spectral and thermal analyses correlate with the structural ones. 1H and 13C NMR spectra confirm the complexes species' presence in the DMSO biological testing medium and their stability in the time range of the bioassays. In addition, molar conductivity measurements indicate complexes' behaviour like 1 : 1 electrolytes. Both complexes showed higher or the same antibacterial activity against Bacillus cereus, Pseudomonas aeruginosa and Staphylococcus aureus as AgNO3 (MIC = 0.063 mM) and higher than silver(I) sulfadiazine (AgSD) (MIC > 0.5 mM) against Pseudomonas aeruginosa. In addition, complex AgPro exerted a strong cytotoxic effect against the tested MDA-MB-231 and Jurkat cancer cell lines (IC50 values equal to 3.7 and 3.0 μM, respectively) compared with AgNO3 (IC50 = 6.1 (5.7) μM) and even significantly higher selectivity than cisplatin (cisPt) against MDA-MB-231 cancer cell lines (SI = 3.05 (AgPro); 1.16 (cisPt), SI – selectivity index). The binding constants and the number of binding sites (n) of AgPro and AgHyp complexes with bovine serum albumin (BSA) were determined at four different temperatures, and the zeta potential of BSA in the presence of silver(I) complexes was also measured. The in ovo method shows the safety of the topical and intravenous application of AgPro and AgHyp. Moreover, the complexes' bioavailability was verified by lipophilicity evaluation from the experimental and theoretical points of view. [ABSTRACT FROM AUTHOR]

Photoinduced nitric oxide (NO) release for complexes [RuNO(L)2(NO2)2OH], where L=methyl isonicotinate (1), ethyl isonicotinate (2), methyl nicotinate (3) and ethyl nicotinate (4) was studied in DMSO, MeCN and water solutions (PBS, CTAB) using spectroscopic methods (UV‐vis, IR, EPR) and spectrometric techniques (ESI‐MS). Additionally, we present methodological evidence for improving the calculation of the quantum yield (QY) of NO release through the utilization of a combined IR‐UV‐vis‐spectroscopy flow‐through setup. According to DFT calculations, the production of nitric oxide occurs through the photoinduced cleavage of the Ru−NO bond, triggered by irradiation at 445 or 532 nm. This cleavage is a consequence of charge transfer from the orbitals of the Ru−OH group and the equatorial ligands (HOMO, HOMO‐1) to the Ru−NO antibonding orbital (LUMO). The cytotoxicity and photoinduced cytotoxicity of the investigated compounds were assessed against the breast adenocarcinoma cell line MCF‐7. Moreover, the investigation of the lipophilic properties of compounds 1–4 unveiled a significant influence of their lipophilicity on cytotoxic behavior, allowing for the modification of cytotoxicity through changes in the ligand L or by light irradiation. [ABSTRACT FROM AUTHOR]

The fluoroalkoxy groups (ORf) are widely used motifs in pharmaceutical and agrochemical fields due to their unique physicochemical properties including higher lipophilicity and increased metabolic stability. Thus, the high value of ORf‐containing derivatives has stimulated the development of fluoroalkoxylation reactions. In this review, we highlight the recent progress of various trifluoroalkoxylating reagents and their applications in organic synthesis in the past five years. [ABSTRACT FROM AUTHOR]

Inhibition of Angiotensin-converting enzyme I (ACE I) is a modern therapeutic approach to treatment of hypertension. In recent years, research into natural ACE peptide inhibitors without side effects has become important. The aim of this study is to isolate and characterize novel bioactive peptides from skim and/or whole cow's milk fermented with selected lactobacillus strains. Several homo/heterofermentative strains of the Lactobacillus species of dairy origin have been pre-selected and different milk fermented samples have been studied. A protocol for analyses was designed and the milk proteins were separated by centrifugation at 4°C at 10000 × g, with molecular mass cut off (MWCO) membranes of 3 and 10 kDa. The samples with molecular mass below 3 kDa were further separated by ultrafiltration by dialysis cell (cut off membrane 1 kDa) by continuous stirring at room temperature. The milk fractions under 1 kDa molecular mass were characterized by UPLC-MS. The ACE-inhibitory activity was determined using the FAPGG (N-[3-(2-Furyl) acryloyl]-L-phenylalanyl-glycyl-glycine) degradation method. All tested samples (1 kDa) exhibit ACE I inhibitory activity with IC50 in a range of 6 - 37 mg mL-1. In silico logP prediction of selected peptides was used to assess whether lipophilicity of the compounds falls within the so-called "therapeutically relevant pharmacokinetic space". [ABSTRACT FROM AUTHOR]

The field of electrochemistry at the interface between two immiscible electrolyte solutions (ITIES) has been continuously expanding over the years due to their vast number of applications, including to investigate the partitioning of ionizable drugs at liquid‐liquid systems. The aim of this Review is to highlight the great potential of ITIES as simple model of biological membranes to gather information on drug partition, lipophilicity, and pharmacokinetics that can be very useful for researchers in the field of drug discovery for development of new drugs with enhanced permeability. Relevant contributions and perspectives to improve the applicability of ITIES in partition studies were highlighted and discussed. The second part of this Review pretends to highlight the application of electrochemistry at the ITIES as experimental technique to investigate interactions between small ligands, including drugs, and DNA, a topic of high research interest in pharmaceutical and biological sciences, which remains with lots of opportunities to explore. [ABSTRACT FROM AUTHOR]

The aim: development of the technology for obtaining the base of xylometazoline, suitable for the development of formulations in combination with essential oils. Development and validation of methods of control of related substances and assay of the obtained base of xylometazoline. Study of the stability of the obtained xylometazoline base under long-term and accelerated conditions. Materials and methods: experimental samples of xylometazoline base were obtained from commercially available xylometazoline hydrochloride and aqueous sodium hydroxide solution. The quality control of the obtained substance was carried out in accordance with the requirements of the internal specification. The analysis of raw materials of xylometazoline hydrochloride was carried out in accordance with the monograph of the European Pharmacopoeia on xylometazoline hydrochloride (Ph. Eur. 10.1, 1162 (01/2008)). Results: a technology for obtaining xylometazoline base from xylometazoline hydrochloride by the action of a 2 % solution of a strong base, namely sodium hydroxide, was developed. Developed and validated methods of quality control of the obtained xylometazoline base according to indicators of related substances and assay. The stability of the substance was studied for 1 year; the results of control under accelerated research conditions meet the requirements of the specification, which allows for establishing a shelf life of 2 years. Conclusions: the technology for obtaining xylometazoline base and quality control methods based on the monograph of the European Pharmacopoeia on xylometazoline hydrochloride was developed. The developed technology ensures the proper quality of the substance in accordance with the requirements of the internal specification. Analytical methods "related substances" and "assay" meet the established criteria during validation. The obtained results were later used to develop a medicine based on xylometazoline and eucalyptus oil - Eukazolin, nasal drops. [ABSTRACT FROM AUTHOR]

Fourteen donepezil‐like acetylcholinesterase (AChE) inhibitors from our library were analyzed using reversed‐phase thin‐layer chromatography to assess their lipophilicity and blood–brain barrier permeability. Compounds possessed N‐benzylpiperidine and N,N‐diarylpiperazine moieties connected via a short carboxamide or amine linker. Retention parameters RM0, b, and C0 were considered as the measures of lipophilicity. Besides, logD of the investigated compounds was determined chromatographically using standard compounds with known logPow and logD values at pH 11. Experimentally obtained lipophilicity parameters correlated well with in silico generated results, and the effect of the nature of the linker between two pharmacophores and substituents on the arylpiperazine part of the molecule was observed. As a result of drug‐likeness analysis, both Lipinski's rule of five and Veber's rule parameters were determined, suggesting that examined compounds could be potential candidates for further drug development. Principal component analysis was performed to obtain an insight into a grouping of compounds based on calculated structural descriptors, experimentally obtained values of lipophilicity, and AChE inhibitory activity. [ABSTRACT FROM AUTHOR]

IntroductionWe developed and produced a new series of 4,6-diaryl-pyrimidines 9–29 as antiproliferative agents targeting EGFR/VEGFR-2.MethodsThe antiproliferative efficacy of the novel targets was assessed against a panel of 60 NCI cancer cell lines and four cancer cell lines in vitro.Results and DiscussionCompounds 14, 17, 19, 22, 25, and 29 demonstrated the greatest potency among the derivatives, with GI50 values between 22 and 33 nM; compounds 22 and 29 exhibited the highest potency, with GI50 values of 22 and 24 nM, respectively. We subsequently examined the most efficient derivatives as dual EGFR/VEGFR-2 inhibitors, finding that compounds 22 and 29 functioned as dual inhibitors. Moreover, 22 and 29 can act as apoptotic inducers by increasing Bax levels and decreasing levels of the anti-apoptotic protein Bcl2. At both 24- and 48-h intervals, the cell migration rates of compounds 22 and 29 were lower than those of untreated cells, according to the migration rate and wound closure percentage assessment. The wound closure rate reached 100% after 72 h of therapy with compound 22 but only 80% with compound 29. The docking study showed that compounds 22 and 29 had docking scores similar to those of Erlotinib and Sorafenib, co-crystallized ligands, for the EGFR and VEGFR-2 proteins. The experiments on lipophilicity showed that the new pyrimidines had a consistent result. This group of compounds has better biological activity in all the biological systems studied with low lipophilicity.

IntroductionOne of the primary tenets in pharmacotherapy is that the applied drug must reach the target tissue at therapeutic concentration. For many therapies intended to treat hearing disorders it has become apparent that we have failed to achieve this goal, contributing to poor outcomes in several important clinical trials. The crux of the delivery problem is that small lipophilic molecules pass with relative ease through membranous boundaries of the body. This initially seems advantageous when the drug is applied intratympanically, enabling entry into perilymph through the round window membrane. Unfortunately, the same property also allows the drug to pass through endothelial cells of blood capillaries, allowing it to be eliminated from perilymph. Drugs that are eliminated rapidly as they diffuse along the cochlear scalae will only treat basal high-frequency cochlear regions and will not reach therapeutic concentrations in the apical regions of the human cochlea.MethodsWe have used the FluidSim program, a computer model of the inner ear fluids, to derive perilymph elimination properties for 15 molecules from published and archival data sets, which are compared with calculated molecular properties.ResultsSmaller, lipophilic drugs are shown to be eliminated from perilymph more rapidly, with half-times as fast as 17 min, compared to larger, polar ones, with half-times as long as 1,304 min (21.7 h).DiscussionBased on their molecular properties’ drugs can be identified that distribute well along the cochlea when applied intratympanically. This excludes many drugs that have been used for, or are currently in development for, inner ear therapy. On the other hand, it opens a vast array of less-studied, larger molecules, many of which would be unsuitable for oral delivery (characterized as “not druglike”) but representing promising candidates for local inner ear therapy. In the earliest stages of consideration, drugs need to be selected based on the properties which govern their ability to reach the appropriate target site and not whether they are efficacious in small animals or have high potency in vitro. Confirmation that the selected drug is reaching the target site(s) in a large animal model should ideally precede expensive clinical trials.

Lavenders include some 28 species of evergreen aromatic shrubs and subshrubs belonging to the mint family, the Lamiaceae. They occur mainly around the Mediterranean and their flowers range from pink to purple and white. It is known that Lavandula angustifolia Mill. is an unpretentious decorative and essential oil crop that is widely used in the pharmaceutical, cosmetic, and food industries. Therefore, the planting material of this crop is in great demand in Ukraine. Cultivated varieties of lavender are very different for vegetative reproduction. A promising path is the testing for new effective and environmentally friendly rooting stimulants. The experiments were conducted in the Horticulture Laboratory of the Khortytsiа National Academy. The study tested the influence of aqueous solutions of a complex of amino acids, polypeptides, amino sugars, hexuronic acids, and microelements called “Bioglobin”, a complex of inorganic compounds containing (nitrogen – 4.7%, phosphorus – 3.4%, potassium – 4.6%, iron – 1.6%, zinc – 1.6%) and organic compounds (alginate acid, betaine, polysaccharides, vitamin complex of groups B, C, D) called “Ferti Root”, a complex of saturated and unsaturated fatty acids (C14–C28), polysaccharides, 15 amino acids, analogs of cytokinin and auxin nature phytohormones called “Emistim S”, a complex of 2.6-dimethylpyridine-1-oxide with α-phenylacetic acid called “Charkor”, disodium salt of 2-(quinolin-4-ylthio) succinic acid on the rooting and development of varieties "Stepova", "Vdala", "Sineva" one-year woodcuttings. The indicators were evaluated in comparison with the control without processing the cuttings before planting, and with the use of (4-(indol-3-yl) butyric acid) called “Kornevin”. Mother plants are 2–3 years old. The experiment was repeated three times, 30 cuttings each. Woodсuttings were planted in open-door ground at early October. In May, the number of rooted cuttings, as well as the number and length of roots was counted. It was found that two preparations had the maximum positive effect on the cuttings rooting: disodium salt of 2-(quinolin-4-ylthio) succinic acid at a concentration of 5 mg/L and “Ferti Root”. Consequently, the rooting percentage increased by 18–20% in all researched varieties compared to the control. The length and number of new formed roots in these experimental versions exceeded the control indicators by 1.5–2.0 times. Other researched preparations did not show a positive effect on the rooting cuttings indicators.

Substituting hydrogen atoms with fluorine alters physicochemical properties often resulting in improved drug action relative to the parent molecule. The high electronegativity of fluorine changes the electron density distribution of the molecule; however, the substitution does not significantly change the size of the molecule because hydrogen and fluorine have similar atomic radii. A trifluoroacetamido derivative (TFA-phenacetin) of phenacetin, an analgesic antipyretic drug, was synthesized to compare its lipophilicity to the parent molecule by determining octanol–water partition coefficients. TFA-phenacetin is over seven times more lipophilic than phenacetin, which suggests that TFA-phenacetin would have better bioavailability relative to phenacetin. The kinetics of cytochromes P-450 (CYP) catalyzed oxidation of phenacetin and TFA-phenacetin were compared using Sprague Dawley (SD) rat liver microsomes. Phenacetin and TFA-phenacetin have the same apparent binding affinity for the SD rat liver microsome CYP proteome and undergo CYP catalyzed oxidation at the same rate in the presence of SD rat liver microsomes.

The development of new compounds to treat Chagas disease is imperative due to the adverse effects of current drugs and their low efficacy in the chronic phase. This study aims to investigate nitroisoxazole derivatives that produce oxidative stress while modifying the compounds' lipophilicity, affecting their ability to fight trypanosomes. The results indicate that these compounds are more effective against the epimastigote form of T. cruzi, with a 52 ± 4% trypanocidal effect for compound 9. However, they are less effective against the trypomastigote form, with a 15 ± 3% trypanocidal effect. Additionally, compound 11 interacts with a higher number of amino acid residues within the active site of the enzyme cruzipain. Furthermore, it was also found that the presence of a nitro group allows for the generation of free radicals; likewise, the large size of the compound enables increased interaction with aminoacidic residues in the active site of cruzipain, contributing to trypanocidal activity. This activity depends on the size and lipophilicity of the compounds. The study recommends exploring new compounds based on the nitroisoxazole skeleton, with larger substituents and lipophilicity to enhance their trypanocidal activity. [ABSTRACT FROM AUTHOR]

The chromatographic behavior of the selected compounds was studied under conditions of hydrophilic interaction liquid chromatography (HILIC). The effect of mobile phase composition on the retention in different chromatographic systems was systematically examined using high‐performance thin‐layer chromatography. The sorbents of different polarity and adsorption characteristics were selected and mixtures of water and organic solvents of various compositions, from pure water to pure organic solvent were used as mobile phases. Increasing the amount of water in the mobile phase leads to a conversion of the separation mechanism, and the retention curves have a characteristic "U" shape. The conversion between the adsorption and partition mechanisms is most likely continuous and depends on the chemical nature of separated substances, the stationary phase as well as on organic component of the mobile phase. Silica gel can be considered the most suitable stationary phase for the systematic investigation of the chromatographic behavior of the test compounds, whereas acetonitrile was the most suitable solvent. The obtained results contribute to the understanding of the dominant separation mechanism, the type, and the intensity of the interactions between separated substances with both stationary and mobile phases. Besides, the lipophilicity parameters obtained under HILIC conditions were evaluated and correlated with the calculated values. [ABSTRACT FROM AUTHOR]

Herein, we report the synthesis, crystal structure, and antibacterial activity of a new Ni(II) complex derived from the N, O donor (E)-2,4-dibromo-6-(2-(1-phenylethylimino) ethyl) phenol ligand. Both the ligand and the complex were characterized by employing FT-IR, UV-Visible, and fluorescence spectroscopy as well as single-crystal X-ray diffraction studies. The crystallographic results reveal that the complex crystalizes in the monoclinic unit cell with the space group C2, and the coordination environment around the Ni centre consists of NiN2O2 donor sites exhibiting a highly distorted tetrahedral geometry. The oxidative assay of DPPH (α,α-diphenyl-β-picrylhydrazyl) was used for evaluating the radical scavenging activity or antioxidant properties of the complex in terms of IC50 values (50% inhibition); it was observed that the complex showed reasonable antioxidant activities with ascorbic acid (AA) as the standard. Detailed interaction studies with calf thymus (CT) DNA and bovine serum albumin (BSA) were performed through various spectroscopic and theoretical approaches and indicated that the complex has promising binding capability with both the systems. Comprehensive biological studies were performed and showed that the complex exhibits notable antibacterial activity against Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) by interfering with its cell wall integrity. Microscopic imaging confirmed cellular abnormalities, such as alterations in the cell shape, size, and quantity. Molecular docking analyses also provided insights into the activities of the complex. In contrast, the complex displayed minimal growth inhibition properties against Gram-negative Klebsiella pneumoniae (KP) even at higher complex concentration, indicating that the specific inhibition activity of the complex is only against Gram-positive MRSA. Moreover, based on optical density readings, the results demonstrated that the complex exhibited effective antibacterial activity against MRSA with an MIC value between 34 and 36 μg ml−1, whereas the MIC value of standard cefoxitin is >70 μg ml−1. Thus, our complex demonstrated better antibacterial activity than the conventional antibiotic. [ABSTRACT FROM AUTHOR]

Simple Summary: This study examines how statins, which are drugs commonly used to lower cholesterol, affect the growth of liver cancer cells. Statins can be either lipophilic (lipid-soluble) or hydrophilic (water-soluble), and this characteristic influences how they enter cells. In our research, we compared the effects of lipophilic simvastatin and hydrophilic pravastatin. We found that simvastatin significantly reduces cancer cell growth and increases cell death depending on the dosage and duration of treatment. In contrast, pravastatin, due to its limited uptake, has a minimal impact on cancer cells. These findings suggest that the type of statin used could be crucial in cancer treatment, potentially offering better outcomes for patients with liver cancer. The HMG-CoA reductase inhibitors, statins, are drugs used globally for lowering the level of cholesterol in the blood. Different clinical studies of statins in cancer patients have indicated a decrease in cancer mortality, particularly in patients using lipophilic statins compared to those on hydrophilic statins. In this paper, we selected two structurally different statins (simvastatin and pravastatin) with different lipophilicities and investigated their effects on the proliferation and apoptosis of hepatocellular carcinoma cells. Lipophilic simvastatin highly influences cancer cell growth and survival in a time- and concentration-dependent manner, while pravastatin, due to its hydrophilic structure and limited cellular uptake, showed minimal cytotoxic effects. [ABSTRACT FROM AUTHOR]

Understanding the pharmacokinetics, safety and efficacy of candidate drugs is crucial for their success. One key aspect is the characterization of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, which require early assessment in the drug discovery and development process. This study aims to present an innovative approach for predicting ADMET properties using attention-based graph neural networks (GNNs). The model utilizes a graph-based representation of molecules directly derived from Simplified Molecular Input Line Entry System (SMILE) notation. Information is processed sequentially, from substructures to the whole molecule, employing a bottom-up approach. The developed GNN is tested and compared with existing approaches using six benchmark datasets and by encompassing regression (lipophilicity and aqueous solubility) and classification (CYP2C9, CYP2C19, CYP2D6 and CYP3A4 inhibition) tasks. Results show the effectiveness of our model, which bypasses the computationally expensive retrieval and selection of molecular descriptors. This approach provides a valuable tool for high-throughput screening, facilitating early assessment of ADMET properties and enhancing the likelihood of drug success in the development pipeline. [ABSTRACT FROM AUTHOR]

Lipophilicity is one of the principal parameters that describe the pharmacokinetic behavior of a drug, including its absorption, distribution, metabolism, elimination, and toxicity. In this study, the lipophilicity and other physicochemical, pharmacokinetic, and toxicity properties that affect the bioavailability of newly synthesized dialkylaminoalkyldiquinothiazine hybrids as potential drug candidates are presented. The lipophilicity, as RM0, was determined experimentally by the RP-TLC method using RP18 plates and acetone–TRIS buffer (pH 7.4) as the mobile phase. The chromatographic parameters of lipophilicity were compared to computationally calculated partition coefficients obtained by various types of programs such as iLOGP, XLOGP3, WLOGP, MLOGP, SILCOS-IT, LogP, logP, and milogP. In addition, the selected ADMET parameters were determined in silico using the SwissADME and pkCSM platforms and correlated with the experimental lipophilicity descriptors. The results of the lipophilicity study confirm that the applied algorithms can be useful for the rapid prediction of logP values during the first stage of study of the examined drug candidates. Of all the algorithms used, the biggest similarity to the chromatographic value (RM0) for certain compounds was seen with iLogP. It was found that both the SwissADME and pkCSM web tools are good sources of a wide range of ADMET parameters that describe the pharmacokinetic profiles of the studied compounds and can be fast and low-cost tools in the evaluation of examined drug candidates during the early stages of the development process. [ABSTRACT FROM AUTHOR]

Purpose: The goal was to assess, for lipophilic drugs, the impact of logP on human volume of distribution at steady-state (VDss) predictions, including intermediate fut and Kp values, from six methods: Oie-Tozer, Rodgers-Rowland (tissue-specific Kp and only muscle Kp), GastroPlus, Korzekwa-Nagar, and TCM-New. Method: A sensitivity analysis with focus on logP was conducted by keeping pKa and fup constant for each of four drugs, while varying logP. VDss was also calculated for the specific literature logP values. Error prediction analysis was conducted by analyzing prediction errors by source of logP values, drug, and overall values. Results: The Rodgers-Rowland methods were highly sensitive to logP values, followed by GastroPlus and Korzekwa-Nagar. The Oie-Tozer and TCM-New methods were only modestly sensitive to logP. Hence, the relative performance of these methods depended upon the source of logP value. As logP values increased, TCM-New and Oie-Tozer were the most accurate methods. TCM-New was the only method that was accurate regardless of logP value source. Oie-Tozer provided accurate predictions for griseofulvin, posaconazole, and isavuconazole; GastroPlus for itraconazole and isavuconazole; Korzekwa-Nagar for posaconazole; and TCM-New for griseofulvin, posaconazole, and isavuconazole. Both Rodgers-Rowland methods provided inaccurate predictions due to the overprediction of VDss. Conclusions: TCM-New was the most accurate prediction of human VDss across four drugs and three logP sources, followed by Oie-Tozer. TCM-New showed to be the best method for VDss prediction of highly lipophilic drugs, suggesting BPR as a favorable surrogate for drug partitioning in the tissues, and which avoids the use of fup. [ABSTRACT FROM AUTHOR]

The 5-heterocyclic 2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles were obtained as potential biologically active compounds. Lipophilicity is one of the most important physicochemical properties of compounds and was already taken into account during the drug candidates design and development. The lipophilicity of compounds was determined using the computational (log P) and chromatography (log kw, RMw) methods. The experimental ones included the reverse-phase column high performance liquid chromatography RP (HPLC) with C8, C18, phosphatidylcholine (IAM), and cholesterol stationary phases and the thin layer chromatography (RP-HPTLC) with C8 and C18 stationary phases and various organic modifiers under the isocratic conditions. Descriptive statistics, correlation, and PCA analyses were used to compare the obtained results. For lipophilicity estimation of the tested compounds by HPTLC, dioxane and MeOH seem to be particularly beneficial as organic modifiers. The chromatographic lipophilicity parameters log kw (RMw) were well correlated and highly redundant (85%) compared with those calculated. Most compounds possess lipophilicity parameters within the recommended range for drug candidates. [ABSTRACT FROM AUTHOR]

The main goal of this study was the assessment of the N, N-disubstituted-2-chloroacetamides' biological profile by chromatographic and in silico approach. Preliminary, their drug-like as well as lead-like properties and the bioactivity scores were analyzed. By applying reversed phase thin-layer chromatography as the simulator of compound's distribution across biological membranes, the assumed bioactivity descriptors of the studied chloroacetamides were obtained. The compliance between obtained chromatographic parameters (RM,0 m) and relevant software lipophilicity/pharmacokinetic/ecotoxicity predictors of studied derivatives were examined by linear regression and additionally supported by more detailed relations established by multivariate methods. Also, it was confirmed that the studied bioactivity properties of the given chloroacetamides are conditioned by the type of the present hydrocarbon substituents (number, arrangement and binding of C atoms). [ABSTRACT FROM AUTHOR]

Hydrazones are a large group of compounds with antibacterial, antituberculosis, antifungal, anticonvulsant, antiviral, antiprotozoal, anticancer and anti-inflammatory properties. Ten newly synthesized hydrazones were tested for their antimicrobial and antituberculosis activities. Screening tests were performed using the disk diffusion method. Then, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration were determined for the most promising compounds. Synergy of the action of the tested substances with reference drugs was also tested. Drugs standardly used in the treatment of tuberculosis: rifampicin and isoniazid were used as reference substances. Based on the obtained results, fractional inhibitory concentration coefficients were calculated for individual combinations. The tested ones showed weak antimicrobial activity. They didn't show either synergism of action with rifampicin and isoniazid. Then, experimental and theoretical lipophilicity parameters were determined for the obtained derivatives. The research was carried out using reversed-phase high-performance liquid chromatography (RP-HPLC), in which the mobile phase is a mixture of methanol and water. To confirm the validity of the chromatographic technique used, both experimental and calculated lipophilicity parameters were correlated. The correlation matrix of these relationships was subjected to principal component analysis (PCA). [ABSTRACT FROM AUTHOR]

A method comprising the use of a fluorinating agent, the Ishikawa's reagent, at one of its steps was developed for the synthesis of 1,3,5-trifluoroadamantane-7-isocyanate from 3,5,7-trifluoroadamantane-1-carboxylic acid and diphenylphosphoryl azide. The reaction of 1,3,5-trifluoroadamantane-7-isocyanate with fluoroanilines gave 1,3-disubstituted ureas in the yields of 58–73%. The influence of number of the fluorine atoms in the adamantyl moiety on the melting point, lipophilicity, and water solubility of ureas was estimated, which allows one to intentionally tune these important properties of ureas as promising enzyme inhibitors. The molecular docking revealed the effectiveness of 4-({4-[3-(3,5,7-trifluoroadamantan-1-yl)ureido]cyclohexyl}oxy)benzoic acid in the inhibition of p38 MAPK, c-Raf and hsEH. [ABSTRACT FROM AUTHOR]

Bulk polytetrafluoroethylene (PTFE) foam is a great potential oil–water separation material, owing to the high hydrophobicity and lipophilicity property. However, the technique of fabricating PTFE foam with low cost, controllable porosity and high mechanical strength remains an urgent requirement due to its high chemical inertness induced limitation. A kind of bulk PTFE foam material is prepared by cold pressing co-sintering method, employing sodium chloride (NaCl) as pore forming agent. SEM measurements reveal that the size and distribution of pore structure are mainly determined by the particle size and content of NaCl, because the migration and diffusion behaviors of PTFE particles suffer from more inhibition induced by increased NaCl particles during sintering. The PTFE foam with uniformly distributed pore structures can be obtained from composite mixed with 70 wt% NaCl and 30 wt% PTFE, with a low thermal conductivity as low as 0.069 W/(m K). With the decrease of PTFE content in raw composite, the density and mechanical properties of PTFE foam gradually declines. However, the tensile strength remains as low as 0.2 MPa, with an elongation rate of 21%, which guarantees the required mechanical strength avoiding being broken when use as a bulk oil absorption material. Remarkably, the PTFE foam shows a strong hydrophobicity, with a mean water contact angle of 137°, and with a mean surface roughness of 4.41 μm. It exhibits separation efficiency larger than 99% in 30 cycles, with separation flux larger than 4000 L/m2/h within 15 cycles, indicating excellent recyclability and stability. The PTFE foam sample also shows desirable continuous separation performance for oil/water mixture. The proposed bulk PTFE foam with low manufacturing cost and stable chemical and mechanical properties will provide data and theoretical support for the material applied in oil/water separation and thermal-protective coating. [ABSTRACT FROM AUTHOR]