Conformational preferences of fluorine-containing agrochemicals and their implications for lipophilicity prediction

• Daniela Rodrigues Silva,
• Joyce K. Daré and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2020, 16, 2469–2476, doi:10.3762/bjoc.16.200

• fluorine-containing agrochemicals. Accordingly, this study aims to determine the most likely conformers of some fluorine-containing agrochemicals and to correlate their molecular dipole moments with the respective n-octanol/water partition coefficients (log P), in order to investigate the dependence of the

• lipophilicity with the molecular conformation. Keywords: dipole moment; fluorinated compounds; gauche effect; herbicides; log P; Introduction Whilst in the last years the agrochemical industry has encountered a period of downturn affected by new regulations, low crop prices, biochemical resistance, among

• preferences. It is worth mentioning that Igg has two gauche relationships between C–F and C–O bonds, which is stabilized by σCH → σCF/CO hyperconjugative interactions [14]. Second, we have searched for the implications of the relative conformational stabilities for log P prediction, the most common parameter

Fluorine-containing substituents: metabolism of the α,α-difluoroethyl thioether motif

• Andrea Rodil,
• Alexandra M. Z. Slawin,
• Nawaf Al-Maharik,
• Ren Tomita and
• David O’Hagan

Beilstein J. Org. Chem. 2019, 15, 1441–1447, doi:10.3762/bjoc.15.144

• literature [3], substituents which are typically introduced to stop metabolism of aryl rings [4]. Other fluorinated motifs are gaining in importance too, such as aryl–OCF3 and aryl–SCF3 ethers, although these substituents can significantly raise lipophilicity (log P) [5][6]. There are relatively few

• reduces relative to the perfluoro substituents [13][14][15]. In this context we recently introduced aryl α,α-difluoroethyl thioethers such as 1 as a motif of this class [16][17][18]. Log P assessments of PhSCF2CH3 (1) indicate that it is more polar than the PhSCF3 (2) and also the aliphatic PhSCH2CH3

• ether 3 as shown in Figure 2. Therefore, there is potential for the inclusion of this motif in candidate molecules without a significant increase in log P. Having explored synthetic routes and log P evaluations, we now report our initial studies on the metabolism of the ArSCF2CH3 substituent. In this

Computational methods in drug discovery

• Sumudu P. Leelananda and
• Steffen Lindert

Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

Interactions between cyclodextrins and cellular components: Towards greener medical applications?

• Loïc Leclercq

Beilstein J. Org. Chem. 2016, 12, 2644–2662, doi:10.3762/bjoc.12.261

• significant number of H-bond donors and acceptors [39]. Indeed, CDs violate three criteria of the Lipinski’s rule: i) no more than 5 H-bond donors, ii) no more than 10 H-bond acceptors, iii) a molecular mass less than 500 g/mol, and iv) an octanol–water partition coefficient (log P) not greater than 5 [40

Biomimetic synthesis and HPLC–ECD analysis of the isomers of dracocephins A and B

• Viktor Ilkei,
• András Spaits,
• Anita Prechl,
• Áron Szigetvári,
• Zoltán Béni,
• Miklós Dékány,
• Csaba Szántay Jr,
• Judit Müller,
• Árpád Könczöl,
• Ádám Szappanos,
• Attila Mándi,
• Sándor Antus,
• Ana Martins,
• Attila Hunyadi,
• György Tibor Balogh,
• György Kalaus (†),
• Hedvig Bölcskei,
• László Hazai and
• Tibor Kurtán

Beilstein J. Org. Chem. 2016, 12, 2523–2534, doi:10.3762/bjoc.12.247

• calculated (total polar surface area; TPSA) and measured (pKa, log P/D and Pe) parameters are shown in Table 1. The lipophilicity of neutral species of naringenin and dracocephins A and B are 3.39, 2.52 and 2.39, respectively. Similarly to this lipophilicity trend, the TPSA value of (±)-naringenin is lower

• -permeable compounds, respectively. These results are in good correlation with a lower lipophilicity (log P/D7.4) and higher TPSA of dracocephins A and B compared to that of naringenin. Pharmacological studies In connection with the BBB penetration studies, 2a–d and 3a–d were tested for their potential

Synthesis, dynamic NMR characterization and XRD studies of novel N,N’-substituted piperazines for bioorthogonal labeling

• Constantin Mamat,
• Marc Pretze,
• Matthew Gott and
• Martin Köckerling

Beilstein J. Org. Chem. 2016, 12, 2478–2489, doi:10.3762/bjoc.12.242

• development of new building blocks for specific and bioorthogonal labeling of biologically active compounds is of high importance. Depending on their size and composition, building blocks can influence (bio-)chemical parameters such as the lipophilicity (log P) affecting the solubility and the biological

• literature [39], the radiochemical yields and the reaction times of [18F]4b and [18F]5b are similar. Finally, the partition coefficients (log P) were determined to be 1.26 ± 0.01 (n = 3) for compound 4b and 1.45 ± 0.01 (n = 3) for 5b. Compared to other standard building blocks like [18F]SFB (log P = 1.8) [40

• ], FBAM (log P = 2.7) [41], 4-fluorobenzaldehyde (log P = 1.9) [42] or the click labeling building block p-[18F]F-SA (log P = 1.7) [43], the lipophilicity of our 18F-building blocks is reduced. The hydrophilic character of the building blocks enables a radiolabeling in aqueous solutions and the influence

Is conformation a fundamental descriptor in QSAR? A case for halogenated anesthetics

• Maria C. Guimarães,
• Mariene H. Duarte,
• Josué M. Silla and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2016, 12, 760–768, doi:10.3762/bjoc.12.76

• structures encode biological activities. A previous study using log P (the octanol/water partition coefficient) as descriptor showed a good correlation with pMAC [21], but the resulting model was not validated. Thus, the present study provided an internal (through leave-one-out cross-validation) and external

• available in the Dragon software. Thus, a major goal in QSAR is to determine and interpret the chemical motifs/properties responsible for the observed biological effects. We have checked that even the simple log P model yields good prediction ability upon selection of test set compounds using the Kennard

Terminal lipophilization of a unique DNA dodecamer by various nucleolipid headgroups: Their incorporation into artificial lipid bilayers and hydrodynamic properties

• Emma Werz and
• Helmut Rosemeyer

Beilstein J. Org. Chem. 2015, 11, 913–929, doi:10.3762/bjoc.11.103

• with respect to efficiency (maximal bilayer brightness) as well as stability against perfusion (final stable bilayer brightness). Attempts to correlate these parameters with the log P values of the corresponding nucleolipid head groups failed, a result which clearly demonstrates that not only the

• brightness values (in MHz) as well as the final stable brightness data (in MHz and %) with the log P values of the corresponding nucleolipid headgroup using Tetko’s ALOGPS method (v. 3.01) for the calculation (Table 2). As can be seen in Table 2, no obvious correlation could be deduced. This means that the

• bilayer (expressed in number of perfusions to reach a stable brightness, and (iv) the final constant bilayer brightness. The log P values can only be correlated with the number of C-atoms of the lipid moieties, which are probably responsible for the binding to the bilayer. Of decisive importance for an

Natural phenolic metabolites with anti-angiogenic properties – a review from the chemical point of view

• Qiu Sun,
• Jörg Heilmann and
• Burkhard König

Beilstein J. Org. Chem. 2015, 11, 249–264, doi:10.3762/bjoc.11.28

• antiproliferative activity of these acylphloroglucinols in HMEC-1 increases with increasing log P. Increasing the number of carbon atoms in the acyl group provides higher lipophilicity, which allows the compound to better penetrate across cellular membranes in the in vitro assay. In contrast, the activity of the

First chemoenzymatic stereodivergent synthesis of both enantiomers of promethazine and ethopropazine

• Paweł Borowiecki,
• Daniel Paprocki and
• Maciej Dranka

Beilstein J. Org. Chem. 2014, 10, 3038–3055, doi:10.3762/bjoc.10.322

• ability to interact with amino acid residues which are responsible for the catalytic activity. For example, it is well documented [67][68][69] that polar solvents (log P < 1) are less suitable for biocatalytic purposes since hydrophilic media (such as methanol, ethanol, acetone, acetonitrile etc.) distort

• (±)-3 as well as a good enzymatic activity and selectivity are retained, is being of particular significance for the overall success of the process. Five different apolar organic solvents (varying in log P, dielectric constant ε, dipolar moment μ) including: n-hexane, pentane, toluene, MTBE, and diethyl

Thermal and oxidative stability of the Ocimum basilicum L. essential oil/β-cyclodextrin supramolecular system

• Daniel I. Hădărugă,
• Nicoleta G. Hădărugă,
• Corina I. Costescu,
• Ioan David and
• Alexandra T. Gruia

Beilstein J. Org. Chem. 2014, 10, 2809–2820, doi:10.3762/bjoc.10.298

• phenolic derivative, is also better encapsulated in β-CD due to its rigid and hydrophobic structure (log P = 2.8), although it is an oxygenated compound. The ether structure renders methylchavicol (6) more similar to limonene (1), which has a relatively rigid and hydrophobic structure. The same behavior

• hydrophobicity and structural characteristics play an important role for both encapsulation efficiency and competitivity. Thus, a statistically significant correlation could be obtained for the encapsulation efficiency (E.E.) of oxygenated monoterpenes if the hydrophobicity (log P) is considered as the parameter

• relative encapsulation efficiency and the hydrophobicity (log P). These two variables include both structural characteristics (from E.E.) and transport/van der Waals interaction aspects (from log P). These parameters retain characteristics from one another. The PCA analysis allows extraction of the useful

Removal of volatile organic compounds using amphiphilic cyclodextrin-coated polypropylene

• Ludmilla Lumholdt,
• Sophie Fourmentin,
• Thorbjørn T. Nielsen and
• Kim L. Larsen

Beilstein J. Org. Chem. 2014, 10, 2743–2750, doi:10.3762/bjoc.10.290

• with 1 (see Table 2 for reference to hydrophobicity of the VOCs, represented by the log P value). Although butylbenzene (6) was expected to have the highest affinity towards the cavity due its hydrophobicity, it seems not to be as prone to complex formation as anticipated. As briefly mentioned above

Effect of cyclodextrin complexation on phenylpropanoids’ solubility and antioxidant activity

• Miriana Kfoury,
• David Landy,
• Lizette Auezova,
• Hélène Greige-Gerges and
• Sophie Fourmentin

Beilstein J. Org. Chem. 2014, 10, 2322–2331, doi:10.3762/bjoc.10.241

• was found between the Kf values and the log P of the guest molecules, meaning that steric considerations have also to be taken into account. Indeed, for β-CD derivatives, phenylpropenes with an allyl group (2 and 4) present higher stability constants than the respective PPs with a propenyl group (1

De novo macrolide–glycolipid macrolactone hybrids: Synthesis, structure and antibiotic activity of carbohydrate-fused macrocycles

• Richard T. Desmond,
• Anniefer N. Magpusao,
• Chris Lorenc,
• Jeremy B. Alverson,
• Nigel Priestley and
• Mark W. Peczuh

Beilstein J. Org. Chem. 2014, 10, 2215–2221, doi:10.3762/bjoc.10.229

• -membered ring macrocycles with a C4’-O-tert-butyldimethylsilyl group. MICs as low as 52 μg/mL against S. aureus, E. faecalis, and B. subtillis were observed. The small data set and low activity of the compounds prevent a QSAR analysis but the influence of a log P effect seems most likely [31][32][33

Synthesis and antibacterial activity of monocyclic 3-carboxamide tetramic acids

• Yong-Chul Jeong and
• Mark G. Moloney

Beilstein J. Org. Chem. 2013, 9, 1899–1906, doi:10.3762/bjoc.9.224

• activity differences between efflux-positive (H3) and negative (H4) H. influenza strains are large, are more lipophilic compared with other active analogues (rel-PSA < 13.5, c log P > 2.79 and c log D (7.4) > 1.41). On the other hand, analogues 2 and 3 show a broad-spectrum activity against Gram-positive

• active, while N-acetyl phenyl derivatives 3e,f were inactive or only very weakly active. This SAR might be accounted for by their physicochemical properties: the less lipophilic character of N-acetyl 3e,f (rel-PSA > 17.0%, c log P < 0.80 and c log D (7.4) < −1.20) compared with those of N-alkyl 2a,b,h

• (rel-PSA < 15.0%, c log P > 1.77 and c log D (7.4) > 0.41) might make penetration of the bacterial cell membrane more difficult. However, 3-carboxamides 2c–g and 3a–d, all possessing alkyl substituents, including a benzyl group on the amide function, are also active to Gram-positive strains

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

• Todd J. Eckroat,
• Abdelrahman S. Mayhoub and
• Sylvie Garneau-Tsodikova

Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116

• TgCRDN8 mouse brain sections by in vitro autoradiography [22]. [18F]-Labeled stilbene derivatives have enhanced brain kinetics rendering them appropriate for clinical use [23][24][25]. In order to control the lipophilicity and keep the partition coefficient (log P) value between 1 and 3, which reduces

• -1,2,4-oxadiazole analogue 51c was more lipophilic than its 1,3,4 counterpart 50a (log P = 3.22 for 51c and 2.43 for 50a) [47]. In general, even though 3,5-diphenyl-1,2,4-oxadiazoles 51a–e show excellent affinity for Aβ aggregates in in vitro binding experiments (Ki = 4.3–47.1 nM), they show poorer brain

Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway

• Paul M. Hershberger,
• Satyamaheshwar Peddibhotla,
• E. Hampton Sessions,
• Daniela B. Divlianska,
• Ricardo G. Correa,
• Anthony B. Pinkerton,
• John C. Reed and
• Gregory P. Roth

Beilstein J. Org. Chem. 2013, 9, 900–907, doi:10.3762/bjoc.9.103

• physicochemical and pharmacological properties Overall, the project probes presented physicochemical properties consistent with those of well-recognized drug-like molecules (Table 1). Molecular weights ranged from 287 to 465 g/mol. Calculated log P values were between 3.1 and 3.5 with the exception of 4, which

• to 5, thereby mitigating the high calculated log P to some degree. Probes 8 and 12 also showed good solubility. Probe 13 had moderate solubility, and 17 showed the lowest solubility across the pH range but still approximately equal to its IC50 value. The PAMPA (parallel artificial membrane

Regioselective synthesis of 7,8-dihydroimidazo[5,1-c][1,2,4]triazine-3,6(2H,4H)-dione derivatives: A new drug-like heterocyclic scaffold

• Nikolay T. Tzvetkov,
• Harald Euler and
• Christa E. Müller

Beilstein J. Org. Chem. 2012, 8, 1584–1593, doi:10.3762/bjoc.8.181

• the physicochemical properties of imidazo[5,1-c][1,2,4]triazine-3,6-dione derivatives we determined water-solubility, log P, and pKa values for compound 25 as a representative of this new class of heterocyclic compounds. Water solubility at physiological pH of 7.4 was found to be 47 µg/mL, which is a

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

• Carolin Fischer and
• Burkhard Koenig

Beilstein J. Org. Chem. 2011, 7, 59–74, doi:10.3762/bjoc.7.10

• modulators. The tariquidar (44) derived compounds showed log P-dependent inhibition activity of the ABCB1 transporter, which represents an important component of the blood–brain barrier and is a major limitation in cancer chemotherapy. Primary and cyclic secondary amines were coupled to 45 to give moderate

N-acylation of ethanolamine using lipase: a chemoselective catalyst

• Mazaahir Kidwai,
• Roona Poddar and
• Poonam Mothsra

Beilstein J. Org. Chem. 2009, 5, No. 10, doi:10.3762/bjoc.5.10

• solution phase, solvent used is 1,4-dioxane, which is non polar (log p = −1.1) and make reaction sluggish in nature. The progress of the reaction is due to polarity of reactants and products ethanolamine 2, fatty acids or esters 1a–h and N-acylated products 3a–d. Choice of solvent The synthesis of N