Determination Of Lipophilicity Research Articles

Chromatographic Determination of Permeability-Relevant Lipophilicity Facilitates Rapid Analysis of Macrocyclic Peptide Scaffolds.

Hydrocarbon-determined shake-flask measurements have demonstrated great utility for optimizing lipophilicity during early drug discovery. Alternatively, chromatographic methods confer reduced experimental error and improved handling of complex mixtures. In this study, we developed a chromatographic approach for estimating hydrocarbon-water shake-flask partition coefficients for a variety of macrocyclic peptides and other bRo5 molecules including PROTACs. The model accurately predicts experimental shake-flask measurements with high reproducibility across a wide range of lipophilicities. The chromatographic retention times revealed subtle conformational effects and correlated with the ability to sequester hydrogen bond donors in low dielectric media. Estimations of shake-flask lipophilicity from our model also accurately predicted trends in MDCK passive cell permeability for a variety of thioether-cyclized decapeptides. This method provides a convenient, high-throughput approach for measuring lipophilic permeability efficiency and predicting passive cell permeability in bRo5 compounds that is suitable for multiplexing pure compounds or investigating the properties of complex library mixtures.

Green Synthesis and Bioactivity of Aliphatic N-Substituted Glycine Derivatives.

Standard amino acids have an asymmetric α-carbon atom to which -COOH, -NH2, -H, and -R groups are bonded. Among them, glycine is the simplest (R = -H) with no asymmetric carbon, and other natural amino acids are C-substituted of glycine. Here, we have designed and made a green synthesis of some new N-substituted glycine derivatives with R-(NH)CH2-COOH formula, where R is flexible and hydrophobic with different chain lengths and benches of the type propyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, 2-aminoheptyl, and octyl. These glycine derivatives were characterized by recording their melting points and FT-IR, mass, 1H NMR, and 13C NMR spectra. DFT studies revealed that 2-aminoheptyl glycine had the highest electronegativity value and can thus act as a good bidentate ligand for the metal centers. ADME comparative results and bioavailability radars indicated that both octyl- and 2-aminoheptyl glycine had the most lipophilicity, making them good agents in cell passing. Furthermore, lipophilicity determination showed that octyl glycine was the best and propylgly was more soluble than others. Based on solubility, lipophilicity, and dipole moment values, propyl- and 2-aminoheptyl-glycine were considered for bio-macromolecular interaction studies. Thus, the interaction of these two agents with DNA and HSA was studied using absorption spectroscopy and circular dichroism techniques. Due to the presence of the R-amine group, they can interact with the DNA by H-binding and hydrophobicity, while electrostatic mode could not be ruled out. Meanwhile, molecular docking studies revealed that octyl- and 2-aminoheptyl glycine had the highest negative docking energy, which reflects their higher tendency to interact with DNA. The DNA binding affinity of two candidate AAs was determined by viscosity measurement and fluorescence emission recording, which confirms that groove binding occurs. Also, the toxicity of these synthesized amino acid derivates was tested against the human foreskin fibroblast (HFF) cell line. They showed IC50 values within the range of 127-344 μM after 48 h with the highest toxicity for 2-aminoheptyl glycine.

Study on binding affinity profile, bioactivity, and lipophilicity of selected antipsychotic drugs

Schizophrenia is a complex mental illness that affects almost 1% of the population and has no curative treatment. Currently, available neuroleptic drugs have severe limitations and induce drug-related adverse effects. Receptor binding affinity parameters and lipophilicity are important characteristics that describe the bioactivity of these drugs. Lipophilicity is an important physicochemical property of a drug, which predicts distribution, binding to plasma protein, crossing the blood–brain barrier, and biological activity. Five antipsychotic drugs (Haloperidol, Risperidone, Aripiprazole, Olanzapine, and Quetiapine) were selected and the experimental determination of lipophilicity was carried out by reverse phase thin-layer chromatography (RP-TLC) using four types of stationary phases (RP-18, CN, Diol, and NH2 modified silica gel HPTLC plates) and acetonitrile-water with increasing percentage of acetonitrile and 0.2% formic acid in each case as mobile phase. Lipophilicity parameters (mRM and RM0) calculated from the experimental chromatographic retention data were discussed in terms of the correlation with different receptor binding affinity parameters determined by computational methods.

Pharmacokinetics of N,N-dimethyltryptamine in Humans.

N,N-dimethyltryptamine (DMT) is a psychedelic compound under development for the treatment of major depressive disorder (MDD). This study evaluated the preclinical and clinical pharmacokinetics and metabolism of DMT in healthy subjects. The physiochemical properties of DMT were determined using a series of in vitro experiments and its metabolic profile was assessed using monoamine oxidase (MAO) and cytochrome P450 (CYP) inhibitors in hepatocyte and mitochondrial fractions. Clinical pharmacokinetics results are from the phase I component of a phase I/IIa randomised, double-blind, placebo-controlled, parallel-group, dose-escalation trial (NCT04673383). Healthy adults received single escalating doses of DMT fumarate (SPL026) via a two-phase intravenous (IV) infusion. Dosing regimens were calculated based on pharmacokinetic modelling and predictions with progression to each subsequent dose level contingent upon safety and tolerability. In vitro clearance of DMT was reduced through the inhibition of MAO-A, CYP2D6 and to a lesser extent CYP2C19. Determination of lipophilicity and plasma protein binding was low, indicating that a high proportion of DMT is available for distribution and metabolism, consistent with the very rapid clinical pharmacokinetics. Twenty-four healthy subjects received escalating doses of DMT administered as a 10-min infusion over the dose range of 9-21.5 mg (DMT freebase). DMT was rapidly cleared for all doses: mean elimination half-life was 9-12 min. All doses were safe and well tolerated and there was no relationship between peak DMT plasma concentrations and body mass index (BMI) or weight. This is the first study to determine, in detail, the full pharmacokinetics profile of DMT following a slow IV infusion in humans, confirming rapid attainment of peak plasma concentrations followed by rapid clearance. These findings provide evidence which supports the development of novel DMT infusion regimens for the treatment of MDD. Registered on ClinicalTrials.gov (NCT04673383).

High-performance liquid chromatography evaluation of lipophilicity and QSRR modeling of a series of dual DNA gyrase and topoisomerase IV inhibitors

AbstractBacterial DNA gyrase and topoisomerase IV control the topological state of DNA during replication and represent important antibacterial drug targets. To be successful as drug candidates, newly synthesized compounds must possess optimal lipophilicity, which enables efficient delivery to the site of action. In this study, retention behavior of twenty-three previously synthesized dual DNA gyrase and topoisomerase IV inhibitors was tested in RP-HPLC system, consisting of C8 column and acetonitrile/phosphate buffer (pH 5.5 and pH 7.4) mobile phase. logD was calculated at both pH values and the best correlation with logD was obtained for retention parameter φ0, indicating that this RP-HPLC system could be used as an alternative to the shake-flask determination of lipophilicity. Subsequent QSRR analysis revealed that intrinsic lipophilicity (logP) and molecular weight (bcutm13) have a positive, while solubility (bcutp3) has a negative influence on this retention parameter.

Determination of lipophilicity and ionization of fentanyl and its 3‑substituted analogs by reversed-phase thin-layer chromatography

Lipophilicity and ionization constant of sixteen fentanyl analogues were investigated by reversed-phase thin-layer chromatography (RP-TLC). Fourteen compounds have nitrogen containing groups at C-3 position of the piperidine ring and two compounds are 3-carbomethoxy derivatives of fentanyl. Among them, five are diastereomeric cis/trans couples and six novel trans diastereomers. In addition, the lipophilicity and ionization constant of fentanyl were also determined by the same method, as a reference. The physicochemical property, lipophilicity, expressed as retention indices RM0, b, and C0, as well as PC1, was determined and correlated with in silico values. Ionization constants were determined on the basis of the relationships between analyte’s retention expressed as RF and mobile phase pH.Calculated structural descriptors together with the retention indices, were subjected to the principal component analysis – PCA and hierarchical cluster analysis – HCA, in order to provide basic insights into the similarities among the studied compounds. The blood – brain barrier (BBB) permeation was investigated in the function of experimentally obtained values of lipophilicity, polar surface area and molecular weight. In general, results of the present research corroborate well with previously determined antinociceptive activities of the investigated compounds, pointing out that besides the cis/trans isomerism, another set of important parameters should be taken into account when designing new derivatives of C-3 substituted fentanyl, especially lipophilicity, voluminosity and HBD/A character of the substituents. Accordingly, RP-TLC can be considered as a valuable asset in the ligand-based drug design.

Liquid Chromatography on the Different Methods for the Determination of Lipophilicity: An Essential Analytical Tool in Medicinal Chemistry

Lipophilicity is one of many parameters involved in the biological activity of drugs, as it affects their pharmacokinetic and pharmacodynamic behavior. Generally, lipophilicity is assessed by the partition coefficient of a compound between a nonpolar phase (n-octanol) and an aqueous phase (water), expressed as P (partition coefficient) or as its decimal logarithm (Log P). The gold standard method for the experimental determination of Log P is the shake-flask method. In this context, chromatographic methods enable the direct and simple quantification of the partitioned compound between the two phases. This review discusses the use of liquid chromatography (LC) for direct and indirect determination of lipophilicity. Beyond the classical isotropic log P determination, methods for assessing anisotropic lipophilicity are also reviewed. Several examples are discussed that highlight the versatility of LC technique and current trends. The last section of this review focuses on a case study describing an experience of our group and emphasizing the dual role of LC in determining Log P.

Accessing Lipophilicity and Biomimetic Chromatography Profile of Biologically Active Ingredients of Botanicals Used in the Treatment of Inflammatory Bowel Disease.

In the present study, various procedures have been compared for the determination of lipophilicity, hydrophobicity, and plasma protein binding of curcuminoids, boswellic acids, andrographolides, and piperine as biologically active ingredients of botanicals used in IBD treatment. Our results have shown that IAM-HPLC assay is the most suitable one for lipophilicity determination of all analytes regardless of their class and botanical source. HSA-HPAC and AGP-HPAC assays revealed that all investigated compounds have a higher affinity for HSA which is the most abundant protein in human plasma. The high affinity of biologically active compounds to all biological structures (phospholipids and proteins) admonishes that their small portion is available for therapeutic effects in IBD patients. Our experimental research is complemented by various theoretical approaches based on different algorithms for pharmacokinetic properties prediction. The similarities between experimental and calculated values were evaluated using PCA and CA as a statistical tool. The statistical analysis implies that plasma protein binding is a complex process, and theoretical approaches still cannot fully replace experimental ones.

Preparation and surface modification of ZnO nanopowder lubricating additive by dielectric barrier discharge plasma assisted ball milling

To improve the lipophilicity of ZnO nanopowder in lubricating oil and analyze the surface modification mechanism, stearic acid, oleic acid, and HTAB-SL were selected as surface modifiers. ZnO nanopowders were prepared and modified in a single step by dielectric barrier discharge plasma assisted ball milling for 10 h. The ZnO nanopowder was characterized and analyzed by SEM, FTIR, TG-DSC, x-ray diffractometer, x-ray photoelectron spectroscopy, lipophilicity determination, COF test, etc. The results showed that the size of ZnO nanopowder was 40–100 nm. The results also revealed that the lipophilic groups –CH2 and –CH3 of modifier were successfully modified by ZnO nanopowder. Meanwhile, hydroxyl groups –OH of ZnO nanopowder chemically adsorbed with hydrophilic carboxyl groups –COO– of modifier. The lipophilicity of modified ZnO nanopowder was significantly increased. The COF of oil sample with modified ZnO nanopowder was smaller than that of oil sample with unmodified ZnO nanopowder. The modification mechanism was attributed to the coupling action of plasma, modifier, and mechanical forces of ball milling. The research demonstrated that modified ZnO nanopowder is more suitable as lubricating additive.

Probing the interaction of new and biologically active Pd(II) complex with DNA/BSA via joint experimental and computational studies along with thermodynamic, NLO, FMO and NBO analysis.

Treatment with transition metal complexes is an efficient method to fight with cancer. Therefore, a new transition metal complex formulated as [Pd(1, 3-pn)(acac)]Cl (pn and acac stand for propylendiamine and acetylacetonate, respectively) was synthesized and analyzed using 1H NMR, Fourier transform infrared, electronic absorption spectroscopy techniques as well as elemental analysis and conductivity measurement. The geometry optimization, frontier molecular orbital (FMO) analysis, molecular electrostatic potential (MEP), natural bond orbital (NBO) analysis and nonlinear optical (NLO) property were accomplished by density functional theory (DFT) at B3LYP level with 6-311G(d,p)/aug-cc-pVTZ-PP basis set. Preliminary determination of antitumor activity and lipophilicity of this metal complex was performed experimentally and the promising results were obtained. This encouraged us to study the interaction and binding mode/modes of this complex with DNA as the primary receptor for the chemotropic drugs and BSA as the transporter protein in the circulatory system. For this reason, the binding of newly made complex was assessed in-vitro under physiological state using experimental and in-silico molecular modeling studies. So, the CT-DNA binding study of this complex was explored using spectrofluorometric as well as spectrophotometric techniques, viscosity and gel electrophoresis experiments. Furthermore, fluorescence, UV-Vis, F[Formula: see text]rster resonance energy transfer and circular dichroism studies were carried out for BSA binding. The experimental and computational interaction studies showed that [Pd(1, 3-pn)(acac)]Cl complex binds to the minor groove of CT-DNA and interacts with BSA by van der Waals forces and hydrogen bond.

Influence of mono- and two-component organic modifiers on determination of lipophilicity of tetradentate Schiff bases

Influence of mono- and two-component organic modifiers on determination of lipophilicity of tetradentate Schiff bases

The spectrophotometric determination of lipophilicity and dissociation constants of ciprofloxacin and levofloxacin

Lipophilicity plays a significant role in the permeability of the drugs through cell membranes and impacts the drug activity in the human body. In this paper, the spectrophotometric method was used to determine the apparent partition coefficients of two amphoteric drugs: ciprofloxacin and levofloxacin. The apparent partition coefficient was determined with the classic shake-flask method with n-octanol according to OECD guidelines. The lipophilicity profiles in a wide range of pH were determined and described quantitatively with the quadratic function. Basing on the macro- and microdissociation constants, the true partition coefficient for both drugs was calculated. Both levofloxacin and ciprofloxacin were lipophilic. The neutral forms, i.e., zwitterionic and uncharged, dominate in the pH relevant to the one in the intestines, the place from which they are absorbed.

Anionic polyhedral boron clusters conjugates with 7-diethylamino-4-hydroxycoumarin. Synthesis and lipophilicity determination

A series of water-soluble conjugates of 7-diethylamino-4-hydroxycoumarin with four different anionic polyhedral boron clusters was synthesized. The distribution coefficients (log D7.4) as a measure of the ability to pass through the cell membrane for novel compounds were determined via a shake-flask methodology in n-octanol/aqueous (pH 7.4) buffer solution system. For two closo-dodecaborate modifications log D7.4 displayed negative lipophilicity values. Conjugates of metallacarboranes containing Co and Fe as long as two 7,8-dicarba-nido-undecaborate coumarin anions were found to have appropriate lipophilicity for medicinal applications.

Biomembrane Modelling in Planar Chromatographic Determination of Lipophilicity Using Olive and Castor Oils

BackgroundLipophilicity is a crucial physicochemical parameter that predicts in vivo pharmacokinetics and should be reliably estimated in early stage drug discovery to reduce incidence of attrition. Previous methodologies for its measurement often lead to technically incorrect decisions due to simplistic architecture and poor biomimetic attributes. Significantly, a certain seed oil, used for biomembrane modelling on planar chromatographic platform, was reported to be sufficiently biomimetic and fit for purpose.ObjectivesTo evaluate olive oil (OL) and olive-castor oil (OL-C) equi-mixture as lipids for biomembrane simulation on planar chromatographic platform.Material and MethodRetention behavior of nabumetone, a model compound was used to optimize these potential lipid membranes using a thin film engineered from 5% Liquid paraffin (LP) as benchmark, while halofantrine, nabumetone , α-naphthol and β-naphthol representing varying molecular polarities, were used for validation studies. The validation involved 2-way analysis of variance (ANOVA) associated with variability in Basic lipophilicity parameter (Rmw), and Specific hydrophobic surface area (SHSA) for the optimized surfaces, relative to LP and octadecylsilane (ODS) Further validation entailed correlation of the lipophilicity descriptor i.e. isocratic chromatographic hydrophobicity index (ICHI) on OL, OL-C, ODS and LP with experimental Log P(octanol/water).ResultsOptimized film thicknesses were produced by 5% OL and 1.25% OL-C (p > 0.05). The 2-way ANOVA revealed great variability in performance characteristics of the surfaces (p < 0.0001), and the new surfaces also gave poorer correlation with Log P values (R2= 0.502 and 0.449 respectively).ConclusionThe 1.25 % OL-C demonstrated a higher biomimetic attribute and warrants further validation studies to ascertain biorelevance, of lipophilicity measurement on this platform, in predicting oral drug absorption.
 Keywords: Lipophilicity, Reversed-phase Thin Layer Chromatography, Retention behaviour, Olive oil, Castor oil

Effect of the versatile bifunctional chelator AAZTA5 on the radiometal labelling properties and the in vitro performance of a gastrin releasing peptide receptor antagonist

BackgroundGastrin Releasing Peptide receptor (GRPr)-based radioligands have shown great promise for diagnostic imaging of GRPr-positive cancers, such as prostate and breast.The present study aims at developing and evaluating a versatile GRPr-based probe for both PET/SPECT imaging as well as intraoperative and therapeutic applications. The influence of the versatile chelator AAZTA5 on the radiometal labelling properties and the in vitro performance of the generated radiotracers were thoroughly investigated.The GRPr-based antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 was functionalized with the chelator 6-[Bis (carboxymethyl)amino]-1,4-bis (carboyxmethyl)-6-methyl-1,4-diazepane (AAZTA5) through the spacer 4-amino-1-carboxymethyl-piperidine (Pip) to obtain AAZTA5-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (LF1). LF1 was radiolabelled with gallium-68 (PET), indium-111 (SPECT, intraoperative applications) and lutetium-177 (therapy, SPECT). In vitro evaluation included stability studies, determination of lipophilicity, protein-binding studies, determination of Kd and Bmax as well as internalization studies using the epithelial human prostate cancer cell line PC3. In vitro monotherapy as well as combination therapy studies were further performed to assess its applicability as a theranostic compound.ResultsLF1 was labelled with gallium-68, indium-111 and lutetium-177 within 5 min at room temperature (RT). The apparent molar activities (Am) were ranging between 50 and 60 GBq/μmol for the 68Ga-labelled LF1, 10–20 GBq/μmol for the 111In- and 177Lu-labelled LF1. The radiotracers were stable for a period of 4 h post labeling exhibiting a hydrophilic profile with an average of a LogDoctanol/PBS of − 3, while the bound activity to the human serum protein was approximately 10%. 68/natGa-LF1, 177/natLu-LF1 and 111/natIn-LF1 exhibited high affinity for the PC3 cells, with Kd values of 16.3 ± 2.4 nM, 10.3 ± 2.73 nM and 5.2 ± 1.9 nM, respectively, and the required concentration of the radiotracers to saturate the receptors (Bmax) was between 0.5 and 0.8 nM which corresponds to approximately 4 × 105 receptors per cell. Low specific internalization rate was found in cell culture, while the total specific cell surface bound uptake always exceeded the internalized activity. In vitro therapy studies showed that inhibition of PC3 cells growth is somewhat more efficient when combination of 177Lu-labelled LF1 with rapamycin is applied compared to 177Lu-laballed LF1 alone.ConclusionEncouraged by these promising in vitro data, preclinical evaluation of the LF1 precursor are planned in tumour models in vivo.

Pd(II) and Rh(III) Complexes with Isoquinoline Derivatives Induced Mitochondria-Mediated Apoptotic and Autophagic Cell Death in HepG2 Cells

Nonplatinum metal complexes of [Pd(L1)Cl2] (C1), [Rh(L1)Cl3(DMSO)] (C2), [Pd(L2)Cl2] (C3), and [Rh(L3)Cl3(DMSO)] (C4) with isoquinoline derivatives have been prepared and characterized. C1–C4 exhib...

Heterocycles 51: Liphophilicity investigation of some thiazole chalcones and aurones by experimental and theoretical methods

Reversed-phase thin-layer chromatography and reversed-phase high-performance liquid chromatography were used for lipophilicity determination of a library of 30 thiazole chalcones and aurones previously synthetized in our laboratory. The experimental lipophilicity data have been compared with theoretical lipophilicity parameters estimated by various computational methods. Good correlations between the experimental and calculated lipophilicity parameters have been found for both investigated classes of compounds. Correlations between the lipophilicity of the thiazole chalcones and aurones and their antiproliferative activity were discussed. The methodologies and data gathered in this study will contribute to the lipophilicity studies of chalcones and aurones derivatives, two important classes of compounds in medicinal chemistry.

Quantitative structure–chromatographic retention relationship of synthesized peptides (HGRFG, NPNPT) and their derivatives

Carapax Trionycis extract peptides (HGRFG, NPNPT) are able to protect against CCl4-induced liver fibrosis. Therefore, this study applies to deal with chromatographic lipophilicity determination of synthesized peptides (HGRFG, NPNPT) and their derivatives using reversed-phase high performance liquid chromatography (RP-HPLC) combined with methanol-water mobile phase and two reversed-phase chromatographic columns (COSMOISL 5C18-MS-II and SHIMADZU-C18). The chromatographic lipophilicity of the analyzed compounds was expressed as logkw constant and correlated with lipophilicity descriptors. Quantitative structure-retention relationships (QSRR) analysis was performed to imitate chromatographic lipophilicity behavior using molecular descriptors. Modeling was performed using linear regression (LR) and multiple linear regression (MLR) methods with the help of principal component analysis (PCA) and hierarchical cluster analysis (HCA). The most influential molecular descriptors were lipophilicity descriptors, which are important for molecules ability to pass through biological membranes. All established QSRR models were statistically validated by standards, cross- and external validation parameters. According to these statistical validation parameters, MLR models (R2 > 0.856) were better for chromatographic lipophilicity prediction of peptide compounds. It can be concluded that chromatographic systems with COSMOISL 5C18-MS-II column were better for modeling of logkw than systems with SHIMADZU-C18 column. Modeling was performed in order to obtain lipophilicity profiles of investigated compounds as future drug candidates.

Lipophilicity Determination of Antifungal Isoxazolo[3,4-b]pyridin-3(1H)-ones and Their N1-Substituted Derivatives with Chromatographic and Computational Methods.

The lipophilicity of a molecule is a well-recognized as a crucial physicochemical factor that conditions the biological activity of a drug candidate. This study was aimed to evaluate the lipophilicity of isoxazolo[3,4-b]pyridine-3(1H)-ones and their N1-substituted derivatives, which demonstrated pronounced antifungal activities. Several methods, including reversed-phase thin layer chromatography (RP-TLC), reversed phase high-performance liquid chromatography (RP-HPLC), and micellar electrokinetic chromatography (MEKC), were employed. Furthermore, the calculated logP values were estimated using various freely and commercially available software packages and online platforms, as well as density functional theory computations (DFT). Similarities and dissimilarities between the determined lipophilicity indices were assessed using several chemometric approaches. Principal component analysis (PCA) indicated that other features beside lipophilicity affect antifungal activities of the investigated derivatives. Quantitative-structure-retention-relationship (QSRR) analysis by means of genetic algorithm—partial least squares (GA-PLS)—was implemented to rationalize the link between the physicochemical descriptors and lipophilicity. Among the studied compounds, structure 16 should be considered as the best starting structure for further studies, since it demonstrated the lowest lipophilic character within the series while retaining biological activity. Sum of ranking differences (SRD) analysis indicated that the chromatographic approach, regardless of the technique employed, should be considered as the best approach for lipophilicity assessment of isoxazolones.

Lipophilicity Determination of Quaternary (Fluoro)Quinolones by Chromatographic and Theoretical Approaches.

Lipophilicity is a vital physicochemical parameter of a molecule, which affects several biological processes such as absorption, tissue distribution, and pharmacokinetic properties. In this study, evaluation of lipophilicities of a series of novel fluoroquinolone-Safirinium dye hybrids using chromatographic and computational methods is presented. Fluoroquinolone-Safirinium dye hybrids have been synthesized as new dual-acting hydrophilic antibacterial agents. Reversed phase thin-layer chromatography and micellar electrokinetic chromatography experiments were carried out. Furthermore, logP values of the target structures were predicted by means of different software platforms and algorithms. In order to assess similarities and dissimilarities of the obtained lipophilicity indexes, cluster analysis and sum of ranking differences were performed. The significant differences of calculated logP values (α = 0.05, p < 0.001) indicated that an experimental approach is necessary for lipophilicity prediction of this class of antibiotics. Chromatographic data indicated that the newly synthesized hybrid (fluoro)quinolone-based quaternary ammonium derivatives show less lipophilic character than the parent (fluoro)quinolones. Additionally, the chromatographically obtained lipophilicity indexes were evaluated for possible application in quantitative retention–activity relationships. The established lipophilicity models have the potential to predict antimicrobial activities of a series of quaternary (fluoro)quinolones against Bacillus subtilis, Escherichia coli, and Proteus vulgaris.