Nonpolar Moieties Research Articles

Structures and Dynamics of Complex Guest Molecules in Confinement, Revealed by Solid-State NMR, Molecular Dynamics, and Calorimetry.

This review gives an overview of current trends in the investigation of confined molecules such as water, small and higher alcohols, carbonic acids, ethylene glycol, and non-ionic surfactants, such as polyethylene glycol or Triton-X, as guest molecules in neat and functionalized mesoporous silica materials employing solid-state NMR spectroscopy, supported by calorimetry and molecular dynamics simulations. The combination of steric interactions, hydrogen bonds, and hydrophobic and hydrophilic interactions results in a fascinating phase behavior in the confinement. Combining solid-state NMR and relaxometry, DNP hyperpolarization, molecular dynamics simulations, and general physicochemical techniques, it is possible to monitor these confined molecules and gain deep insights into this phase behavior and the underlying molecular arrangements. In many cases, the competition between hydrogen bonding and electrostatic interactions between polar and non-polar moieties of the guests and the host leads to the formation of ordered structures, despite the cramped surroundings inside the pores.

A Quantitative Approach to Characterize the Surface Modification on Nanoparticles Based on Localized Dielectric Environments.

Nanoparticles (NPs) are utilized for the functionalization of composite materials and nanofluids. Although oxide NPs (e.g., silica (SiO2)) exhibit less dispersibility in organic solvents or polymers due to their hydrophilic surface, the surface modification using silane coupling agents can improve their dispersibility in media with low dielectric constants. Herein, SiO2 NPs were functionalized using octyltriethoxysilane (OTES, C8) and dodecyltriethoxysilane (DTES, C12), wherein the degrees of surface modification of SiO2@C8 and SiO2@C12 were quantitatively evaluated based on the ratio of modifier to surface silanol group (θ) and the volume fraction of organic modifier to total particle volume (ϕR). The variations of surface properties were revealed by analyzing the Hansen solubility parameters (HSP). Particularly, the surface modification using OTES or DTES significantly affected the polarity (δP) of NPs. The local dielectric environments of surface-modified SiO2 NPs were characterized using a solvatochromic dye, Laurdan. By analyzing the peak position of the steady-state emission spectrum of Laurdan in a NP suspension, the apparent dielectric environments surrounding NPs (εapp) were obtained. A good correlation between ϕR and εapp was observed, indicating that ϕR is a reliable quantity for understanding the properties of surface-modified NPs. Furthermore, the generalized polarization (GP) of NPs was investigated. The surface-modified SiO2 NPs with higher ϕR (≥0.15) exhibited GP > 0, suggesting that the modifiers are well-organized on the surface of NPs. The localized dielectric environment surrounding NPs could be predicted by analyzing the volume fraction of nonpolar moieties derived from modifiers. Alternatively, εapp and GP can be utilized for understanding the properties of inorganic-organic hybrid NPs.

Attraction between Like Charged Ions in Ionic Liquids: Unveiling the Enigma of Tetracyanoborate Anions.

Intermolecular interactions in ionic liquids are mainly governed by Coulombic forces. Attraction between cations has been previously observed and was attributed to dispersion interactions between nonpolar moieties, hydrogen bonding, or π stacking. In this study, we present the intriguing behavior of tetracyanoborate anions in ionic liquids that, unlike their dicyanamide and tricyanomethanide counterparts, form dimers in both solid and liquid phases. A joint simulation and experimental study uncovers the origin of such anion-anion attraction: stabilization by induction and dispersion forces between several cyano groups, which is strong enough to overcome electrostatic repulsion. These findings open up new opportunities in the rational design of ionic liquids, where interactions between ions of the same charge can be controlled and fine-tuned by the presence of cyano groups.

Diphenylsulfoxide exhibits an outstanding solubility in Methanol: Physicochemical and quantum chemical evidences. Comparison to acetonitrile

Diphenylsulfoxide (Ph2SO) represents a noteworthy organic substance composed of bulky amphiphilic molecules. The chemical interest in Ph2SO arises from a peculiar combination of the strongly polar and strongly nonpolar moieties which are uniquely packed. The solubility of Ph2SO in conventional organic solvents is a cornerstone of its prospective applications. In the present work, the full concentration ranges of the possible homogeneous solutions of diphenylsulfoxide (Ph2SO) in acetonitrile (ACN) and methanol (MEOH) have been investigated by densitometry, UV–vis, FTIR spectroscopy, and quantum-chemical calculations. For the first time, we unraveled an outstanding solubility of Ph2SO in MEOH. The homogeneous solutions form up to the molality of 0.9 mol kg−1. This observation is unexpected from the conventional chemical wisdom because Ph2SO contains twenty-two non-polar interaction sites vs. two polar interaction sites. Based on the volumetric measurements, we revealed that the partial molar volumes of Ph2SO depend somewhat on solvent (MEOH, ACN) peculiarities. The effects of solvent on the spectral characteristics of diphenylsulfoxide have been considered. The numerical simulations based on the systematic potential landscape exploration corroborate the existence of several types of supramolecular species involving Ph2SO and solvent molecules simultaneously. The peculiar anisotropic Ph2SO-MEOH coupling, which is a strong hydrogen bonding, along with the small size of the solvent molecules is responsible for the recorded outstanding solubility in the methanol media. In turn, the performance of ACN is somewhat less encouraging notwithstanding the way higher dipole moment of its molecules. As an amphiphilic solute, Ph2SO may boost the solubilities of hydrophobic solutes by interfacing its coupling with polar media. The reported results inspire further explorations of Ph2SO to design task-specific liquid systems.

Inhibiting Angiogenesis by Anti-Cancer Saponins: From Phytochemistry to Cellular Signaling Pathways

Saponins are one of the broadest classes of high-molecular-weight natural compounds, consisting mainly of a non-polar moiety with 27 to 30 carbons and a polar moiety containing sugars attached to the sapogenin structure. Saponins are found in more than 100 plant families as well as found in marine organisms. Saponins have several therapeutic effects, including their administration in the treatment of various cancers. These compounds also reveal noteworthy anti-angiogenesis effects as one of the critical strategies for inhibiting cancer growth and metastasis. In this study, a comprehensive review is performed on electronic databases, including PubMed, Scopus, ScienceDirect, and ProQuest. Accordingly, the structural characteristics of triterpenoid/steroid saponins and their anti-cancer effects were highlighted, focusing on their anti-angiogenic effects and related mechanisms. Consequently, the anti-angiogenic effects of saponins, inhibiting the expression of genes related to vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-α (HIF-1α) are two main anti-angiogenic mechanisms of triterpenoid and steroidal saponins. The inhibition of inflammatory signaling pathways that stimulate angiogenesis, such as pro-inflammatory cytokines, mitogen-activated protein kinase (MAPKs), and phosphoinositide 3-kinases/protein kinase B (PI3K/Akt), are other anti-angiogenic mechanisms of saponins. Furthermore, the anti-angiogenic and anti-cancer activity of saponins was closely related to the binding site of the sugar moiety, the type and number of their monosaccharide units, as well as the presence of some functional groups in their aglycone structure. Therefore, saponins are suitable candidates for cancer treatment by inhibiting angiogenesis, for which extensive pre-clinical and comprehensive clinical trial studies are recommended.

Surfactant-Assisted Sulfonated Covalent Organic Nanosheets: Extrinsic Charge for Improved Ion Transport and Salinity-Gradient Energy Harvesting.

Charge-governed ion transport is the vital property of nanofluidic channels for salinity-gradient energy harvesting and other electrochemical energy conversion technologies. 2D nanofluidic channels constructed by nanosheets exhibit great superiority in ion selectivity, but a high ion transport rate remains challenging due to the insufficiency of intrinsic surface charge density in nanoconfinement. Herein, extrinsic surface charge into nanofluidic channels composed of surfactant-assisted sulfonated covalent organic nanosheets (SCONs), which enable tunable ion transport behaviors, is demonstrated. The polar moiety of surfactant is embedded in SCONs to adjust in-plane surface charges, and the aggregation of nonpolar moiety results in the sol-to-gel transformation of SCON solution for membrane fabrication. The combination endows SCON/surfactant membranes with considerable water-resistance, and the designable extrinsic charges promise fast ion transport and high ion selectivity. Additionally, the SCON/surfactant membrane, serving as a power generator, exhibits huge potential in harvesting salinity-gradient energy where corresponding output power density can reach up to 9.08W m-2 under a 50-fold salinity gradient (0.5m NaCl|0.01m NaCl). The approach to extrinsic surface charge provides new and promising insight into regulating ion transport behaviors.

Solubilization of α-tocopherol and curcumin by polyoxyethylene alkyl ether surfactants: Effect of alkyl chain structure

The effects of the structural characteristics of the alkyl chains of polyoxyethylene alkyl ether-type surfactants (Brij) on the solubilization of α-tocopherol and curcumin by surfactant micelles were investigated: Brij L23 (lauryl; C12:0); S20 (stearyl; C18:0); and Brij O20 (oleyl; C18:1). When α-tocopherol or curcumin were solubilized in Brij micelle solutions below their maximum solubilization concentrations (Cmax), the Brij L23 micelles exhibited the largest increase in dimensions due to the presence of the guest molecules. Above Cmax, excess α-tocopherol existed as microemulsion droplets whereas excess curcumin existed as insoluble crystals. Our results suggest that the guest molecules were preferentially located within the palisade layers of micelles, which can be attributed to the fact that they contained bother polar and non-polar moieties. These results may be important for the formulation of colloidal delivery systems to encapsulate and deliver oil-soluble vitamins and nutraceuticals.

A Structure-Based Mechanism for the Denaturing Action of Urea, Guanidinium Ion and Thiocyanate Ion.

An exhaustive analysis of all the protein structures deposited in the Protein Data Bank, here performed, has allowed the identification of hundredths of protein-bound urea molecules and the structural characterization of such binding sites. It emerged that, even though urea molecules are largely involved in hydrogen bonds with both backbone and side chains, they are also able to make van der Waals contacts with nonpolar moieties. As similar findings have also been previously reported for guanidinium and thiocyanate, this observation suggests that promiscuity is a general property of protein denaturants. Present data provide strong support for a mechanism based on the protein-denaturant direct interactions with a denaturant binding model to equal and independent sites. In this general framework, our investigations also highlight some interesting insights into the different denaturing power of urea compared to guanidinium/thiocyanate.

Structure-Based Virtual Screening and De Novo Design to Identify Submicromolar Inhibitors of G2019S Mutant of Leucine-Rich Repeat Kinase 2.

Missense mutations of leucine-rich repeat kinase 2 (LRRK2), including the G2019S mutant, are responsible for the pathogenesis of Parkinson's disease. In this work, structure-based virtual screening of a large chemical library was carried out to identify a number of novel inhibitors of the G2019S mutant of LRRK2, the biochemical potencies of which ranged from the low micromolar to the submicromolar level. The discovery of these potent inhibitors was made possible due to the modification of the original protein-ligand binding energy function in order to include an accurate ligand dehydration energy term. The results of extensive molecular docking simulations indicated that the newly identified inhibitors were bound to the ATP-binding site of the G2019S mutant of LRRK2 through the multiple hydrogen bonds with backbone amide groups in the hinge region as well as the hydrophobic interactions with the nonpolar residues in the P-loop, hinge region, and interdomain region. Among 18 inhibitors derived from virtual screening, 4-(2-amino-5-phenylpyrimidin-4-yl)benzene-1,3-diol (Inhibitor 2) is most likely to serve as a new molecular scaffold to optimize the biochemical potency, because it revealed submicromolar inhibitory activity in spite of its low molecular weight (279.3 amu). Indeed, a highly potent inhibitor (Inhibitor 2n) of the G2019S mutant was derived via the structure-based de novo design using the structure of Inhibitor 2 as the molecular core. The biochemical potency of Inhibitor 2n surged to the nanomolar level due to the strengthening of hydrophobic interactions in the ATP-binding site, which were presumably caused by the substitutions of small nonpolar moieties. Due to the high biochemical potency against the G2019S mutant of LRRK2 and the putatively good physicochemical properties, Inhibitor 2n is anticipated to serve as a new lead compound for the discovery of antiparkinsonian medicines.

Predictive solubility of amino acids in deep eutectic solvents for chicken feather waste valorisation

Waste chicken feathers can be potentially utilized by its dissolution in deep eutectic solvents (DESs) to extract keratin. Keratin in chicken feathers is composed by a series of amino acids which can be categorized into negatively charged, positively charged, hydrophobic and hydrophilic natures. As the DESs are also composed by polar and non-polar moieties, their capability to dissolve amino acids needs to be investigated. In this study, the relative solubility of these amino acids in DESs were screened using Conductor-like Screening Method for Real Solvents (COSMO-RS). Five DESs were selected from literature as the targeted solvents, i.e., choline chloride:urea (ChCl:Ur (1:2)), choline chloride:oxalic acid (ChCl:OA (1:2)), choline chloride:ethylene glycol (ChCl:EG (1:2)), sodium acetate:urea (NaAc:Ur (1:2)) and urea:acetate (Ur:Ace (1:2)), to dissolve amino acids in keratin according to the reported compositions. Additionally, the performance of these DESs were benchmarked with other common volatile organic solvents. It was found that the hydrophobic amino acids, particularly cystine, are highly soluble in ChCl:Ur (1:2), ChCl:OA (1:2) and Ur:Ace (1:2). The selected DESs were also predicted to have good dissolution capacity towards the hydrophobic amino acids. It was concluded that the use of DESs in dissolution and extraction of keratin provides more flexible dissolving capability and more environmentally friendly compared to the conventional organic or acidic solvents. This study provides positive insights on the potential of valorising chicken waste feathers using DESs.

A subtle interplay between hydrophilic and hydrophobic hydration governs butanol (de)mixing in water

A possible molecular origin of the contorting water-solubility of butanol isomers lies in the self-association propensity of alcohols as well as on the specific interaction between the hydrophilic and hydrophobic moiety of butanol(s) with water. We have made a synergistic approach using far-IR (50–600 cm−1)-FTIR and MD simulation measurements to probe the extent of alteration of HBond structure of water-network in water-alcohol mixtures.The experimental and computational observations infer that extent of hydration of the non-polar moiety of the alcohol self-aggregates plays a decisive role in the (de)mixing of butanol(s) in water.

Enantioselective alkylative cross-coupling of unactivated aromatic C–O electrophiles

Nonpolar alkyl moieties, especially methyl group, are frequently used to modify bioactive molecules during lead optimization in medicinal chemistry. Thus transition-metal catalyzed alkylative cross-coupling reactions by using readily available and environmentally benign C–O electrophiles have been established as powerful tools to install alkyl groups, however, the C(sp3)–C(sp2) cross-coupling via asymmetric activation of aromatic C–O bond for the synthesis of alkylated chiral compounds remains elusive. Here, we unlock a C(sp3)–C(sp2) cross-coupling via enantioselective activation of aromatic C–O bond for the efficient synthesis of versatile axially chiral 2-alkyl-2’-hydroxyl-biaryl compounds. By employing a unique chiral N-heterocyclic carbene ligand, this transformation is accomplished via nickel catalysis with good enantiocontrol. Mechanistic studies indicate that bis-ligated nickel complexes might be formed as catalytically active species in the enantioselective alkylative cross-coupling. Moreover, further derivation experiments suggest this developed methodology holds great promise for complex molecule synthesis and asymmetric catalysis.

Nonane and Hexanol Adsorption in the Lamellar Phase of a Nonionic Surfactant: Molecular Simulations and Comparison to Ideal Adsorbed Solution Theory

Adsorption of n-nonane/1-hexanol (C9/C6OH) mixtures into the lamellar phase formed by a 50/50 w/w triethylene glycol mono-n-decyl ether (C10E3)/water system was studied using configurational-bias Monte Carlo simulations in the osmotic Gibbs ensemble. The interactions were described by the Shinoda-Devane-Klein coarse-grained force field. Prior simulations probing single-component adsorption indicated that C9 molecules preferentially load near the center of the bilayer, increasing the bilayer thickness, whereas C6OH molecules are more likely to be found near the interface of the polar and nonpolar moieties, swelling the bilayer in the lateral dimension. Here, we extend this work to binary C9/C6OH adsorption to probe whether the difference in the spatial preferences may lead to a synergistic effect and enhanced loadings for the mixture. Comparing loading trends and the thermodynamics of binary adsorption to unary adsorption reveals that C9-C9 interactions lead to the largest enhancement, whereas C9-C6OH and C6OH-C6OH interactions are less favorable for this bilayer system. Ideal adsorbed solution theory yields satisfactory predictions of the binary loading.

LDAmy, an α-amylase from Colorado potato beetle (Leptinotarsa decemlineata) with transglycosylation activity

Potential of α-amylase from the gut of Leptinotarsa decemlineata (LDAmy) to catalyse transfer reactions was investigated. LDAmy as a component of insect gut extract showed significant transfer activity on reducing-end- and both-end-protected maltoheptamer substrates. Transfer reaction was examined using purified enzyme, 2-chloro-4-nitrophenyl β-d-glucopyranoside as acceptor and starch and maltooligosaccharides as donors. In addition to suitability of various donors, effect of pH and acetonitrile (MeCN) concentration were also studied. The reactions were followed using separation of reaction products by a reversed phase HPLC method. LDAmy catalysed the hydrolysis and transglycosylation of the both-end-protected substrate 4,6-O-benzylidene-4-nitrophenyl β-maltoheptaoside in parallel reactions. Shorter and longer both-end-protected products with degree of polymerization 4–10 were formed. Identification of products was carried out based on HPLC retention time, UV and mass spectra. Ratio of transglycosylation to hydrolysis reached 0.5 in presence of 20% MeCN as organic solvent. Aromatic protecting group at the non-reducing end was favourable for transfer reaction. Lack of the mobile loop and presence of more nonpolar aromatic moieties near to the active site may be the reason for the enhanced transfer activity of LDAmy based on the comparison of the sequence and structure of mammalian and insect-derived α-amylases. Highlights Transferase activity of Colorado potato beetle derived α-amylase LDAmy is presented. Effect of pH and organic co-solvent on transfer reaction of LDAmy were studied. Shorter and longer products were formed from a both-end protected maltoheptamer. The unusual transfer ability was explained by sequence differences of α-amylases.

Validated HPLC-UV Method for Simultaneous Estimation of Paclitaxel and Doxorubicin Employing Ion Pair Chromatography: Application in Formulation Development and Pharmacokinetic Studies.

Though paclitaxel (PTX) and doxorubicin (DOX) are amongst the most widely used and investigated drug pair for combination chemotherapy but surprisingly, not a single validated HPLC-UV method is available to analyze PTX and DOX simultaneously. So, herein a HPLC-UV method is developed and validated for the same, filling an indispensable gap in the literature. As these two moieties have characteristically different polarities, resolving them under the common chromatographic conditions is a challenging task. Herein, the principle of ion pair chromatography is utilized to resolve these two moieties on a C18 column employing an isocratic mobile phase comprised of acetonitrile and octane sulfonic acid buffer (67 : 37) and detected simultaneously at 231 nm using a UV detector only. The retention time is 4.4 and 7.2 min for PTX and DOX, respectively, with a total analysis time of less than 10 minutes, suitable for the formulation development and research, while LOQ is less than 0.066 μg/ml for both the drugs, suitable for the therapeutic drug monitoring at preclinical and clinical research setup. To substantiate the applicability of the developed method, a nanoformulation coloaded with PTX and DOX was designed and analyzed using the developed protocol. The method is also applied successfully to study the plasma kinetic profile of both the moieties simultaneously in Balb/c mice. Further, the method is validated as per the ICH guidelines fulfilling the unmet need of a validated analytical tool to simultaneously estimate PTX and DOX. Moreover, the results suggest that the principal of common ion chromatography demonstrated here can also be applied further for the simultaneous chromatographic separation of other polar and nonpolar moieties too. Consequently, the reported method surely will advance the toolset required for the precision-based combination chemotherapy.

A Protein Data Bank survey of multimodal binding of thiocyanate to proteins: Evidence for thiocyanate promiscuity

Over the last one and half century, a myriad of studies has demonstrated that Hofmeister ions have a major impact on protein stability and solubility. Nevertheless, the definition of the physico-chemical basis of their activity has proved to be highly challenging and controversial. Here, by exploiting the enormous information content of the Protein Data Bank, we explored the binding to proteins of thiocyanate, the anion of the series exerting the highest solubilization/destabilization effects. The survey, which led to the identification and characterization of 712 thiocyanate binding sites, provides a comprehensive and atomic-level view of the varied interactions that the ion forms with proteins. The inspection of these sites highlights a limited tendency of thiocyanate to interact with structured water molecules, in line with the reported poor hydration of the ion. On the other hand, the thiocyanate makes interactions with protein nonpolar moieties, especially with the backbone Cα atom. In as many as 104 cases, the ion exclusively makes nonpolar contacts. In conclusion, these findings suggest that the ability of thiocyanate to bind all types of protein exposed patches may lead to the formation of a negatively charged electrostatic barrier that could prevent protein-protein aggregation and promote protein solubility. Moreover, the denaturing action of thiocyanate may be ascribed to its ability to establish multiple attractive interactions with protein surfaces.

Solubility of tadalafil in aqueous mixtures of Transcutol® and PEG 400 revisited: correlation, thermodynamics and preferential solvation

ABSTRACT Mole fraction solubilities of tadalafil (3) in aqueous mixtures of Transcutol® and PEG 400 at temperatures from 298.15 to 333.15 K were analysed following Hildebrand solubility parameters. Cosolvency models for representing tadalafil solubility at various temperatures were also provided for correlation/prediction purposes. Apparent thermodynamic quantities for tadalafil dissolution processes were calculated based on van’t Hoff and Gibbs equations. Non-linear enthalpy–entropy compensation was observed for tadalafil transfer from more polar to less polar solvent systems. Preferential solvation parameters of tadalafil at 298.15 and 313.15 K were determined by means of the inverse Kirkwood-Buff integrals (IKBI). Tadalafil is preferentially solvated by water in water-rich mixtures of Transcutol® but preferentially solvated by Transcutol® in mixtures of 0.12 < x 1 < 1.00. In the former case, this result could be due to hydrophobic hydration around the non-polar moieties of tadalafil. Otherwise, tadalafil is preferentially solvated by PEG 400 in all the aqueous mixtures.

In Silico Elucidation of Potent Inhibitors and Rational Drug Design against SARS-CoV-2 Papain-like Protease.

Global public health has been a critical problem by the sudden increase of the COVID-19 outbreak. The papain-like protease (PLpro) of SARS-CoV-2 is a key promising target for antiviral drug development since it plays a pivotal role in viral replication and innate immunity. Here, we employed the all-atom molecular dynamics (MD) simulations and binding free energy calculations based on MM-PB(GB)SA and SIE methods to elucidate and compare the binding behaviors of five inhibitors derived from peptidomimetic inhibitors (VIR250 and VIR251) and naphthalene-based inhibitors (GRL-0617, compound 3, and compound Y96) against SARS-CoV-2 PLpro. The obtained results revealed that all inhibitors interacting within the PLpro active site are mostly driven by vdW interactions, and the hydrogen bond formation in residues G163 and G271 with peptidomimetics and the Q269 residue with naphthalene-based inhibitors was essential for stabilizing the protein–ligand complexes. Among the five studied inhibitors, VIR250 exhibited the most binding efficiency with SARS-CoV-2 PLpro, and thus, it was chosen for the rational drug design. Based on the computationally designed ligand–protein complexes, the replacement of aromatic rings including heteroatoms (e.g., thiazolopyridine) at the P2 and P4 sites could help to improve the inhibitor-binding efficiency. Furthermore, the hydrophobic interactions with residues at P1–P3 sites can be increased by enlarging the nonpolar moieties (e.g., ethene) at the N-terminal of VIR250. We expect that the structural data obtained will contribute to the development of new PLpro inhibitors with more inhibitory potency for COVID-19.

Mutual miscibility of diethyl sulfoxide and acetonitrile: Fundamental origin

Diethyl sulfoxide (DESO) is an environmentally friendly liquid that has prospective applications in the accomplishment of robust freezing/thawing of biological entities. DESO possesses one polar and two symmetric non-polar moieties thus exhibiting a mixed solvation behavior. Understanding the intermolecular interactions of DESO with other common liquids is a cornerstone of fostering its efficient usage. Herein, we report global- and local-minimum molecular configurations of a few DESO/acetonitrile (ACN) mixtures using a comprehensive electronic-structure modeling of the potential energy surface. We discuss energetics, distributions functions, structure descriptors, and vibrational spectra of the mixture components. The presented results provide a clear understanding of the DESO/ACN miscibility origin and unambiguously rationalize the previously reported experimental results on these liquid systems.

Solubility of 6-phenyl-4,5-dihydropyridazin-3(2H)-one in aqueous mixtures of Transcutol and PEG 400 revisited: Correlation and preferential solvation

Reported equilibrium mole fraction solubility values of 6-phenyl-4,5-dihydropyridazin-3(2H)-one (PDP-6) (3) in {Transcutol (1) + water (2)} and {PEG 400 (1) + water (2)} mixtures at five temperatures from T = (293.15 to 313.15) K were analyzed based on the Hildebrand solubility parameter of the respective aqueous mixtures. Cosolvency models for representing the equilibrium solubility of PDP-6 in both binary solvent systems at various temperatures were also provided for correlation/prediction purposes. Moreover, the preferential solvation parameters of PDP-6 in these aqueous-cosolvent mixtures at T = (298.15 and 313.15) K were determined by means of the “inverse Kirkwood-Buff integrals” (IKBI). PDP-6 is preferentially solvated by water in water-rich mixtures of {Transcutol (1) + water (2)} system but preferentially solvated by Transcutol in mixtures of 0.13 < x1 < 1.00. In the former case this result could be due to hydrophobic hydration around the non-polar moieties of PDP-6. Otherwise, PDP-6 is preferentially solvated by PEG 400 in all the aqueous mixtures. Moreover, in the systems where preferentially solvation of PDP-6 by cosolvents are observed, these results could be due to the Lewis acidic behavior of PDP-6 in front of Transcutol or PEG 400 molecules because these cosolvents exhibit higher Lewis basic behavior than water.