Cyclohexane Ring Research Articles

Novel D-A-π-A1 Type Organic Sensitizers from 4,7-Dibromobenzo[d][1,2,3]thiadiazole and Indoline Donors for Dye-Sensitized Solar Cells.

Two novel D-A-π-A1 metal-free organic dyes of the KEA series containing benzo[d][1,2,3]thiadiazole (isoBT) internal acceptor, indoline donors fused with cyclopentane or cyclohexane rings (D), a thiophene as a π-spacer, and a cyanoacrylate as an anchor part were synthesized. Monoarylation of 4,7-dibromobenzo[d][1,2,3]thiadiazole by Suzuki-Miyamura cross-coupling reaction showed that in the case of indoline and carbazole donors, the reaction was non-selective, i.e., two monosubstituted derivatives were isolated in each case, whereas only one mono-isomer was formed with phenyl- and 2-thienylboronic acids. This was explained by the fact that heterocyclic indoline and carbazole fragments are much stronger donor groups compared to thiophene and benzene, as confirmed by cyclic voltammetry measurements and calculation of HOMO energies of indoline, carbazole, thiophene and benzene molecules. The structure of monoaryl(hetaryl) derivatives was strictly proven by NMR spectroscopy and X-ray diffraction. The optical and photovoltaic properties observed for the KEA dyes showed that these compounds are promising for the creation of solar cells. A comparison with symmetrical benzo[c][1,2,3]thiadiazole dyes WS-2 and MAX114 showed that the asymmetric nature of benzo[d][1,2,3]thiadiazole KEA dyes leads to a hypsochromic shift of the ICT band in comparison with the corresponding benzo[c][1,2,5]thiadiazole isomers. KEA dyes have a narrow HOMO-LUMO gap of 1.5–1.6 eV. Amongst these dyes, KEA321 recorded the best power efficiency (PCE), i.e., 5.17%, which is superior to the corresponding symmetrical benzo[c][1,2,3]thiadiazole dyes WS-2 and MAX114 (5.07 and 4.90%).

Crystal structure and Hirshfeld surface analysis of 3-benzoyl-6-(1,3-dioxo-1-phenyl-butan-2-yl)-2-hy-droxy-2-methyl-4-phenyl-cyclo-hexane-1,1-dicarbo-nitrile.

The central cyclo-hexane ring of the title compound, C32H28N2O4, adopts a chair conformation, with puckering parameters Q T = 0.618 (2) Å, θ = 176.72 (19)° and φ = 290 (3)°. In the crystal, mol-ecules are linked by O-H⋯O, C-H⋯O and C-H⋯N hydrogen bonds, forming layers parallel to (100). These layers are linked by weak C-H⋯π inter-actions and van der Waals forces. A Hirshfeld surface analysis indicates that the contributions from the most prevalent inter-actions are H⋯H (41.2% contribution), C⋯H/H⋯C (20.3%), O⋯H/H⋯O (17.8%) and N⋯H/H⋯N (10.6%).

Synthesis of 4, 5-Dihydro-N(2)-Phenylindazole from Diversely Substituted Cyclic-β-Keto Esters and Its Structural Analysis

To achieve the N-phenyl tetrahydroindazoles, t(3)-aryl-r(2),c(4)-bis(isopropoxycarbonyl)-c(5)-hydroxy-t(5)-methylcyclohexanones were treated with phenylhydrazine. Characterizations reveal the resultant products are respective N-phenyl dihydroindazoles. The reaction has been taken place in regioselctive manner. Plausible mechanism was proposed for the regioselective formation of dihydroindazoles with the phenyl substituent at N(2) position. Dehydration of hydroxyl group at C-6 position results double bond formation at C(6)–C(7). Besides, an investigation about the prior attempts which are unsuccessful for the synthesis of 2-phenylindazoles from a few cylic-β-keto esters has been discussed. Synthesized compounds were characterized by IR, One and Two dimensional NMR spectra. For all the synthesized compounds 7-13, 1H and 13C NMR spectra was recorded. HMBC and HSQC spectra recorded for a representative compound 7. HMBC spectrum also recorded for compound 8. Stereochemistry of the cyclohex-3-ene ring part in the dihydroindazole is in half chair form, where as in tetrahydroindazole, cyclohexane ring part is in normal chair conformation. Key Words: Dihydroindazole, phenylindazole, substituted indazoles, fused heterocycles, one and two dimensional NMR.

Design, Synthesis, and Biological Evaluation of (+)-Camphor- and (-)-Fenchone-Based Derivatives as Potent Orthopoxvirus Inhibitors.

In this work, a library of (+)-camphor and (-)-fenchone based N-acylhydrazones, amides, and esters, including para-substituted aromatic/hetaromatic/cyclohexane ring was synthesized, with potent orthopoxvirus inhibitors identified among them. Investigations of the structure-activity relationship revealed the significance of the substituent at the para-position of the aromatic ring. Also, the nature of the linker between a hydrophobic moiety and aromatic ring was clarified. Derivatives with p-Cl, p-Br, p-CF3, and p-NO2 substituted aromatic ring and derivatives with cyclohexane ring showed the highest antiviral activity against vaccinia virus, cowpox, and ectromelia virus. The hydrazone and the amide group were more favourable as a linker for antiviral activity than the ester group. Compounds 3 b and 7 e with high antiviral activity were examined using the time-of-addition assay and molecular docking study. The results revealed the tested compounds to inhibit the late processes of the orthopoxvirus replication cycle and the p37 viral protein to be a possible biological target.

BF3–Catalyzed Diels–Alder Reaction between Butadiene and Methyl Acrylate in Aqueous Solution—An URVA and Local Vibrational Mode Study

In this study we investigate the Diels–Alder reaction between methyl acrylate and butadiene, which is catalyzed by BF3 Lewis acid in explicit water solution, using URVA and Local Mode Analysis as major tools complemented with NBO, electron density and ring puckering analyses. We considered four different starting orientations of methyl acrylate and butadiene, which led to 16 DA reactions in total. In order to isolate the catalytic effects of the BF3 catalyst and those of the water environment and exploring how these effects are synchronized, we systematically compared the non-catalyzed reaction in gas phase and aqueous solution with the catalyzed reaction in gas phase and aqueous solution. Gas phase studies were performed at the B3LYP/6-311+G(2d,p) level of theory and studies in aqueous solution were performed utilizing a QM/MM approach at the B3LYP/6-311+G(2d,p)/AMBER level of theory. The URVA results revealed reaction path curvature profiles with an overall similar pattern for all 16 reactions showing the same sequence of CC single bond formation for all of them. In contrast to the parent DA reaction with symmetric substrates causing a synchronous bond formation process, here, first the new CC single bond on the CH2 side of methyl acrylate is formed followed by the CC bond at the ester side. As for the parent DA reaction, both bond formation events occur after the TS, i.e., they do not contribute to the energy barrier. What determines the barrier is the preparation process for CC bond formation, including the approach diene and dienophile, CC bond length changes and, in particular, rehybridization of the carbon atoms involved in the formation of the cyclohexene ring. This process is modified by both the BF3 catalyst and the water environment, where both work in a hand-in-hand fashion leading to the lowest energy barrier of 9.06 kcal/mol found for the catalyzed reaction R1 in aqueous solution compared to the highest energy barrier of 20.68 kcal/mol found for the non-catalyzed reaction R1 in the gas phase. The major effect of the BF3 catalyst is the increased mutual polarization and the increased charge transfer between methyl acrylate and butadiene, facilitating the approach of diene and dienophile and the pyramidalization of the CC atoms involved in the ring formation, which leads to a lowering of the activation energy. The catalytic effect of water solution is threefold. The polar environment leads also to increased polarization and charge transfer between the reacting species, similar as in the case of the BF3 catalyst, although to a smaller extend. More important is the formation of hydrogen bonds with the reaction complex, which are stronger for the TS than for the reactant, thus stabilizing the TS which leads to a further reduction of the activation energy. As shown by the ring puckering analysis, the third effect of water is space confinement of the reacting partners, conserving the boat form of the six-member ring from the entrance to the exit reaction channel. In summary, URVA combined with LMA has led to a clearer picture on how both BF3 catalyst and aqueous environment in a synchronized effort lower the reaction barrier. These new insights will serve to further fine-tune the DA reaction of methyl acrylate and butadiene and DA reactions in general.

Nanofiltration Membranes Formed through Interfacial Polymerization Involving Cycloalkane Amine Monomer and Trimesoyl Chloride Showing Some Tolerance to Chlorine during Dye Desalination.

Wastewater effluents containing high concentrations of dyes are highly toxic to the environment and aquatic organisms. Recycle and reuse of both water and dye in textile industries can save energy and costs. Thus, new materials are being explored to fabricate highly efficient nanofiltration membranes for fulfilling industrial needs. In this work, three diamines, 1,4-cyclohexanediamine (CHD), ethylenediamine (EDA), and p-phenylenediamine (PPD), are reacted with TMC separately to fabricate a thin film composite polyamide membrane for dye desalination. Their chemical structures are different, with the difference located in the middle of two terminal amines. The surface morphology, roughness, and thickness of the polyamide layer are dependent on the reactivity of the diamines with TMC. EDA has a short linear alkane chain, which can easily react with TMC, forming a very dense selective layer. CHD has a cyclohexane ring, making it more sterically hindered than EDA. As such, CHD’s reaction with TMC is slower than EDA’s, leading to a thinner polyamide layer. PPD has a benzene ring, which should make it the most sterically hindered structure; however, its benzene ring has a pi-pi interaction with TMC that can facilitate a faster reaction between PPD and TMC, leading to a thicker polyamide layer. Among the TFC membranes, TFCCHD exhibited the highest separation efficiency (pure water flux = 192.13 ± 7.11 L∙m−2∙h−1, dye rejection = 99.92 ± 0.10%, and NaCl rejection = 15.46 ± 1.68% at 6 bar and 1000 ppm salt or 50 ppm of dye solution). After exposure at 12,000 ppm∙h of active chlorine, the flux of TFCCHD was enhanced with maintained high dye rejection. Therefore, the TFCCHD membrane has a potential application for dye desalination process.

Traction behavior and mechanism of molecular level with effects of molecular structure and sliding velocity in boundary lubrication regime: A molecular dynamics study

The traction mechanism in power transmission systems with effects of sliding velocity and molecular structure are revealed at high temperature and pressure through molecular dynamics approach. Firstly, the simulated traction coefficients agree well with the experimental values, and the linear correlation between traction coefficient and bond energy is created to predict the coefficient. The molecule with higher bond energy and more –CH3 groups between two terminal cyclohexane rings shows higher traction coefficient. Then, the typical shear localization is found from the layered structure of alicyclic molecules confined between Fe2O3 slabs. The increase of sliding velocity has a very week effect on the velocity profile but benefits the slip length shrinkage on the whole. The traction coefficient increases fast and then converges toward a plateau with increasing velocity. Finally, the power transmission mechanism in molecular level is discussed and attributed to three effects, i.e., the interlocking effect between alicyclic rings in layer, the cross-linkage effect between layers, and the rotation resistance effect of alicyclic structure. This mechanism is desirable to be achieved with low degrees of slip, and thus maximize the efficiency of the device and help designing new traction fluids.

Enhanced Dehydrogenative H2 Release from N-Containing Amphicyclic LOHC Boosted by Pd-Supported Nanosheet MFI Zeolites Having Strong Acidity and Large Mesoporosity

The amount and rate of H2 discharge from 2-[(n-methylcyclohexyl)methyl]piperidine (H12-MBP), an amphicyclic liquid organic hydrogen carrier (LOHC) having two cycle moieties (cyclohexane and piperidine) with different reactivities, are determined by dehydrogenation of a cyclohexane ring with less reactivity. To realize high H2 yields with rapid kinetics, the cyclohexane ring in the partially dehydrogenated 2-[n-methylcyclohexyl]methyl)pyridine (H6-MBP) that is generated as the intermediate species should be fully dehydrogenated to 2-(n-methylbenzyl)pyridine (H0-MBP). This is approached using Pd-supported nanosheet zeolites having mesoporous structures bearing high concentrations of strongly acidic sites on external surfaces, which can not only enhance the diffusion of bulky H12-MBP but also strongly bind the basic piperidine ring in H12-MBP and H6-MBP. The H2 yields and rate constants are correlated with the acidity, mesoporosity, and adsorption behaviors of the LOHCs. As these factors are strengthened, H2 yield and rate constants increased dramatically within the ranges of 16.0–64.7% and 0.0001–0.0013 min–1, respectively. The results prove that mesoporous zeolites can be used for constructing supported Pd catalysts achieving high H2 yields with rapid kinetics from N-containing amphicyclic LOHCs.

Investigation of the μ- and κ-opioid receptor activation by eight new synthetic opioids using the [35 S]-GTPγS assay: U-47700, isopropyl U-47700, U-49900, U-47931E, N-methyl U-47931E, U-51754, U-48520, and U-48800.

In 2009, new synthetic opioids appeared on the new psychoactive substances market. This class of new psychoactive substances generally poses a health risk due to the high affinity and potency of most of these compounds for the opioid receptors. It is known that overdoses can lead to respiratory depression and result in death. However, for many new synthetic opioids, data on toxicological and toxicokinetic properties are scarce. In the present study, eight U-opioids were investigated for their structure activity relationships at the μ- and κ-opioid receptors using a [35 S]-GTPγS assay. The potencies of the investigated U-opioids were lower than those of the reference compounds (μ-opioid receptor: hydromorphone, fentanyl; κ-opioid receptor: U-69593, U-50488). At the μ-opioid receptor, U-47700 showed the highest potency with an EC50 value of 111 nM, and at the κ-opioid receptor, U-51754 was found to be the most potent compound with an EC50 value of 120 nM. The following structural features were advantageous for activating the μ-opioid receptor: two chlorine substituents in 3,4-position at the aromatic ring, the absence of the methylene group between the amide group and the aromatic ring, a methyl group at the amide nitrogen, and/or a dimethylamine residue at the amine nitrogen of the cyclohexane ring. Further, the following structural features were beneficial for κ-opioid receptor activation: a methylene group between the amide group and the aromatic ring, a pyrrolidine residue at the amine nitrogen of the cyclohexane ring, a methyl group at the amide nitrogen, and/or a chlorine substitution at the 3,4-position of the aromatic ring.

Synthesis of Aminoethyl-Substituted Piperidine Derivatives as σ1 Receptor Ligands with Antiproliferative Properties.

A series of novel σ1 receptor ligands with a 4‐(2‐aminoethyl)piperidine scaffold was prepared and biologically evaluated. The underlying concept of our project was the improvement of the lipophilic ligand efficiency of previously synthesized potent σ1 ligands. The key steps of the synthesis comprise the conjugate addition of phenylboronic acid at dihydropyridin‐4(1H)‐ones 7, homologation of the ketones 8 and introduction of diverse amino moieties and piperidine N‐substituents. 1‐Methylpiperidines showed particular high σ1 receptor affinity and selectivity over the σ2 subtype, whilst piperidines with a proton, a tosyl moiety or an ethyl moiety exhibited considerably lower σ1 affinity. Molecular dynamics simulations with per‐residue binding free energy deconvolution demonstrated that different interactions of the basic piperidine‐N‐atom and its substituents (or the cyclohexane ring) with the lipophilic binding pocket consisting of Leu105, Thr181, Leu182, Ala185, Leu186, Thr202 and Tyr206 are responsible for the different σ1 receptor affinities. Recorded logD7.4 and calculated clogP values of 4a and 18a indicate low lipophilicity and thus high lipophilic ligand efficiency. Piperidine 4a inhibited the growth of human non‐small cell lung cancer cells A427 to a similar extent as the σ1 antagonist haloperidol. 1‐Methylpiperidines 20a, 21a and 22a showed stronger antiproliferative effects on androgen negative human prostate cancer cells DU145 than the σ1 ligands NE100 and S1RA.

Stable isotope fractionation associated with the synthesis of hexachlorocyclohexane isomers for characterizing sources

The stable isotope fingerprints of hexachlorocyclohexane (HCH) isomers have potential for identifying sources as they are related to the synthesis processes and isotopic compositions of raw materials. However, the isotopic fractionation associated with the synthesis processes has not been investigated. Therefore, photochemical synthesis experiments using benzene and chlorine gas were conducted to characterize the associated isotopic fractionation under different conditions. Different patterns of isotopic fractionation factors (αC, αCl, and αH) were observed in each experiment. The large variability of αH is related to the accumulating secondary hydrogen isotope effects or the rearrangement of C–H bonds at the cyclohexane ring. An increase of δ13C and δ37Cl values of HCH isomers was observed during synthesis, which is related to the C–Cl bond formation in the radical dichlorination forming HCH and the subsequent chlorine substitution forming heptachlorocyclohexanes. The large variability of δ2H values is related to the secondary and primary hydrogen isotope effects. Different δ13C, δ37Cl and δ2H values among HCH isomers were observed, indicating that conformational complexity of HCH caused by arrangement of C–Cl bonds in planar and axial positions also influence the isotope values. The understanding of isotopic fractionation during HCH synthesis can be indicative for source identification in the field.

Crystal structures of two dioxomolybdenum complexes stabilized by salan ligands featuring phenyl and cyclo-hexyl backbones.

Two cis-dioxomolybdenum complexes based on salan ligands with different backbones are reported. The first complex, dioxido{2,2'-[l,2-phenyl-enebis(imino-methyl-ene)]bis-(phenolato)}molybdenum(VI) di-methyl-formamide disolvate, [Mo(C20H18N2O2)O2]·2C3H7NO (PhLMoO2, 1b), features a phenyl backbone, while the second complex, (6,6'-{[(cyclo-hexane-1,2-di-yl)bis(aza-nedi-yl)]bis-(methyl-ene)}bis-(2,4-di-tert-butyl-phenolato))dioxidomolybdenum(VI) methanol disolvate, [Mo(C36H56N2O2)O2]·2CH3OH (CyLMoO2, 2b), is based on a cyclo-hexyl backbone. These complexes crystallized as solvated species, 1b·2DMF and 2b·2MeOH. The salan ligands PhLH2 (1a) and CyLH2 (2a) coordinate to the molybdenum center in these complexes 1b and 2b in a κ2 N,κ2 O fashion, forming a distorted octa-hedral geometry. The Mo-N and Mo-O distances are 2.3475 (16) and 1.9567 (16) Å, respectively, in 1b while the corresponding measurements are Mo-N = 2.3412 (12) Å, and Mo-O = 1.9428 (10) Å for 2b. A key geometrical feature is that the N-Mo-N angle of 72.40 (4)° in CyLMoO2 is slightly less than that of the PhLMoO2 angle of 75.18 (6)°, which is attributed to the flexibility of the cyclo-hexane ring between the nitro-gen as compared to the rigid phenyl ring in the PhLMoO2.

Conformation-dependent low-temperature oxidation chemistry of methylcyclohexane: First oxygen addition and chain-branching

Conformational effect is an important feature of the low-temperature (low-T) oxidation chemistry of cycloalkanes. In this work, both theoretical calculation and conformational analysis were performed for the first oxygen addition in methylcyclohexane (MCH) oxidation to better understand the influence of the spatial orientation and the steric hindrance of substituted functional groups. Based on synchrotron vacuum ultraviolet photoionization mass spectrometry (SVUV-PIMS) measurements and adiabatic ionization energy calculations, reactive hydroperoxides, highly oxygenated molecules and stable products were identified in the jet-stirred reactor (JSR) oxidation of 1.0% and 0.5% MCH at 1.04 bar, 500–900 K and the equivalence ratio of 0.25. The abundant formation of 1-methylcyclohexene and the observation of alkenylhydroperoxides and their decomposition products verify the existence of conformation-dependent pathways in first and second oxygen addition in low-T MCH oxidation, respectively. A MCH oxidation model incorporated with conformation-dependent pathways was constructed to consider the conformational effects of cyclohexane ring and sidechain, and was validated against experimental data over a wide range of conditions in this work and literature. The consideration of conformational effects of cyclohexane ring and sidechain can generally better predict the measured species profiles and ignition delay time under low-T conditions. Based on modeling analysis, conformational effects of cyclohexane ring were found to play important roles in first oxygen addition and chain-branching in low-T MCH oxidation. Compared with the situation in low-T cyclohexane oxidation, the methyl substitution on cyclohexane ring reduces its conformational effects on chain-branching process.

Poloxamer-enhanced solubility of griseofulvin and its related antifungal activity against Trichophyton spp.

Poorly water-soluble drugs, such as the antifungal drug griseofulvin (GF), exhibit limited bioavailability, despite their high membrane permeability. Several technological approaches have been proposed to enhance the water solubility and bioavailability of GF, including micellar solubilization. Poloxamers are amphiphilic block copolymers that increase drug solubility by forming micelles and supra-micellar structures via molecular self-association. In this regard, the aim of this study was to evaluate the water solubility increment of GF by poloxamer 407 (P407) and its effect on the antifungal activity against three Trichophyton mentagrophytes and two T. rubrum isolates. The GF water solubility profile with P407 revealed a non-linear behavior, well-fitted by the sigmoid model of Morgan-Mercer-Flodin. The polymer promoted an 8-fold increase in GF water solubility. Fourier-transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), and 2D nuclear magnetic resonance (NMR Roesy) spectroscopy suggested a GF-P407 interaction, which occurs in the GF cyclohexene ring. These results were supported by an increase in the water solubility of the GF impurities with the same molecular structure. The MIC values recorded for GF ranged from 0.0028 to 0.0172 mM, except for T. Mentagrophytes TME34. Notably, the micellar solubilization of GF did not increase its antifungal activity, which could be related to the high binding constant between GF and P407.

Production and structural characterization of the cytochrome P450 enzymes in carotene ring hydroxylation.

The superfamily of cytochrome P450 (CYP) enzymes participate in diverse metabolic reactions. Although structural characterization of prokaryotic CYPs has been performed extensively, structural studies for eukaryotic, especially plant, CYPs remain scanty. Members of CYP family 97 are hydroxylases devoted to carotene ring hydroxylation. Specifically, members of the CYP97A and CYP97C subfamilies work synergistically to hydroxylate the β- and ɛ-rings of α-carotene to form lutein. The stereospecific reactions introduce an R-chiral center at the C-3 position of each cyclohexene ring. The Arabidopsis thaliana genome encodes CYP97A3, CYP97B3, and CYP97C1. Recently, we determined crystal structures of CYP97A3 in unliganded and retinaldehyde-bound forms and of CYP97C1 in complex with detergent octylthioglucoside. These structures showed how the active site favors pro-R-hydroxylation. This chapter summarizes the steps for production of CYP97A3, CYP97B3, and CYP97C1. The in vitro assays to test hydroxylase activity and ligand binding affinity are also described, including the steps for production of the redox partner. We also review the details for crystallization and structural determination of CYP97A3 and CYP97C1. Characterization of the active site by high-resolution structure analysis provides clues to substrate channeling, which awaits further investigation.

DMSO-assisted environmentally benign synthesis of benzo[c]-chromeno[4,3,2-gh]phenanthridines by remote oxidative hetero cross-coupling cyclization and aromatization reaction.

An unprecedented metal-free and catalyst-free synthesis of benzo[c]chromeno[4,3,2-gh]phenanthridine derivatives, a class of 1,6-diheterophenalenoid heterocycle, is reported for the first time. The oxidative cross-coupling reaction for the remote cyclization is achieved through the in situ generated o-quinone methide intermediate followed by an electrocyclic ring closure reaction. The aromatization of the cyclohexane ring is achieved by sequential H shift, hydroxylation, and elimination reaction. DMSO-assisted concomitant cyclization and aromatization reactions are also disclosed for the first time.

Crystal structure, Hirshfeld surface analysis, and DFT studies of N-(2-chlorophenylcarbamothioyl)cyclohexanecarboxamide

N-(2-Chlorophenylcarbamothioyl)cyclohexanecarboxamide was characterized by a single crystal X-ray diffraction study. Crystal data for this compound, C14H17ClN2OS; Monoclinic, space group P21/n with Z = 4, a = 5.2385(10) Å, b = 17.902(4) Å, c = 15.021(3) Å, β = 90.86(3)°, V = 1408.5(5) Å3, T = 153(2) K, μ(MoKα) = 0.413 mm-1, Dcalc = 1.400 g/cm3, 9840 reflections measured (7.082° ≤ 2Θ ≤ 50.378°), 2519 unique (Rint = 0.0406, Rsigma = 0.0335) which were used in all calculations. The final R1 was 0.0397 (I > 2σ(I)) and wR2 was 0.0887 (all data). The puckering parameters (q2 = 0.019(3) Å, q3 = 0.578(3) Å, θ = 1.0(3)° and φ = 51(8)°) of the title compound show that the cyclohexane ring adopts a chair conformation. The molecular conformation of the title compound is stabilized by intramolecular hydrogen bonds (N2-H2⋅⋅⋅Cl1, N2-H2⋅⋅⋅O1, and C2-H2A⋅⋅⋅S1) and intermolecular hydrogen bonds (N1-H1⋅⋅⋅S1i and C9-HA⋅⋅⋅S1ii: 2-x, 2-y, 1-z). The intramolecular hydrogen bonds (N2-H2⋅⋅⋅O1 and C2-H2A⋅⋅⋅S1) are also form two pseudo-six-membered rings. Density functional theory optimized structure in the gaseous phase at B3LYP/6-311G(d,p) level of theory has been compared with the experimentally defined molecular structure. The molecular orbitals HOMO and LUMO with the energy gap for the title compound are calculated and the estimated energy gap (ΔE) between the HOMO and LUMO energies levels of the title compound is 3.5399 eV, which implies that the title molecule is very reactive. The Hirshfeld surface analysis reveals that the most important contributions to crystal packing are from H···H (49.0%), H···C/C···H (12.5%), H···Cl/Cl···H (10.9%), and H···S/S···H (10.0%) interactions. The energy-framework calculations are used to analyze and visualize the three-dimensional topology of the crystal packing. The intermolecular energy analysis confirmed a significant contribution of dispersion to the stabilization of molecular packings in the title compound.

Structure-Activity Relationship Study of Subtype-Selective Positive Modulators of KCa2 Channels.

A series of modified N-cyclohexyl-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylpyrimidin-4-amine (CyPPA) analogues were synthesized by replacing the cyclohexane moiety with different 4-substituted cyclohexane rings, tyrosine analogues, or mono- and dihalophenyl rings and were subsequently studied for their potentiation of KCa2 channel activity. Among the N-benzene-N-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine derivatives, halogen decoration at positions 2 and 5 of benzene-substituted 4-pyrimidineamine in compound 2q conferred a ∼10-fold higher potency, while halogen substitution at positions 3 and 4 of benzene-substituted 4-pyrimidineamine in compound 2o conferred a ∼7-fold higher potency on potentiating KCa2.2a channels, compared to that of the parent template CyPPA. Both compounds retained the KCa2.2a/KCa2.3 subtype selectivity. Based on the initial evaluation, compounds 2o and 2q were selected for testing in an electrophysiological model of spinocerebellar ataxia type 2 (SCA2). Both compounds were able to normalize the abnormal firing of Purkinje cells in cerebellar slices from SCA2 mice, suggesting the potential therapeutic usefulness of these compounds for treating symptoms of ataxia.

CYP2C8-Mediated Formation of a Human Disproportionate Metabolite of the Selective NaV1.7 Inhibitor DS-1971a, a Mixed Cytochrome P450 and Aldehyde Oxidase Substrate.

Predicting human disproportionate metabolites is difficult, especially when drugs undergo species-specific metabolism mediated by cytochrome P450s (P450s) and/or non-P450 enzymes. This study assessed human metabolites of DS-1971a, a potent Nav1.7-selective blocker, by performing human mass balance studies and characterizing DS-1971a metabolites, in accordance with the Metabolites in Safety Testing guidance. In addition, we investigated the mechanism by which the major human disproportionate metabolite (M1) was formed. After oral administration of radiolabeled DS-1971a, the major metabolites in human plasma were P450-mediated monoxidized metabolites M1 and M2 with area under the curve ratios of 27% and 10% of total drug-related exposure, respectively; the minor metabolites were dioxidized metabolites produced by aldehyde oxidase and P450s. By comparing exposure levels of M1 and M2 between humans and safety assessment animals, M1 but not M2 was found to be a human disproportionate metabolite, requiring further characterization under the Metabolites in Safety Testing guidance. Incubation studies with human liver microsomes indicated that CYP2C8 was responsible for the formation of M1. Docking simulation indicated that, in the formation of M1 and M2, there would be hydrogen bonding and/or electrostatic interactions between the pyrimidine and sulfonamide moieties of DS-1971a and amino acid residues Ser100, Ile102, Ile106, Thr107, and Asn217 in CYP2C8, and that the cyclohexane ring of DS-1971a would be located near the heme iron of CYP2C8. These results clearly indicate that M1 is the predominant metabolite in humans and a human disproportionate metabolite due to species-specific differences in metabolism. SIGNIFICANCE STATEMENT: This report is the first to show a human disproportionate metabolite generated by CYP2C8-mediated primary metabolism. We clearly demonstrate that DS-1971a, a mixed aldehyde oxidase and cytochrome P450 substrate, was predominantly metabolized by CYP2C8 to form M1, a human disproportionate metabolite. Species differences in the formation of M1 highlight the regio- and stereoselective metabolism by CYP2C8, and the proposed interaction between DS-1971a and CYP2C8 provides new knowledge of CYP2C8-mediated metabolism of cyclohexane-containing substrates.

INVESTIGATION OF THE POSSIBILITY OF USING THE METHOD OF DIFFERENTIAL SPECTROPHOTOMETRY FOR THE ANALYSIS OF OVERLAPPING ABSORPTION BANDS OF TRITERPENE SAPONINS CHROMOPHORES AND THEIR QUANTITATIVE DETERMINATION IN AQUEOUS SOLUTIONS

A detailed analysis of the absorption spectra of mono- and bidesmoside triterpene glycosides was performed. It is suggested that the maximum in the region of 198–208 nm is attributed to the absorption of the double bond in the cyclohexene ring of the aglycone. The second less seen maximum at a wavelength of 280 nm is observed in the spectrum of saponin Quillaja Saponaria and is almost completely absent in the spectrum of saponin Mukorossi Sapindus. Identification of this maximum is extremely difficult, since its presence can be due to both the aldehyde group in the aglycone and the hydroxyl and carboxyl groups in the carbohydrate molecules.
 Using the method of differential spectrophotometry, a method for decomposing the UV spectrum of saponins into its constituent components is proposed and justified. A spectral analysis was performed, including the assignment of the absorption bands to the functional groups of the studied compounds. The possibility of estimating changes in the spectral properties of glycoside solutions with changes in the acidity of the medium is considered. The possibility of a bathochromic shift of the maximum absorption of the aglyconic part of saponin depending on the microenvironment (the structure of the carbohydrate part) and changes in the pH of the solution is established. It is shown that the bands at 274, 280.5 nm correspond to n-π* transitions of carbonyl and carboxyl groups and are determined only in the regions of high concentrations in Quillaja Saponaria saponin solutions. Based on the results obtained, calibration models for the quantitative determination of saponins in solutions are proposed. The regression analysis of the calibration equations is carried out, the main statistical indicators are calculated.