Expanding the scope of prenylated 1,2,3-triazoles as new antiparasitic drug candidates

We have previously shown that prenyl and aliphatic triazoles are interesting motifs to prepare new chemical entities for antiparasitic and antituberculosis drug development. In this opportunity a new series of prenyl-1,2,3-triazoles were prepared from isoprenyl azides and different alkynes looking for new antimalarial drug candidates. The compounds were prepared by copper(I) catalyzed dipolar cycloaddition of the isoprenyl azide equilibrium mixture providing exclusively 1,4-disubstituted 1,2,3-triazols in a regiospecific fashion. The complete collection of 64 compounds was tested on chloroquine -sensitive, Sierra Leone (D6), and the chloroquine-resistant, Indochina (W2), strains of Plasmodium falciparum and those compounds which were not previously reported were also tested against Leishmania donovani , the causative agent for visceral leishmaniasis. Thirteen analogs displayed antimalarial activity with IC50 below 10 uM, while the antileishmanial activity was less potent than the previously reported analogs. The cytotoxicity assay against Vero cells revealed that none of the compounds was cytotoxic up to concentrations of 4.75 ug/mL. Compounds 1o and 1r were identified as the most promising antimalarial drug leads with IC50 below 3.0 uM for both CQ-sensitive and resistant P. falciparum strains. Finally, a chemoinformatic in silico analysis was performed to evaluate physicochemical parameters, cytotoxicity risk and drug score. The validation of a bifunctional farnesyl/geranylgeranyl diphosphate synthase PfFPPS/GGPPS as the potential target of the antimalarial activity of selected analogs should be further investigated.

Formazans: a Structural and Spectroscopic Study of 3-Substituted-1,5-Diphenylformazans

<p>A series of thirteen isomeric 1,5-diphenylformazans have been structurally characterised both in the solid state and in solution by the combined techniques of x-ray crystallography, nuclear magnetic resonance, Raman, mass and absorption spectroscopies. 1,5-Diphenylformazan is known to exist in the anti, s-trans configuration in the solid state and this is shown to be the solution dominant species. In aprotic solvents an equilibrium involving the anti, s-trans and syn, s-cis configurations is evidenced. 3-Methyl-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. C14H14N4 belongs to the monoclinic space group P2/c, a = 8.133(1), b = 19.085(4), c = 9.364(2) A, beta = 105.93 degrees,U = 1397.6(5) A3, Z = 4. The anti, s-trans configuration of the solid state is also preferred in solution where it is in equilibrium with the syn, s-cis configuration. 3-Ethyl-1,5-diphenylformazan exists in two isomers in the solid state, both of which have been characterised by an x-ray crystal analysis. The red isomer of 3-ethyl-1,5-diphenylformazan belongs to the orthorhombic space group P2l2l2l and adopts the syn, s-trans configuration in the solid state. The orange, light stable isomer of 3-ethyl-1,5-diphenylformazan belongs to the monoclinic space group P2l/c and adopts the anti, s-trans configuration in the solid state. The rate of return of the photo-activated orange isomer to the dark-stable red isomer follows first order kinetics dependent upon the total concentration of the formazan and the water content of the solvent. 3-Tertiary-butyl-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. C17H20N4, belongs to the monoclinic space group P2/c, a = 11.235(3), b = 20.117(5), c = 14.176(3) A, beta = 92.14(2) degrees, U = 3202(1) A3, Z = 8. The syn, s-cis configuration of the solid state is maintained in solution. 1,3,5-Triphenylformazan is shown to exist in two red forms in the solid state. The syn, s-cis and syn, s-trans isomers are both present in the crystalline sample. These isomers are also evident in solution with the syn, s-trans configuration becoming more dominant in aprotic solvents. 1,5-Diphenylformazan reacts with bromine in solution in a single reaction to give di(3-bromo-1,5-diphenyltetrazolium)-decabromide and 3-bromo-1,5-di-para-phenylformazan, both of which have been characterised by an x-ray crystal analysis. C13H10.6N4Br5.3 belongs to the triclinic space group Pl, a = 8.572(1), b = 9.711(1), c = 14.166(3) A, alpha = 75.18(1), beta = 89.84(1), gamma = 70.42(1) degrees, Z = 2. Stacks of anti-parallel pairs of 3-bromo-1,5-diphenyltetrazolium cations are interleaved by pairs of Br102- anions. The polybromide represents a new type of polyhalogen network for bromine, Br102-, the Raman spectrum of which has been recorded for the first time. C13H9N4Br3 belong to the orthorhombic space group Pnma, a = 7.343(2), b = 32.793(12), c = 5.912(1) A, Z = 4. The formazan adopts the anti, s-trans configuration in the solid state. 3-Chloro-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. Preliminary results indicate that the formazan adopts the anti, s-trans configuration in the solid state. 3-Mercapto-1,5-diphenylformazan is shown to exist in the anti, s-trans configuration in CDCl3, solution. 3-Methylthio-1,5-diphenylformazan is shown to exist in an equilibrium mixture of syn, s-trans and anti, s-trans configurations in solution. The ratio of the two isomers is approximately equal. 3-Ethylthio-1,5-diphenylformazan exists in two isomers in the solid state, one of which has been characterised by an x-ray crystal analysis. Preliminary results indicate that the orange isomer of 3-ethylthio-1,5-diphenylformazan. C15H16N4S belongs to the monoclinic space group P2l/a, a = 11.027(6). b = 8.627(7), c = 15.487(8) A, b = 93.70(5) degrees, U = 1470 A3, Z = 4, and exists in the anti, s-trans configuration on the solid state. The orange and red isomers are both present in an equilibrium mixture in solution. The red isomer is shown to exist in the syn, s-trans configuration in the solid. 3-isopropylthio-1,5-diphenylformazan is shown to exist in an equilibrium mixture of anti, s-trans and syn, s-trans configurations in solution. 1-Methyl-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. C14H14N4 belongs to the monoclinic space group 12/1, a = 28.402(7), b = 5.640(1), c = 15.688(4) A, beta = 97.34 degrees, U = 2493(1) A3, Z = 8. The formazan adopts the anti, s-trans configuration in the solid state. The formazan retains its configurational integrity in both protic and aprotic solutions. The excitation profile of the Raman active phonons based upon coupled vibrations of the formazan backbone indicate a maximum corresponding to the absorption spectra in both the solid state and in solution. Preliminary results of a kinetic investigation of some primary metal dithizonates indicate that the thermal-path return is strictly first order. The mechanism would appear to be essentially similar to that operating in 3-ethyl-1,5-diphenylformazan. The mass spectra of the series of formazan follow similar splitting schemes irrespective of the solid-state configuration.</p>

Formazans: a Structural and Spectroscopic Study of 3-Substituted-1,5-Diphenylformazans

<p>A series of thirteen isomeric 1,5-diphenylformazans have been structurally characterised both in the solid state and in solution by the combined techniques of x-ray crystallography, nuclear magnetic resonance, Raman, mass and absorption spectroscopies. 1,5-Diphenylformazan is known to exist in the anti, s-trans configuration in the solid state and this is shown to be the solution dominant species. In aprotic solvents an equilibrium involving the anti, s-trans and syn, s-cis configurations is evidenced. 3-Methyl-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. C14H14N4 belongs to the monoclinic space group P2/c, a = 8.133(1), b = 19.085(4), c = 9.364(2) A, beta = 105.93 degrees,U = 1397.6(5) A3, Z = 4. The anti, s-trans configuration of the solid state is also preferred in solution where it is in equilibrium with the syn, s-cis configuration. 3-Ethyl-1,5-diphenylformazan exists in two isomers in the solid state, both of which have been characterised by an x-ray crystal analysis. The red isomer of 3-ethyl-1,5-diphenylformazan belongs to the orthorhombic space group P2l2l2l and adopts the syn, s-trans configuration in the solid state. The orange, light stable isomer of 3-ethyl-1,5-diphenylformazan belongs to the monoclinic space group P2l/c and adopts the anti, s-trans configuration in the solid state. The rate of return of the photo-activated orange isomer to the dark-stable red isomer follows first order kinetics dependent upon the total concentration of the formazan and the water content of the solvent. 3-Tertiary-butyl-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. C17H20N4, belongs to the monoclinic space group P2/c, a = 11.235(3), b = 20.117(5), c = 14.176(3) A, beta = 92.14(2) degrees, U = 3202(1) A3, Z = 8. The syn, s-cis configuration of the solid state is maintained in solution. 1,3,5-Triphenylformazan is shown to exist in two red forms in the solid state. The syn, s-cis and syn, s-trans isomers are both present in the crystalline sample. These isomers are also evident in solution with the syn, s-trans configuration becoming more dominant in aprotic solvents. 1,5-Diphenylformazan reacts with bromine in solution in a single reaction to give di(3-bromo-1,5-diphenyltetrazolium)-decabromide and 3-bromo-1,5-di-para-phenylformazan, both of which have been characterised by an x-ray crystal analysis. C13H10.6N4Br5.3 belongs to the triclinic space group Pl, a = 8.572(1), b = 9.711(1), c = 14.166(3) A, alpha = 75.18(1), beta = 89.84(1), gamma = 70.42(1) degrees, Z = 2. Stacks of anti-parallel pairs of 3-bromo-1,5-diphenyltetrazolium cations are interleaved by pairs of Br102- anions. The polybromide represents a new type of polyhalogen network for bromine, Br102-, the Raman spectrum of which has been recorded for the first time. C13H9N4Br3 belong to the orthorhombic space group Pnma, a = 7.343(2), b = 32.793(12), c = 5.912(1) A, Z = 4. The formazan adopts the anti, s-trans configuration in the solid state. 3-Chloro-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. Preliminary results indicate that the formazan adopts the anti, s-trans configuration in the solid state. 3-Mercapto-1,5-diphenylformazan is shown to exist in the anti, s-trans configuration in CDCl3, solution. 3-Methylthio-1,5-diphenylformazan is shown to exist in an equilibrium mixture of syn, s-trans and anti, s-trans configurations in solution. The ratio of the two isomers is approximately equal. 3-Ethylthio-1,5-diphenylformazan exists in two isomers in the solid state, one of which has been characterised by an x-ray crystal analysis. Preliminary results indicate that the orange isomer of 3-ethylthio-1,5-diphenylformazan. C15H16N4S belongs to the monoclinic space group P2l/a, a = 11.027(6). b = 8.627(7), c = 15.487(8) A, b = 93.70(5) degrees, U = 1470 A3, Z = 4, and exists in the anti, s-trans configuration on the solid state. The orange and red isomers are both present in an equilibrium mixture in solution. The red isomer is shown to exist in the syn, s-trans configuration in the solid. 3-isopropylthio-1,5-diphenylformazan is shown to exist in an equilibrium mixture of anti, s-trans and syn, s-trans configurations in solution. 1-Methyl-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. C14H14N4 belongs to the monoclinic space group 12/1, a = 28.402(7), b = 5.640(1), c = 15.688(4) A, beta = 97.34 degrees, U = 2493(1) A3, Z = 8. The formazan adopts the anti, s-trans configuration in the solid state. The formazan retains its configurational integrity in both protic and aprotic solutions. The excitation profile of the Raman active phonons based upon coupled vibrations of the formazan backbone indicate a maximum corresponding to the absorption spectra in both the solid state and in solution. Preliminary results of a kinetic investigation of some primary metal dithizonates indicate that the thermal-path return is strictly first order. The mechanism would appear to be essentially similar to that operating in 3-ethyl-1,5-diphenylformazan. The mass spectra of the series of formazan follow similar splitting schemes irrespective of the solid-state configuration.</p>

Coproduction of 5-Aminovalerate and δ-Valerolactam for the Synthesis of Nylon 5 From L-Lysine in Escherichia coli

The compounds 5-aminovalerate and δ-valerolactam are important building blocks that can be used to synthesize bioplastics. The production of 5-aminovalerate and δ-valerolactam in microorganisms provides an ideal source that reduces the cost. To achieve efficient biobased coproduction of 5-aminovalerate and δ-valerolactam in Escherichia coli, a single biotransformation step from L-lysine was constructed. First, an equilibrium mixture was formed by L-lysine α-oxidase RaiP from Scomber japonicus. In addition, by adjusting the pH and H2O2 concentration, the titers of 5-aminovalerate and δ-valerolactam reached 10.24 and 1.82 g/L from 40 g/L L-lysine HCl at pH 5.0 and 10 mM H2O2, respectively. With the optimized pH value, the δ-valerolactam titer was improved to 6.88 g/L at pH 9.0 with a molar yield of 0.35 mol/mol lysine. The ratio of 5AVA and δ-valerolactam was obviously affected by pH value. The ratio of 5AVA and δ-valerolactam could be obtained in the range of 5.63:1–0.58:1 at pH 5.0–9.0 from the equilibrium mixture. As a result, the simultaneous synthesis of 5-aminovalerate and δ-valerolactam from L-lysine in Escherichia coli is highly promising. To our knowledge, this result constitutes the highest δ-valerolactam titer reported by biological methods. In summary, a commercially implied bioprocess developed for the coproduction of 5-aminovalerate and δ-valerolactam using engineered Escherichia coli.

PROTOLYTIC EQUILIBRIUM OF TETRA- AND PENTANITROFLUORESCEINS IN A BINARY SOLVENT ACETONITRILE – DIMETHYL SULFOXIDE (MASS RATIO 96 : 4)

In this paper, the acid-base and tautomeric equilibria of four nitrofluorescein dyes, 2,4,5,7-tetranitrofluorescein, 2,4,5,7,4’-pentanitrofluorescein, 2,4,5,7,5’-pentanitrofluorescein, and 2,4,5,7-tetranitrofluorescein methyl ester, were studied. As reaction media, a binary solvent acetonitrile – dimethyl sulfoxide (96 : 4 by mass) was used. The acidity scale in this solvent was established previously. The indices of the dissociation constants of the dyes were determined using the spectrophotometric method. Interpreting the values ​​requires an understanding of the state of tautomeric equilibria. The behavior of these compounds differs significantly from that of other fluorescein dyes, e.g., halogen derivatives. In the case of the first three compounds, i.e., for dyes with a free carboxylic group, the lactonic structure is predominant not only for the neutral form, but even for the double-charged anion. The single-charged anionic form exists as an equilibrium mixture of a colored (and fluorescent) tautomer and an almost colorless lactone. The fourth compound with esterified carboxylic group exhibits extreme stability in its anionic form. Evaluation of the tautomerization constants made it possible to calculate the microscopic equilibrium constants of the stepwise dissociation of dye lactones, k1L and k2L. The consideration of the difference (pk2L – pk1L) allowed estimating the effective relative permittivity of the space between the ionizing groups basing on the Bjerrum – Kirkwood – Westheimer equation. Tautomerism of anions was discussed from the point of view of stabilization of symmetric structures.

α-Ketophosphonates in the Synthesis of α-iminophosphonates

The potentialities of condensation of α-ketophosphonates with primary amines for direct synthesis of α-iminophosphonates have been revealed. Diesters of α-ketophosphonic acids react with the primary amines by two competitive pathways: with a formation of α-iminophosphonates or a C-P bond cleavage resulting in a hydrogen phosphonate and an acylated amine. In many cases, the latter undesirable pathway is dominant, especially for more nucleophilic alkyl amines. Using metallic salts of α-ketophosphonates avoids the C-P bond cleavage, allowing direct preparation of α-phosphorylated imines by the reaction with primary amines. This strategy provides an atom economy single-stage synthesis of iminophosphonates – precursors of bio relevant phosphorus analogs of α-amino acids. Methyl sodium iminophosphonates, bearing aryl or heteryl substituents at the imino carbon atom exist in solutions at room temperature as an equilibrium mixture of Z- and E-isomers. A configuration of the C=N bond can be controlled by the solvent: changing the aprotic dipolar solvent DMSO-d6 by water or alcohols leads to the change from a predominant Z-isomer to almost an exclusive E-form. In contrast, diesters of the respective iminophosphonates exist in non-protic solvents predominantly in Econfiguration. The solvent effect on E-Z stereochemistry is demonstrated by DFT calculations.

High-Resolution Simulations for Aerogel Using Two-Phase Flow Equations and Godunov Methods

Aerogel is studied numerically using a one-dimensional two-phase flow equations system. A hyperbolic and conservative two-phase flow model is applied to a mixture of porous media containing nanofluids. The application of non-equilibrium mixture behavior between phases is adopted and promoted in this current investigation. By establishing mixture conservation balance laws, finite volume techniques using Godunov methods of centered type are extended to aerogel simulations. Numerical results are compared with other methods providing a remarkable agreement. The computed results demonstrate the key capabilities of this existing mixture model in the resolution of discontinuities in aerogel problems and more reliable than applying a sophisticated single-phase flows with complex property models.

Total Synthesis of the Antitumor Depsipeptide FE399 and its S-Benzyl Derivative: A Macrolactamization Approach

<div>An efficient and practical method for the synthesis of (9R,14R,17R)-FE399, a novel antitumor bicyclic depsipeptide, was developed. A 2-methyl-6-nitrobenzoic anhydride (MNBA)-mediated dehydration condensation reaction was effectively employed for the formation of the 16-membered macrocyclic depsipeptide moiety of FE399. FE399 was found to exist as an inseparable equilibrium mixture of conformational isomers; the mixture was quantitatively transformed into the corresponding S-benzyl product and isolated as a single isomer. Thus, we could confirm that the molecular structure of FE399 obtained by this method is identical to that of the natural product.</div>

Total Synthesis of the Antitumor Depsipeptide FE399 and its S-Benzyl Derivative: A Macrolactamization Approach

<div>An efficient and practical method for the synthesis of (9R,14R,17R)-FE399, a novel antitumor bicyclic depsipeptide, was developed. A 2-methyl-6-nitrobenzoic anhydride (MNBA)-mediated dehydration condensation reaction was effectively employed for the formation of the 16-membered macrocyclic depsipeptide moiety of FE399. FE399 was found to exist as an inseparable equilibrium mixture of conformational isomers; the mixture was quantitatively transformed into the corresponding S-benzyl product and isolated as a single isomer. Thus, we could confirm that the molecular structure of FE399 obtained by this method is identical to that of the natural product.</div>

Total Synthesis of the Antitumor Depsipeptide FE399 and its S-Benzyl Derivative: A Macrolactamization Approach

<div>An efficient and practical method for the synthesis of (9R,14R,17R)-FE399, a novel antitumor bicyclic depsipeptide, was developed. A 2-methyl-6-nitrobenzoic anhydride (MNBA)-mediated dehydration condensation reaction was effectively employed for the formation of the 16-membered macrocyclic depsipeptide moiety of FE399. FE399 was found to exist as an inseparable equilibrium mixture of conformational isomers; the mixture was quantitatively transformed into the corresponding S-benzyl product and isolated as a single isomer. Thus, we could confirm that the molecular structure of FE399 obtained by this method is identical to that of the natural product.</div>